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Disruptive Innovation by Genetic Modifi cation Technology as a Market Driver to Target Unmet Vaccine Needs
‘Infl uenza in the Limelight’
B. Ramezanpour
Members of the Thesis Committee:
Prof.dr. J. Broerse, Vrije Universiteit AmsterdamProf.dr. R. Kort, Vrije Universiteit AmsterdamProf.dr. G. Rimmelzwaan, Erasmus University Medical Center RotterdamProf.dr. L. Hellebrekers, Wageningen University & Research Center
Printing of this dissertation was supported by international sponsors mentioned in the acknowledg-ments.
Cover design: Nourmedia, Bahareh Ramezanpour, Alex de RuiterCover image: Nourmedia | www.nourmedia.nlChapter images: Van Orsouw Design | www.vanorsouwdesign.nl
Printed by: Nourmedia | media- & communicatiebureauPublished by: Bahareh Ramezanpour | www.baharramezanpour.com
ISBN: 978-90-9029739-2
© Bahareh Ramezanpour, The Netherlands 2016
All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without permission in writing from the author.
VRIJE UNIVERSITEIT
Disruptive Innovation by Genetic Modifi cation Technology as a Market Driver to Target Unmet
Vaccine Needs
‘Infl uenza in the Limelight’
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad Doctor aande Vrije Universiteit Amsterdam,op gezag van de rector magnifi cus
prof.dr. V. Subramaniam,in het openbaar te verdedigen
ten overstaan van de promotiecommissievan de Faculteit der Aard- en Levenswetenschappen
op donderdag 9 juni 2016 om 9.45 uurin de aula van de universiteit,
De Boelelaan 1105
door
Bahareh Ramezanpour
geboren te Karadj, Iran
promotoren: prof.dr. H.J.H.M. Claassenprof.dr. A.D.M.E. Osterhaus
Weenen TC, Ramezanpour B, Pronker ES, Commandeur H, Claassen E. Food-pharma Convergence in Medical Nutrition- Best of Both Worlds? PLoS One. 2013;8(12):e82609. DOI: 10.1371/journal.pone.0082609.
Ramezanpour B, Pronker ES, Kreijtz JH, Osterhaus AD, Claassen E. Market Implementation of the MVA Platform for Pre-pandemic and Pandemic Influenza Vaccines: A Quantitative Key Opinion Leader Analysis. Vaccine. 2015;33(35):4349-58. DOI: 10.1016/j.vaccine.2015.04.086.
Ramezanpour B, Riemens T, Van de Burgwal L, Claassen E. An Interdisciplinary Analysis of Genetically Modified Vaccines: From Clinical Trials to Market. International Journal of Clinical Trials. 2015;2(4):64-74. DOI: 10.18203/2349-3259.ijct20151235.
Ramezanpour B, Kamphuis PGA, Claassen E. A Key Opinion Leaders Analysis of the Critical Success Factors for the Market Potential of Genetically Modified Vaccines. International Journal of Innovative Research in Sciende, Engineering and Technology. 2016;5(4). DOI: 10.15680/IJIRSET.2016.0504101.
Ramezanpour B, Haan I, Claassen E. Vector-based Genetically Modified Vaccines: Exploiting Jenner's Legacy. Vaccine. 2016. (In press)
Ramezanpour B, Osterhaus ADME, Claassen E. Cross-sectoral Perspectives of Market Implementation of the MVA Platform for Influenza Vaccines: Regulatory, Industry and Academia. Journal of Vaccines & Vaccination. 2016;7(3). DOI: 4172/2157-7560.1000318.
Ramezanpour B, de Foucauld J, Kortekaas J. Emergency Deployment of Veterinary Vaccines in Europe. Vaccine. 2016. (In press)
Anne M. G. Neevel, Linda H. M van de Burgwal, Bahar Ramezanpour, Eric Claassen (2016). Towards a One Health Approach for Rabies Disease: A Quantitative Key Opinion Leader Analysis. One Health. 2016. (In progress)
Kreijtz JHCM, Ramezanpour B, Fernald KDS, van Burgwal LHM, editors. GM Vaccines: From Bench to Bedside COGEM; research report CGM/2014-082014.
PublicationsC
hapt
ers
Acknowledgments
The author would like to acknowledge the support by ViroClinics Biosciences BV, Ohkura Phar-maceutical Co., Trask Britt, Sovalacc BV, ViroNovative BV, Yakult Netherlands BV, and Murdin Biotechnology Consulting.
The author would like also like to acknowledge Prof.dr. Justin Jansen and Dr. Joost Kreijtz for their participation in the ‘grote commissie’.
Table of contents
Chapter 1: Introduction 13
1.1. General Benefi ts of Immunizations and Vaccines 151.2. Need for New Vaccines and Novel Technologies 161.3. Opportunities and Limitations; Novel Vaccines and Technologies 181.4. Why GM Vector-based Vaccines? 201.5. Why Use modifi ed vaccinia virus Ankara (MVA) as a Vector? 211.6. Why Infl uenza? 221.7. Theoretical Background 24
1.8. Outline of Research and Dissertation 28
Chapter 2: A Key Opinion Leaders Analysis of the Critical Success Factors for the Market Potential of Genetically Modifi ed Vaccines 35
2.1. Introduction 372.2. Methodology 39
2.2.1. Literature 392.2.2. Interviews 392.2.3. Ranking Survey 40
2.2.3.1. Survey Analysis 412.3. Results 42
2.3.1. Interviews 422.3.2. Survey 43
2.3.2.1. Technical Potential 442.3.2.2. Commercial Potential 452.3.2.3. Rules & Regulations 452.3.2.4. Societal Potential 45
2.3.3. Target Market 47
2.4. Discussion 48Appendix 52
Chapter 3: An Interdisciplinary Analysis of Genetically Modifi ed Vaccines: From Clinical Trials to Market 55
3.1. Introduction 573.2. Methodology 58
3.2.1. Literature Search 583.2.2. Terminology 593.2.3. Patent Analysis 593.2.4. Clinical Trials Analysis 613.2.5. Registered Vaccines 63
3.3. Results 633.3.1. Patent Literature 633.3.2. Clinical Trials 643.3.3. Registered Vaccines and Patents 66
3.4. Discussion and Conclusions 70Appendix 73
Chapter 4: Vector-based Genetically Modifi ed Vaccines: Exploiting Jenner’s Legacy 75
4.1. Introduction 774.2. Methodology 78
4.2.1. Literature Research 784.2.2. Search for Patents 804.2.3. Search for Clinical Trials 814.2.4. Search for Registered GM and non-GM Vaccines 824.2.5. Data Convergence 83
4.2.5.1. Patents and Clinical Trials 834.2.5.2. Evolution of GM Vaccines: Convergence of all three Databases 83
4.3. Results 874.3.1. Analyzing the Market 87
4.3.1.1. Data Convergence 904.4. Discussion 93
Chapter 5: Cross-sectoral Perspectives of Market Implementation of the MVA Platform for Infl uenza Vaccines: Regulatory, Industry and Academia 97
5.1. Introduction 995.2. Methodology 101
5.2.1. Descriptive Study Design 1025.2.1.1. Root Cause Analysis (RCA) 1025.2.1.2. Interviews 1025.2.1.3. Integrated Assessment (IA) Approach 1025.2.1.4. Perspective Method 1035.2.1.5. Rank-frequency and Importance-frequency Method 103
5.3. Results 1035.3.1. Dimensional Perspective Construction; Three Perspectives, their Similarities and Differences 1045.3.2. RCA Tree 105
5.3.2.1. Production and Speed 1055.3.2.2. Technical 1065.3.2.3. Immunogenicity 1065.3.2.4. Competitors 1065.3.2.5. Pandemic/Mock-up 1065.3.2.6. Regulatory 106
5.3.3. Importance Frequency 109
5.4. Discussion and Conclusions 110
Chapter 6: Market Implementation of the MVA Platform for Pre-pandemic and Pandemic Infl uenza Vaccines: A Quantitative Key Opinion Leader Analysis 113
6.1. Introduction 1156.2. Methodology 117
6.2.1. Literature Reviews & Interviews 1186.2.1.1. Interview Participants 1186.2.1.2. Explanatory Interviews 1186.2.1.3. Interview Questions 118
6.2.2. SWOT Analysis 1196.2.3. AHP Analysis 1196.2.4. SWOT-AHP Analysis Model 121
6.3. Results 1226.3.1. Descriptive Results, Strengths 1246.3.2. Descriptive Results, Weaknesses 1246.3.3. Descriptive Results, Opportunities 1246.3.4. Descriptive Results, Threats 125
6.4. Discussion 131Appendix 134
Chapter 7: Emergency Deployment of Genetically Engineered Veterinary Vaccines in Europe 137
7.1. Introduction 1397.2. Current European Regulations for Genetically Engineered Vaccines 1417.3. Opportunities for Fast-track Deployment of Vaccines within the Boundaries of Current Legislation 1437.4. Longer-term Opportunities; New Ways to Fast-track Deployment of Live Genetically Engineered Vaccine in Europe 1457.5. Recommendations to Amend Directive 2001/18/EC and 2001/82/EC 1457.6. Conclusions 146
Chapter 8: Conclusions and Discussion 149
8.1. Introduction 1508.2. Summarizing Conclusions and Contributions 1518.3. Urgency of Addressing Unmet Vaccine Needs 1588.4. Prerequisites Successful Market 1598.5. MVA Vectored Vaccines; A Next Generation Technology 1618.6. Intrinsic/Extrinsic Assets Novel Technologies 1638.7. Vaccine Landscape 1648.8. Suggestions for Future Vaccine Research 167
Summary 169Samenvatting 171Abbreviations and Glossary of Terminologies 173About the Author 174Dankwoord 175References 179
Chapter 1Introduction
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1. Introduction
This dissertation evaluates the market potential of next generation genetically modifi ed (GM) vac-cines, as a market driver for disruptive innovation to target unmet vaccine needs, with a special focus on infl uenza vaccines. Here we identify critical success factors (CSFs) that play an essential role in the successful application of GM vaccines. This study indicates that the most prominent success fac-tor is the potential of GM vaccines to address previously untargeted -other than infectious- diseases. Hence, as many diseases are about to get targeted by emerging GM vaccines, elucidating the current and future prospects of the global GM vaccine market is a prerequisite.
Due to the complex nature of the topic, an interdisciplinary approach is applied to provide an over-view of the global GM vaccine market, revealing trends in patent applications, vaccine approvals, and next generation GM vaccines. Furthermore, calculated phase transition success rate in GM vaccine value chain enabled us to predict next generation GM vaccines with relatively high chance of marketing approval. Increasing volume of the global GM vaccine market alludes to a compelling need of a clear delineation of GM vaccine development and production technologies providing more insights in its current state of global research and development.
Vector-based technology as one of the most prominent, advanced, and applied technologies in the fi eld of GM vaccine development comprises a signifi cant part of all GM vaccine candidates in the pipeline. Further focus of the studies in this dissertation primarily lies on the potential of currently applied and newly generated vectors in the fi eld of GM vaccine development. Moreover, different sources of information (literature, patents, and clinical trials databases) identify modifi ed vaccinia virus Ankara (MVA) as the most prevalent vector with a signifi cant rapidly increased usage in clin-ical trials, which emphasizes the prominent role that MVA plays within the emerging GM vaccine market.
Key opinion leaders (KOLs) in the vaccine fi eld from different disciplines (regulatory, industry, academia) were approached in order to uncover and expose high-priority market implementation challenges of the MVA platform. Due to the complex nature of the topic, a unique overview com-piled from this multidisciplinary perspective made it possible to identify foremost underlying causes that contribute to the challenges novel vaccines have to face for successful market implementation. A more in-depth approach allowed quantifying strengths, weaknesses, opportunities, and threats that come with such platform. Moreover, the studies presented evaluate different views and opinions, identify inherent risks and barriers, and anticipate future challenges with the purpose of preparing for future threats and preventing poor decision-making.
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In essence, the data suggest that vector-based vaccines may offer a cost-effective alternative for pro-duction of safe and effective vaccines against diseases for which no or less effective vaccines exist today, fulfi lling a major unmet medical need.
1.1. General Benefi ts of Immunizations and Vaccines
The unprecedented success of immunization in providing protection, control and prevention of dis-ease [1] thus improving and maintaining global health is undeniable [1, 2]. Vaccination programs have resulted in over 99% decrease in polio incidence [3] and the global eradication of two devastat-ing infectious diseases of humans and animals: smallpox and rinderpest, respectively. In addition to the eradication of these viral diseases and a signifi cant reduction of many other infectious diseases, an annual prevention of an estimated 6 million deaths worldwide continues to be realized [4, 5].
These successes exemplify the outstanding accomplishments that vaccination has made so far [6, 7]. This achievement has not been equaled by any other medical or veterinary intervention [6-8]. Although immunization has proven to be the most cost-effective medical tool to prevent, fi ght, and control infectious diseases, its full potential has not yet been reached and immunization can make an even greater contribution to public health worldwide [1, 9]. Table 1.1. demonstrates the benefi ts of vaccination classifi ed in three broad categories based on their relation to health gains, productiv-ity gains, and community externalities (indirect benefi ts such as herd immunity). For this purpose, “narrow perspective” is defi ned as traditional economic evaluations, meaning that they are generally short-term and restricted to the individual and/or care givers. A narrow perspective can result into an underestimation of vaccination benefi ts and to an overestimation of its costs, which might lead to poor decision-making.
A more comprehensive and realistic view of immunization benefi ts should comprise a broad per-spective involving both health and non-health benefi ts. This calls for a “broader perspective” char-acteristically effecting evaluation processes involving broad externalities and long-term effects [10-17]. In economics an external effect, so called an externality, is defi ned as a consequence of an activity that is experienced by an unrelated third party [18]. An externality can be positive or negative. On a community level, vaccination is associated with positive externalities due to its effect on the pathogen-host ecology [19, 20]. For instance, vaccination can reduce disease incidence in un-vaccinated members of a community since vaccinated individuals will no longer transmit a disease, reducing disease transmission in a population. This phenomenon is also known as herd immunity and is considered a positive community related ecological externality. An example of a negative eco-logical externality is changes in pathogen ecology as a consequence of selective pressure (serotype
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replacement or antibiotic resistance) [20].
According to CDC Atlanta, health equity is achieved when every person has the opportunity to “at-tain his or her full health potential” and no one is “disadvantaged from achieving this potential be-cause of social position or other socially determined circumstances”. Health inequities are refl ected in differences in length or quality of life; severity or rates of disease, disability, death, and access to treatment [21]. Health equity, affordability, and fi nancial sustainability are important consideration and should be incorporated into cost-effectiveness analyses that usually precede vaccine introduc-tion [10]. Therefore, public health interventions may reduce socioeconomic health inequity by pro-viding an effective strategy to achieve equal distribution of health in a population [22].
A broader perspective can lead to diffusion and lack of focus. Therefore, this broader perspective should be limited to a relatively small number of new vaccine candidates and novel technologies for optimal progression.
1.2. Need for New Vaccines and Novel Technologies
Currently a wide variety of vaccines is available, including live-attenuated, inactivated, subunit or split, toxoid, conjugate, DNA, and recombinant vectored vaccines [23]. While conventional vac-cines, like live-attenuated or inactivated wild-type vaccines, have successfully provided protection against various infectious diseases, they proved not applicable to most infectious diseases [24, 25].
Despite successes achieved by conventional vaccines, a broad repertoire of infectious diseases re-mains diffi cult to target [26-28]. Human immunodefi ciency virus (HIV), tuberculosis (TB), and ma-laria, the so-called “big three”, are considered major public health challenges creating a huge burden on global public health [29]. According to the World Health Organization (WHO) data, at the end of 2013, 1.5 million AIDS-related, 1.5 million TB-related, and 584 thousand malaria-related deaths were reported globally that year. These diseases are amongst the deadliest infectious diseases world-wide, reasons including but not being limited to lack of vaccine availability, anti-TB drug resistance, and malaria spreading to new areas [30]. In addition to these alarming facts, the annual occurrence of 218 million new infections by the big three emphasizes the necessity and urgency to develop novel generation vaccines to combat these so far untargeted or under-targeted diseases. This requires better insights in their pathogeneses and correlates of immune mediated protection and pathology, as well as development and use of novel technologies [31].
Interventions for most viral diseases still represent a signifi cant unmet medical need. Reasons in-
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Conventional vaccine production methods, which predominantly use viruses and bacteria or their products, produced with classical production methods, are labour intensive, expensive, and time consuming, while some of the desired immunogens cannot be produced in this way [34]. Further-
Table 1.1. Classified list of types of benefit categories of vaccination. Definitions of different categories are adapted from Bä rnighausen et al. and Deogaonkar et al. [10, 12].
Perspectives Benefit Categories DefinitionHeath gains Reduction in morbidity and mortality Health-care cost savings Savings of medical expenditure
Productivity gains related to care Reduction in lost productive time due to sickness or caring for a sick patient
Productivity gains related to short-term outcomes
Reduction in lost productive time due to sickness or death of effected individuals
Productivity gains related to long-term outcomes
Increased productivity because a better health improves cognition, educational attainment, and physical strengths
Productivity gains related to household behaviour
Benefits due to changes in household choices such as fertility and consumption choices
Ecological effects Health improvement in unvaccinated community members as a result of ecological effects such as herd immunity and reduced antibiotics usage
Health equity Increase in equal distribution of health outcomes
Financial sustainability Improved financial sustainability of health care programs as a result of synergies with vaccination programs and/or stimulation of private demand
Macroeconomic impact Changes in national and/or individual sectors of economy
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clude absence of safe and effective vaccines, lack of vaccine availability, accessibility, and afford-ability [32]. State-of-the-art technologies are being used to overcome at least some of these limita-tions with little or no signifi cant success [33]. Recent advances and novel approaches in the fi eld of vaccine development provide new opportunities for improving state-of-the-art technologies.
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more, highly virulent pathogens can only be produced under expensive special safety conditions. Vaccines based on attenuated agents may suffer from the tendency of the attenuated agent of re-verting to their pathogenic form and can usually only be used in immunocompetent individuals [35]. Moreover, ensuring an adequate and timely supply of vaccines remains challenging primarily associated with the limitations of current technologies [4, 6-9].
Continuously advancing developments in bioengineering including the development of cell and tissue culturing techniques, recombinant and GM technology, and nucleic acid sequencing, have all contributed to vaccine development and have provided many explored and yet unexplored possibili-ties in vaccine development against virtually all pathogens [36, 37]. The introduction of novel tech-nologies in the vaccine fi eld such as genetic modifi cation (GM) allows the production of tailor made GM vaccines and enables targeting new disease entities including cancer, autoimmunity, allergy, and addictions [29, 38]. Furthermore, GM technology may contribute to generating more sophisticated vaccines like nucleic acid based and vector-based but also to subunit vaccines, virus like particles, and virosomes [27, 39, 40].
1.3. Opportunities and Limitations; Novel Vaccines and Technologies
The need for novel technologies to overcome the challenges of traditional vaccine development and production are being repeatedly emphasized [41-46]. The advent of such novel technologies may also be expected to create various opportunities and improvements at different levels including medical, societal, business, and global public health. Hence, these technologies are not only desired for improvements in the medical fi eld i.e. to improve immunological or clinical outcomes, their con-tribution to societal outcomes are of great value as well [5, 47]. Health-care cost savings, extending life expectancy, improving quality of life, and equity enhancement exemplify their contributions to societal improvements [5]. Furthermore, development of novel vaccines targeting new indications and/or application fi elds not only will make a great contribution to global public health benefi ts, it simultaneously provides business opportunities [48, 49] for vaccine manufacturers to expand their vaccine repertoire and cover new markets in the vaccine fi eld. Benefi ts of investing in vaccines go beyond prevention and control of disease and public health and well-being. From the fi nancial per-spective, this could also protect people’s income and savings, and contribute to economic growth [17]. According to WHO facts, the global vaccine market tripled in value from 5 billion US dollar in 2000 to almost 24 billion in 2013 [50].
Vaccine technology has evolved signifi cantly over the last two decades leading to major changes in future of vaccine design, development, and production [51]. However, continuous pandemic threats
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such as sporadic infl uenza pandemics, Ebola in 2015 [52], and Zika in 2016 [53] emphasize the urgent need for faster development of effi cacious and safe vaccines, by reducing the response time to such emerging threats. Parallel use of different vaccine approaches, vaccine formulations and production platforms as well as development of alternative manufacturing platforms can contribute to rapid production of vaccine in a short period of time in case of a pandemic event.
While the fi rst vaccines were produced by harvesting tissues of infected animals as starting mate-rials, like the brains of rabies virus infected animals [54, 55], production of vaccines from infected embryonated eggs dates back to 1931, after Woodruff and Goodpasteure reported that fowlpox virus could be propagated in embryonated chicken eggs [56]. It was not until 1948 that cell culture was fi rst reported by Weller and Enders for mumps and infl uenza [57]. Although egg-based production suffers from several intrinsic disadvantages, the production of some human and veterinary vaccines is still based on this traditional production method with human infl uenza vaccines as a famous ex-ample [58, 59]. A signifi cant disadvantage is the limited possibility of scaling-up by limited embryo-nated chicken egg supplying mechanisms in the face of an increased surge in vaccine demand during a pandemic [10] as well as the virulence of pandemic infl uenza virus strains that may be lethal to embryonated chicken eggs [4].
The use of cell substrates for infl uenza vaccine production entails several advantages including rel-atively easy scale-up of the production process [60-64] and since many virus isolates can be grown in cell culture, there is no need to make high growth re-assortant viruses prior to production process [65]. Moreover, application of novel technologies such as gene synthesis and reverse genetics allow for rapid generation of GM vaccines from only sequence information [62, 66]. Other novel technologies that contribute to speed up vaccine production, in particular pandemic vac-cines, include synthetic vaccine technology, structure-based antigen design, production platforms based on insect and plant cells [67-71], novel cell-lines [72], and bacterial systems [73, 74]. More-over, the use of GM techniques has made the need for live viruses redundant [69] and also allows to prevent the occurrence of adaptive antigenic changes that viruses may undergo during differ-ent phases of development/production processes [75]. Furthermore, novel adjuvants allow for dose sparing, broadening antibody response specifi city, and help induce long lasting immune responses [76, 77].
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1.4. Why GM Vector-based Vaccines?
Since there are many major indications for which no or no effective vaccines are available such as HIV/AIDS, tuberculosis, and malaria, the exploitation of novel technologies in combination with a better understanding of correlates of immune mediated protection and pathogenesis may offer roads to safe and effective vaccines. An increasing number of novel development/production approaches may eventually allow us to fi ll the gap of this unmet medical need.
An interesting approach for vaccine development based on GM technology is the use of expression systems, so called “vectors”. They can either be used for the in vitro production of immunogens of pathogens that may be incorporated in vaccines, or as such be incorporated in vaccines to express genes encoding these immunogens in the vaccinated human or animal host in order to directly in-duce protective immune responses [78-80]. Vectors can either be fully replicative or cause abortive infection, still allowing the expression of the desired immunogens. Vectors applied for this type of vaccine delivery systems include viral, and bacterial vectors, although also nucleic acids may be used in different presentation forms [78, 81].
Several viral vector-based vaccine platforms exist, such as adeno-, pox-, parainfl uenza-, and al-pha-virus-based expression systems. Those and others allow the establishment of vaccines for het-erologous pathogens [32, 78, 82] and all of these have their inherent advantages and disadvantages.
A major advantage of vector-based GM technology, is that the immunogens of interest are de novo synthesized, not only allowing for the induction of antibody and T helper cell mediated immuni-ty, but also for the induction of cytotoxic T cell responses, mimicking a natural immune response against the immunogen. This balanced immune response opens pathways that were previously inac-cessible with traditional vaccine technology using ‘non-live’ immunogens. Especially the induction of CD8+ CTL responses may be of particular interest for vaccines against certain virus infections and cancers [83].
Furthermore, viral vector vaccines are among several vaccine approaches such as cell-derived whole or detergent split, recombinant protein, virus-like particle, and DNA/RNA vaccines [10, 11]. While all these technologies have inherent potential to improve vaccines by increasing production capabil-ity and providing shorter production time, many are limited by effi cacy and safety concerns. Recent research shows the promise of using viral vector vaccines with certain additional assets, including the ability to induce balanced humoral and cellular immune responses and feasibility for large-scale deployment in a short period of time without the safety concerns associated with the production of pathogenic viruses [4, 10, 12].
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1.5. Why Use modifi ed vaccinia virus Ankara (MVA) as a Vector?
According to the literature, poxviruses are among the most prominent vectors that have been widely evaluated for their use in GM vaccine development [27, 83-85]. In the recent decades recombinant poxviruses of mammals and birds have shown potential as platforms for the development of safe vaccines that induce protective immunity against various infectious and neoplastic conditions of humans and animals [86-88]. Examples of the most widely used poxviruses as vaccine candidates for human use include orthopoxviruses, MVA and New York attenuated vaccinia (NYVAC), and avipoxviruses, canarypox (ALVAC) and fowlpox 9 (FP9) [83, 85, 86, 89].
MVA is a highly attenuated strain of vaccinia virus, originating from chorioallantois membrane pro-duced vaccinia virus Ankara after more than 570 serial passages in primary chicken embryo fi bro-blasts (CEF). This serial passaging of MVA resulted in a loss of virulence and immune evasion genes as well as its ability to replicate in most mammalian cells [90, 91].
Despite these supportive data and the apparent potential of poxvirus-based platforms and their cur-rent use in animal vaccines, there is still no recombinant poxvirus based vaccine registered for use in humans [92]. Nevertheless, several incremental improvements, such as techniques allowing for better quantitative and qualitative target antigen expression characteristics, prime-boost regimens, as well as improved vector virus manufacturing and purifi cation technology, justify the expectation that poxvirus vector-based vaccine candidates for humans are approaching their fi nal stages of de-velopment [83, 86, 93].
Various vaccinia virus vectors are being used in different clinical trials against various diseases such as HIV [94-96], hepatitis [97], infl uenza [98], malaria [99, 100], tuberculosis [101], and can-cer [102]. Despite the availability of a series of attenuated poxviral vaccine vectors with a good safety profi le, MVA is among the most advanced, best-characterized, and widely used attenuated vaccine vectors currently in human clinical trials [86, 87, 103]. In comparison to other vaccinia virus strains, MVA vectors have proven to be relatively safe [104, 105]. Furthermore, the European Medicine Agency (EMA) has approved the non-recombinant vaccine against smallpox containing MVA, which implies safety of this backbone vector system as a vaccine platform [84].
Multiple advantages and disadvantages of MVA as viral vector platform for vaccines against, inter alia, infl uenza and other viral respiratory diseases are described in literature [106-110]. Unique properties of MVA include its biological safety profi le, relative easy production process for large-scale manufacturing, and potential to effi ciently express a plethora of foreign genes either alone or in combination enabling the use of MVA as a versatile and multivalent vaccine [84, 88, 111]. More-over, MVA has immunostimulatory capacities to induce protective immune responses against many
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infectious agents. In particular stimulating the innate immune system which in addition to its activa-tion of the adaptive immune system obviates the need of adjuvant usage [88]. Replication defi ciency of MVA has been confi rmed in various in vivo mammalian models including animals with severe immunodefi ciencies [84]. Furthermore, recombinant MVA viruses can be used under conditions of (relatively low) biosafety level 1 in most countries. These features provide advantages compared to replication competent poxvirus vectors and other viral vectors [84]. Pre-existing anti-vector im-munity may hamper the effectiveness of vectored vaccines. Nonetheless, it is noteworthy that MVA vectored vaccine candidates induce solid immunity in the presence of pre-existing specifi c antibod-ies and differ in this respect from other viral vectors, of which the effi cacy is usually impaired by the presence of such pre-existing antibodies [84, 87, 88, 112-116].
Some limitations of other vector platforms also apply to MVA viral vectored vaccine candidates. For example: each new recombinant MVA construct expressing a foreign gene of interest is considered a new biological entity and thus requires proper quality assessment. However, the large genome of poxviruses like MVA, allows for the simultaneous expression of more than one antigen, thus reducing the need for registration efforts. Furthermore it was shown that also the intrinsic potential to induce immunity against poxvirus infections in animals, could be an additional advantage. It was e.g. recently claimed that an MVA based candidate vaccine against MERS would also protect against camelpox [117]. Finally it should be realized that heterologous prime-boost vaccination strategies,as suggested by some researchers will also complicate the regulatory approval process [84].
1.6. Why Infl uenza?
Infl uenza viruses are among the major infectious disease threats to humans, causing worldwide an-nual epidemics and occasional pandemics. These viruses have the capacity to continuously evolve to evade the immune system and to emerge from the animal world [118, 119]. According to the WHO, seasonal infl uenza viruses continue to emerge and re-emerge with a global disease burden and annu-al attack rate estimated at 5%-10% in adults and 20%-30% in children, causing approximately 3 to 5 million cases of severe illness, and 250 to 500 thousand deaths annually [120].
Seasonal vaccines that are currently used as prophylactic vaccines against infl uenza require annual updates and have to be re-administered annually to induce an immune response towards the virus strains that are predicted to circulate in the upcoming infl uenza season [121]. These infl uenza vi-ruses can escape infection and vaccine-induced antibody mediated immunity due to the antigenic variability of their surface antigens. From time to time selected seasonal vaccine strains do not match circulating virus strains, which antigenic mismatch may render the seasonal vaccine used in
23
that season less- or non-effective [122, 123]. This e.g. happened to be the case during the 2014/2015 seasonal infl uenza epidemic [124].
Pandemics of infl uenza with varying rates of illness and death have probably occurred throughout history; three worldwide infl uenza pandemic outbreaks occurred in the 20th century in 1918, 1957, and 1968 [125, 126]. The most notable was the 1918–1919 pandemic, which apart from causing serious infl uenza in a substantial proportion of the world population, claimed an estimated 50 to 100 million lives worldwide [127]. The Spanish infl uenza pandemic of 1918 caused more deaths than World War I [127, 128]. The Asian fl u pandemic of 1957 killed 1-4 million worldwide. In 1968, the Hong Kong fl u pandemic killed approximately 1-2 million people [129]. These pandemics were followed by the fi rst infl uenza pandemic of the 21st century in 2009, the Mexican fl u, with a global death estimation of about 300 thousand people worldwide [130]. The extent of the societal burden of infl uenza epidemics and pandemics is often underestimated. The impact of infl uenza on societies in terms of morbidity, mortality, and fi nancial resources varies for each outbreak [131, 132]. Epidemi-ological records on infl uenza burden show that it has a large impact on society including increased demands on health-care systems, long-term illness, and disability. Furthermore, infl uenza epidemics and pandemics have a hugely variable socioeconomic burden on populations worldwide due to their variability and broad distribution in humans [129]. Also outbreaks of infl uenza in domestic poultry, and to a lesser extent in mammalian species like horses, pigs and dogs, may cause major socioeco-nomic burden due to mass mortalities, production losses and animal suffering. Various estimates have been made in diverse socioeconomic contexts as assessment tools to determine the best vac-cination-, preventive strategies, and clinical treatments. The signifi cant economic impact of human infl uenza include loss of human life among productive people, of reduced or lost productivity due to work absenteeism, decreased performance, and hospitalization costs [129], as listed in Table 1.1.
Infl uenza viruses with pandemic potential are present in avian and mammalian reservoirs and emerge unexpectedly as was the case for the last time for the Mexican fl u pandemic in 2009 [133]. Therefore, development and manufacturing of an infl uenza vaccine for a newly emerging pandemic strain in time, that offers protective immunity against the emerging pandemic virus continues to be a challenge [133, 134].
Limitations of infl uenza vaccines today involve both current vaccine technologies and regulato-ry issues leading to relatively long production times, limited worldwide vaccine capacity, lack of cross-protection, and inadequate effi cacy [47], leaving the population largely unprotected until after the peak of pandemic virus outbreak [135]. New technologies that allow faster production of vaccine seed strains in combination with alternative production platforms and vaccine formulations may shorten the time gap between emergence of a new infl uenza virus and vaccine availability.
24
Development of an effective vaccine that provides broad and long-lasting protective immunity against different infl uenza subtypes requires novel development and production technologies. Both current state-of-the-art and novel knowledge and technologies are required to achieve this common goal and develop a vaccine with such properties. In addition, use of different adjuvants entails ben-efi ts such as an increased and rapid immune response, use of lower antigen dose, broaden antibody response, and long-term immunity [76].
Recently, most approaches used to develop infl uenza vaccines are based on conventional systems focused primarily on stimulating immunity against the highly polymorphic head of the viral hemag-glutinin (HA) [32, 133]. Given that these vaccines induce relatively limited and strain-specifi c neu-tralizing antibodies, a more universal infl uenza vaccine that would protect against more conserved HA epitopes is among today’s largest unmet medical needs. New insights into cross-protection and broad humoral and cellular immune responses provide promising innovation opportunities for vac-cine development as well as production platforms, leading to optimization of vaccine strategies and development of new generation vaccines [135]. Currently, several universal infl uenza virus vaccine candidates are in the late stage pre-clinical or in early stage clinical development [136] with the potential of abolishing the need for seasonal vaccination and thereby contribution to public health benefi t.
1.7. Theoretical Background
The concept of a societal unmet vaccine need is adopted from the FDA defi nition of unmet medical need; “a condition whose treatment or diagnosis is not addressed adequately by available therapy. An unmet medical need includes an immediate need for a defi ned population (i.e., to treat a serious condition with no or limited treatment) or a longer-need for society (e.g., to address the development of resistance to antibacterial drugs)” [137]. Exploring the complex and broad concept of unmet vaccine need requires involvement of various areas of expertise through using a multidisciplinary approach involving at least the three main stakeholders within this fi eld, namely: regulatory author-ities, industry, and academia [138-140].
The health and life sciences industry, which is an important driver behind the public health and vaccine development, revolves around continuously addressing these unmet needs. To achieve this purpose, vaccine development, production, and market implementation evaluations from a regula-tory, industry, and academia perspective are required to identify and prioritize medical needs, which subsequently could be used as the fundament for research priorities [138, 141].
25
Primary goal of the vaccine-development-technology-innovation is to address and ultimately target unmet needs against previously untargeted diseases, for the benefi t of public health. In essence, the desired outcome of vaccine valorization and technological innovation is realizing a public health unmet need and/or market demand [142, 143]. These unmet needs seem to exist in, inter alia, the following fi elds: target infectious pathogen, manufacturing technology, antigen delivery technology, and immunostimulating compounds [142].
Figure 1.1. Theoretical framework. The unmet medical need is considered the principal and the regulatory, industry, and academia are considered the agents.
26
Using the principal-agent theory (PAT), actors can be divided into ‘principal’ – the one that dele-gates activities – and ‘agent’ – the one that subsequently conducts the delegated activities [144]. The response to the unmet vaccine needs is generally provided by the vaccine industry. In this case, a candidate antigen has to complete the vaccine value chain, which are the (inter)nationally regulated chronological stages starting from the discovery phase through to human clinical trials [145], fol-lowed by market implementation, Figure 1.1.
Based on PAT, confl ict of interests and internal preferences between different disciplines involved in the vaccine fi eld exist. According to this theory, since the principal delegates the agent to conduct different activities, this dyadic social interaction is infl uenced by four main factors including infor-mation, risk, external environment, and self interest. Focusing on the internal preferences, the con-fl ict of interests may create mutually inaccurate beliefs, ineffective strategies, and a general distrust between different disciplines [144, 146]. As a result, since the last decade, the vaccine industry has been experiencing a productivity gap, whereby the expected turnover falls behind the proportion of consumed resources [146, 147]. Consequently, generating a lack of suffi cient amount of new vac-cine development to sustain current business models and fulfi ll unmet vaccine needs [148-150]. This threat, mainly due to increasing R&D costs, obligates the vaccine industry to continue technological innovation in order to meet the vaccine needs [148, 151, 152], which inevitably involves application of novel GM technologies.
According to the experts from the vaccine fi eld, targeting previously untargeted diseases should become the center of attention at all time during the process of addressing unmet vaccine need. Application of novel GM technologies provides the opportunity to improve vaccine quality through the development and production of “smart vaccines”. However, only after the regulatory authorities have granted market authorization for these novel vaccines, the purpose of targeting yet untargeted diseases, thereby accommodating the unmet medical needs of public health and eventually contribu-tion to meet societal unmet need will be achieved (Figure 1.1).
However, Pronker suggests that converting the aforementioned conventional vaccine-value-chain into a demand-driven value chain confi guration will result in aligning interest for the benefi t of every party involved [143, 146]. In this case, the unmet vaccine need should be considered as the principal and the regulatory authorities, industry, and academia as the agents creating an ecosystem for the benefi t of public health. The three agents would interact with the common purpose of fulfi lling the task set by the principal. Furthermore, this provides the opportunity for the agents to act directly on the unmet demand. In this thesis research, we intend to provide a novel and unique quantitative data set to investigate this line of reasoning.
27
The vaccine arena can be defi ned as a fi eld with a high unmet medical need due to a high prevalence of untargeted diseases. Therefore, these new disease areas will offer future innovation opportunities for vaccine companies developing new generation vaccines based on novel technologies. Moreover, the conventional vaccine development and production technologies are not applicable for all types of pathogens, generating a requirement for GM technology approaches in order to target more and complex previously untargeted diseases. In this case these needs can be fulfi lled through “market pull” strategy, where these unmet needs function as the innovation opportunity input [141, 153]. Furthermore, staying innovative enables the vaccine companies to maintain their competitive edge and continue to endeavor towards the opportunities to meet the unmet vaccine needs of society.
28
1.8. Outline of Research and Dissertation
Figure 1.2. Outline of the research and dissertation in a schematic view.
29
The studies of this dissertation are organized according to the framework described in Figure 1.2. The fi rst chapter is a general introduction to immunization and need for vaccine development based on novel technologies. The second chapter concentrates on the market potential of GM vaccines involving KOLs. Chapter three evaluates current and future prospects of GM vaccine market R&D with respect to different disciplines. The fourth chapter reviews the state-of-the-art of vector-based technologies in the fi eld of GM vaccine development. Chapters fi ve and six focus on the market and commercial potential of the MVA platform, respectively. Chapter seven proposes innovations that are needed in regulatory procedures to enable emergency deployment of GM veterinary vaccines in Europe. The dissertation ends with a discussion, presenting an overall evaluation and recommenda-tion regarding innovation by GM technology as a market driver to target unmet vaccine need.
Chapter 2 introduces a quantitative KOLs analysis of the GM vaccine market potential, by pre-senting a consensus overview of CSFs for successful introduction of novel vaccines combining both qualitative and quantitative research. Comprehensive evaluation of GM-vaccine-CSFs requires investigating both benefi ts and barriers from the GM vaccine fi eld. Application of this customized concept, combining both the added value and the barriers to describe the CSFs, provides an overview of the market potential of GM vaccines. Literature was collected to obtain background information on GM vaccines. Subsequently, exploratory interviews were conducted with KOLs, to identify the CSFs for a successful introduction of GM vaccines. Finally, a survey was used to quantify, weigh, and prioritize the importance of the collected CSFs. This study shows that GM vaccines may provide possibilities to target previously unmet need diseases. As many of these diseases are about to get targeted by GM vaccines currently in different phases of clinical trials, the focus of future research needs to lie on providing insights in the current and future prospects of global GM vaccine market.
Chapter 3 presents an overview of the current GM vaccine market and a description of its prospects for future growth considering the changes, developments, and concerns in the fi eld of vaccines. This chapter further presents an overview of the global GM vaccine market, revealing trends in patent applications, vaccine approvals, and additionally next generation GM vaccine forecasts. New and unique datasets were developed for an interdisciplinary analysis of the current GM vaccine market. The methods applied in this chapter were performed in different stages to provide a thorough and complete overview of the GM vaccine market. First a literature study was conducted to obtain search-specifi c-terminology on GM vaccine publications. Subsequently, patents, clinical trials, and registered vaccines were explored and three separate unique datasets were compiled for the purpose of in-depth analysis. On the basis of the evidence revealed from this study on the growth of global GM vaccine market and advances in vaccine R&D, a clear defi nition of GM vaccine technologies, and future research on GM vaccine production platforms must be evaluated.
30
Chapter 4 evaluates the potential of vector-based vaccines, as these vaccines show great promise for next generation vaccine development, using data obtained from literature, granted patents, and different stage clinical trials. This data set is synthesized and analyzed in the light of data from currently registered vaccines providing an overview of the potential of currently used and newly generated vectors in the fi eld of vaccine development. The methods applied in this chapter have been split in four stages: evaluation of literature, patents, clinical trials, and registered GM as well as non-GM vaccines. Each stage was individually examined in detail and the complete data set was compiled. These stages were decided upon in order to provide a complete overview of the GM vec-tor-based vaccine pipeline and market. Ultimately we attempted to answer the question: what is the state-of-the-art of used and newly generated vector-based technologies in the fi eld of GM vaccine development? Although this study shows that poxviruses and adenoviruses are among the most prominent vectors in GM vaccine development, the most prevalent vector with a signifi cant rapid usage in clinical trials is identifi ed to be MVA. Yet, the market implementation potential of this novel platform and the essential role that MVA plays within the GM vaccine market remains unexplored.
Chapter 5 uncovers market implementation challenges of the MVA platform, in particular its ap-plication for infl uenza vaccines, by performing semi-structured interviews with KOLs from the vaccine fi eld representing the ‘golden triad’: regulatory, industry, and academia. A novel approach in this study quantifi es expert’s opinions regarding market implementation challenges of the MVA platform and exposes high-prioritized barriers specifi c to such novel technologies. This study also provides, through various ranking methods (integrated assessment (IA) approach, perspective meth-od, and rank-frequency and importance frequency methods) a unique overview from a multidisci-plinary perspective, making it possible to identify foremost underlying causes that contribute to the challenges novel vaccines have to face for successful market entry. Ultimately, a multidisciplinary approach involving the most infl uential stakeholders in the fi eld of vaccine R&D and manufacturing (regulatory, industry, and academia) is required to explore strengths, weaknesses, opportunities, and threats of such platforms.
Chapter 6 evaluates the commercial potential of MVA vector-based vaccine technology for pre-pan-demic and pandemic infl uenza. KOLs in the fi eld of infl uenza vaccine development were approached, in order to obtain a balanced view on its strengths, weaknesses, opportunities, and threats using the SWOT-AHP combined analytic method. An empirically validated contemporary industry view of MVA as a vaccine technology platform is provided. This study demonstrates that MVA is considered a suitable platform for vaccine development, and argues that there is a future for MVA based vector platforms to develop not only preventive, but also therapeutic vaccines to address unmet public health needs in the fi eld of infectious diseases, provided that vector development is paralleled by in-depth studies concerning correlates of immune mediated protection and pathogenesis. The meth-
31
odology used is comprised of three data collection moments. First, collecting background informa-tion from the literature in order to, inter alia, develop a balanced set of interview questions. Next, quantifi cation of the qualitative data generated from interviews with KOLs by means of SWOT-AHP application. Furthermore, this study allows to explore different views, evaluate different options, identify inherent risks and barriers, and consequently anticipate future challenges and prepare for future threats.
Chapter 7 represents one of our next steps as part of a strategic plan to face identifi ed novel vaccine implementation barriers, in particular in case of an emergency situation. This work has already been initiated by different stakeholders with different backgrounds in the “One Health” fi eld. Furthermore, this chapter identifi es and proposes several necessary amendments in the direc-tives within existing legislation for a fast-track deployment of GM veterinary vaccines during an emergency situation.
Chapter 8 concludes this dissertation by summarizing the key fi ndings and recapitulates the indi-vidual position of each study to existing literature. Furthermore, the main conclusions and the prior-itized innovation barriers for implementation of GM vaccines are discussed and recommendations for future research are suggested.
32
1 In
trod
uctio
n 2
A K
ey O
pini
on L
eade
rs
Ana
lysi
s of
the
Crit
ical
S
ucce
ss F
acto
rs fo
r th
e M
arke
t Pot
entia
l of G
enet
ical
ly
Mod
ified
Vac
cine
s
Wha
t is
the
mar
ket p
oten
tial o
f gen
etic
ally
m
odifi
ed v
acci
nes,
acc
ordi
ng to
Key
Opi
nion
Le
ader
s (K
OLs
)?
- W
hat a
re th
e cr
itica
l suc
cess
fact
ors
(CS
Fs)
for
succ
essf
ul m
arke
t int
rodu
ctio
n?
- W
hich
add
ed v
alue
s m
ake
GM
vac
cine
s su
perio
r ov
er c
onve
ntio
nal v
acci
nes?
-
Whi
ch b
arrie
rs h
ave
to b
e ov
erco
me
for
succ
essf
ul
appl
icat
ion
of G
M v
acci
nes?
- Li
tera
ture
sea
rch
- In
terv
iew
s -
Key
Opi
nion
Lea
ders
ana
lysi
s -
Crit
ical
Suc
cess
Fac
tor
anal
ysis
-
Ran
king
sur
vey
- C
ritic
al S
ucce
ss F
acto
rs g
roup
ed in
to 4
cat
egor
ies:
Tec
hnic
al,
Com
mer
cial
, Rul
es &
Reg
ulat
ions
, and
Soc
ieta
l -
GM
vac
cine
pro
vide
s ne
w m
arke
t opp
ortu
nity
to c
omba
t pr
evio
usly
unt
arge
ted
dise
ases
-
Cat
egor
ies
rule
s &
reg
ulat
ions
and
soc
ieta
l req
uire
imm
edia
te
atte
ntio
n, c
onsi
dera
tion,
and
inte
rven
tion
mea
sure
men
ts
Inte
rnat
iona
l Jou
rnal
of
Inno
vativ
e R
esea
rch
in
Sci
ence
, Eng
inee
ring
and
Tec
hnol
ogy
Pub
lishe
d [1
54]
Ove
rall
mo
st p
rom
inen
t fa
cto
r is
th
e p
oss
ibili
ty G
M v
acci
nes
pro
vid
e to
tar
get
pre
vio
usl
y u
nm
et n
eed
dis
ease
s. A
s m
any
dis
ease
s ar
e ab
ou
t to
get
tar
get
ed b
y em
erg
ing
GM
vac
cin
es, f
utu
re r
esea
rch
nee
ds
to f
ocu
s o
n t
he
curr
ent
and
fu
ture
pro
spec
ts o
f g
lob
al G
M v
acci
ne
mar
ket.
3 A
n In
terd
isci
plin
ary
Ana
lysi
s of
G
enet
ical
ly M
odifi
ed V
acci
nes:
F
rom
Clin
ical
Tria
ls to
Mar
ket
Wha
t is
the
curr
ent s
tate
and
futu
re
pros
pect
s of
glo
bal G
M v
acci
ne m
arke
t R&
D
with
res
pect
to d
iffer
ent d
isci
plin
es: m
edic
al
stud
ies,
IP, c
linic
al tr
ials
, and
reg
iste
red
vacc
ines
?
- W
hat a
re th
e tr
ends
in p
aten
t lite
ratu
re?
- W
hat a
re th
e tr
ends
in c
linic
al tr
ial p
hase
s?
- W
hat a
re th
e tr
ends
in v
acci
ne a
ppro
vals
? -
Cou
ld y
ou fo
reca
st N
ext g
ener
atio
n G
M v
acci
ne?
- Li
tera
ture
sea
rch
- P
aten
t ana
lysi
s -
Clin
ical
tria
ls a
naly
sis
- R
egis
tere
d va
ccin
es a
naly
sis
- D
ata
conv
erge
nce
- H
igh
tran
sitio
n su
cces
s ra
te o
f GM
vac
cine
s in
CT
, (P
1-P
2:
82%
) (P
2-P
3: 7
6%)
- In
crea
se o
f glo
bal G
M v
acci
ne m
arke
t sha
re, 2
0% (
risin
g tr
ends
in p
aten
t app
licat
ion
& v
acci
ne r
egis
trat
ion)
-
Mos
t via
ble
regi
ons
for
GM
vac
cine
mar
kets
: Nor
th A
mer
ica,
A
sia,
and
Eur
ope
- P
redi
ctio
n of
GM
vac
cine
s ta
rget
ing
canc
er a
nd m
alar
ia in
the
com
ing
year
s
Inte
rnat
iona
l Jou
rnal
of
Clin
ical
Tria
ls
Pub
lishe
d [1
55]
Evi
den
ce o
n t
he
gro
wth
of
wo
rld
wid
e G
M v
acci
ne
mar
ket
po
int
ou
t a
com
pel
ling
nee
d o
f a
clea
r d
efin
itio
n o
f G
M v
acci
nes
, tec
hn
olo
gie
s, a
nd
fu
ture
res
earc
h o
n G
M v
acci
ne
pro
du
ctio
n p
latf
orm
s4
Vec
tor-
base
d G
enet
ical
ly
Mod
ified
Vac
cine
s:
Exp
loiti
ng J
enne
r’s L
egac
y
Wha
t is
the
curr
ent s
tate
-of-
the-
art u
sed
and
new
ly g
ener
ated
vec
tor-
base
d te
chno
logi
es
in th
e fie
ld o
f GM
vac
cine
dev
elop
men
t?
- W
hat a
re th
e m
ost p
rom
isin
g ve
ctor
s fo
r va
ccin
e de
velo
pmen
t at t
his
mom
ent,
liter
atur
e?
- W
hat a
re th
e m
ost p
rom
isin
g ve
ctor
s, fo
r G
M
vacc
ine
deve
lopm
ent a
t thi
s m
omen
t, pa
tent
s an
d cl
inic
al tr
ials
? -
Wha
t are
the
curr
ently
use
d ve
ctor
s av
aila
ble
in
the
clin
ical
tria
ls?
And
whi
ch in
dica
tions
are
bei
ng
targ
eted
?
- Li
tera
ture
sea
rch
- P
aten
t sea
rch
- C
linic
al tr
ials
sea
rch
- (N
on)
Reg
iste
red
GM
vac
cine
sea
rch
- P
oxvi
ruse
s an
d ad
enov
iruse
s ar
e am
ong
the
mos
t pro
min
ent
vect
ors
in G
M v
acci
ne d
evel
opm
ent
- V
ecto
r-ba
sed
vacc
ines
com
pris
e a
sign
ifica
nt p
art o
f all
GM
va
ccin
es in
the
pipe
line,
26%
-
Can
cer,
HIV
, and
mal
aria
sho
w a
larg
e pr
esen
ce in
bot
h pa
tent
and
clin
ical
tria
ls.
- R
apid
incr
ease
in M
VA
vec
tor
usag
e in
vec
tor-
base
d va
ccin
e de
velo
pmen
t tria
ls
Vac
cine
In
pre
ss [1
56]
Vec
tor-
bas
ed G
M li
tera
ture
, pat
ents
, an
d c
linic
al t
rial
s in
dic
ate
that
po
xvir
use
s an
d a
den
ovi
ruse
s ar
e am
on
g t
he
mo
st p
rom
inen
t ve
cto
rs in
GM
vac
cin
e d
evel
op
men
t. M
VA
is t
he
mo
st p
reva
len
t ve
cto
r w
ith
a s
ign
ific
ant
rap
id in
crea
se u
sag
e in
clin
ical
tri
als,
em
ph
asiz
ing
th
e es
sen
tial
ro
le t
hat
MV
A p
lays
wit
hin
th
e G
M v
acci
ne
mar
ket
5 C
ross
-Sec
tora
l Per
spec
tives
of
Mar
ket I
mpl
emen
tatio
n of
the
MV
A P
latfo
rm fo
r In
fluen
za
Vac
cine
s: R
egul
ator
y, In
dust
ry
and
Aca
dem
ia
Wha
t are
the
mar
ket i
mpl
emen
tatio
n po
tent
ial o
f MV
A p
latfo
rm to
gen
erat
e ne
xt-
gene
ratio
n in
fluen
za v
acci
nes,
acc
ordi
ng to
re
gula
tory
, ind
ustr
y, a
nd a
cade
mia
?
- W
hat a
re th
e m
ain
mar
ket i
mpl
emen
tatio
n ba
rrie
rs
for
MV
A p
latfo
rm?
- W
hat a
re th
e fo
rem
ost u
nder
lyin
g ca
uses
cre
atin
g th
ese
mar
ket i
mpl
emen
tatio
n ba
rrie
rs?
-
Whi
ch b
arrie
rs a
nd th
eir
unde
rlyin
g ca
uses
hav
e pr
iorit
y w
ith r
espe
ct to
thei
r im
port
ance
?
- Li
tera
ture
stu
dy
- In
terv
iew
s -
Roo
t Cau
se A
naly
sis
(RC
A)
- In
tegr
ated
Ass
essm
ent (
IA)
appr
oach
-
Per
spec
tive
met
hod
- R
ank-
freq
uenc
y &
Impo
rtan
ce fr
eque
ncy
met
hods
- Im
plem
enta
tion
barr
iers
can
be
grou
ped
into
6 m
ain
cate
gorie
s -
Top
3 c
ateg
orie
s, a
ccor
ding
to r
anki
ng a
nd im
port
ance
fr
eque
ncy,
coi
ncid
e w
ith to
p 3
cate
gorie
s sh
ared
by
all
pers
pect
ives
-
Nec
essi
ty fo
r ap
proa
chin
g K
OLs
with
diff
eren
t bac
kgro
unds
fr
om d
iffer
ent f
ield
s in
dica
tes
com
plex
ity o
f MV
A m
arke
t im
plem
enta
tion
-
Onl
y co
llabo
ratio
n &
join
tly e
ffort
s ca
n en
sure
an
effe
ctiv
e an
d su
cces
sful
long
-ter
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A
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to K
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terv
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)
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ive
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acy
are
over
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mpo
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t con
side
ratio
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r su
cces
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plem
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gths
: hel
p in
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se c
omm
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and
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th v
alue
, pro
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regu
lato
ry a
ppro
val a
nd
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de y
et u
nrea
ched
mar
kets
Vac
cine
P
ublis
hed
[109
]
An
exa
mp
le:
Pra
ctic
al a
pp
licat
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of
the
stu
die
s p
rese
nte
d h
ere
7 E
mer
genc
y D
eplo
ymen
t of
Gen
etic
ally
Eng
inee
red
Vet
erin
ary
Vac
cine
s in
Eur
ope
How
vet
erin
ary
vacc
ines
can
be
depl
oyed
m
ore
rapi
dly
to a
ppro
pria
tely
res
pond
to
futu
re e
pizo
otic
s in
Eur
ope
- W
hat a
re th
e cu
rren
t reg
ulat
ory
path
way
s fo
r ge
netic
ally
eng
inee
red
vacc
ines
? -
Wha
t are
the
oppo
rtun
ities
for
fast
-tra
ck
depl
oym
ent o
f vac
cine
s? W
ithin
the
boun
darie
s of
cu
rren
t leg
isla
tion
AN
D N
ew o
ppor
tuni
ties
- Li
tera
ture
rev
iew
s -
Con
gres
s w
orks
hop
with
key
st
akeh
olde
rs
- In
the
curr
ent r
egul
ator
y ar
ena,
it is
not
pos
sibl
e to
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regi
stra
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of g
enet
ical
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d va
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es
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sho
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evie
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-
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r “m
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up”
doss
iers
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tical
ly e
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es s
houl
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dev
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and
pol
itici
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per
cept
ions
sho
uld
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ken
into
ac
coun
t
Vac
cine
S
ubm
itted
, U
nder
rev
iew
8
Con
clus
ions
and
Dis
cuss
ion
Tabl
e 1.
2. O
verv
iew
of t
he in
divi
dual
cha
pter
s of t
his d
isse
rtat
ion.
33
34
Chapter 2A Key Opinion Leaders Analysis of the Critical
Success Factors for the Market Potential of Genetically Modified Vaccines
Published as:Ramezanpour, B., Kamphuis, P.G.A. and Prof. dr. Claassen, E. International Journal of Innovative Research in Science, Engineering and Technology. 2016;5(4). DOI:10.15680/IJIRSET.2016.0504101
36
Abstract
Conventional vaccines have been very successful in preventing and controlling many diseases. One of the next steps in vaccine innovation is the introduction of genetic modifi cation, which provides various novel opportunities in the vaccine fi eld. Although the market potential for conventional vaccines has been evaluated in detail, the market potential of genetically modifi ed vaccines has not been investigated yet. Interviews with key opinion leaders were conducted to extract critical success factors, which subsequently were quantifi ed, weighed, and prioritized by a ranking survey. Results of this study revealed that critical success factors could be classifi ed into four categories: technical, commercial, rules & regulations, and societal. The key opinion leaders indicated that the category “rules & regulations” requires immediate attention and consideration. Additionally, the “societal potential” category demands intervention measurements, as both these categories included highly prioritized barriers. The key opinion leaders further indicated that genetically modifi ed vaccines provide new market opportunities against previously untargeted diseases (e.g., HIV, malaria, tuber-culosis, rabies, Alzheimer, auto-immune diseases, allergies, and cancers). Opportunity to produce multi-targeted vaccines is also considered to be an important added value driver though in the long-term future.
37
2.1. Introduction
The astonishing success of vaccines in disease control and prevention is and remains undeniable. The global eradication of smallpox and rinderpest exemplifi es the outstanding achievements that vaccination has made so far [6, 7]. Moreover, vaccination is considered the most cost-effective med-ical tool to control infectious diseases [86]. Despite successes achieved by conventional vaccines, there are still a lot of diseases that are diffi cult to target [27, 157, 158]. These untargeted diseases include ‘the big three’: malaria, tuberculosis, and HIV/AIDS [29]. ‘The big three’ are responsible for the occurrence of 217.9 million new infections each year [159], emphasizing the necessity and urgency of vaccine development against these diseases. Furthermore, this need provides not only business opportunities [48, 146] for vaccine manufacturers to expand their vaccine repertoire and cover new markets in the vaccine fi eld but it also makes a great contribution to global public health benefi t.
According to WHO facts, the global vaccine market tripled in value from 5 billion US dollar in 2000 to almost 24 billion in 2013. In 2010, only 3% of the global pharmaceutical market could be allocated to vaccine revenues. Furthermore, the vaccine market undergoes a spectacular growth rate of 10-15% per year as opposed to the 5-7% of the global pharmaceutical market. The global vaccine market is becoming an engine for the pharmaceutical industry and is expected to reach 100 billion US dollar by 2025 [50].
The introduction of novel technologies such as genetic modifi cation in the vaccine fi eld can provide numerous opportunities. Genetically modifi ed (GM) vaccines could lead to the generation of vac-cines against virtually all pathogens [39, 160]. Furthermore, GM technology allows generating more complex vaccines like, vector-based vaccines, DNA vaccines, RNA vaccines, virus like particles, and virosomes [27, 39, 40]. The application opportunities in the medical fi eld go beyond infectious diseases, e.g., tumour immunology [38].
Although the market potential of conventional vaccines has been evaluated in detail [161, 162] that of the GM vaccines has not been investigated yet. The market potential of GM vaccines differs from conventional vaccines due to their novelty and specifi c characteristics. Furthermore, different barriers need to be taken into account including one of the most profound and well-known hurdles against genetic modifi cation technology in general: public perception.
GM vaccines are considered as the next step in vaccine development [40]. Hence, gaining knowl-edge about their market potential is considered essential, as many new GM vaccines will enter the market in the near future [158]. Furthermore, our prior study showed the strengths of one of the most
38
promising GM vaccine platforms, the modifi ed vaccinia virus Ankara (MVA) [160]. The aim of this study is to provide a quantitative key opinion leaders (KOLs) analysis of the GM vaccine market potential, by presenting a consensus overview of the critical success factors (CSFs) for successful introduction of these novel vaccines.
CSFs were fi rst described by Rockart in 1979, as a tool for chief executive offi cer’s information needs. This concept was based on an idea described earlier by Daniel (1961) and was applied in the 1980s to identify the success components indicating why some companies were more success-ful than others. CSFs are the key areas in which good results will secure a successful competitive performance, and where ‘things must go right’ if a company wants to be successful [163, 164]. It is described to provide information measures that refl ect critical areas providing a set of requirements. CSFs are applied in different ways in a large variety of industries, especially in combination with enterprise resource planning implementation [165-169].
CSFs are variables, which can affect the competitive position of various businesses within an in-dustry. More importantly, CSFs vary from industry to industry and are infl uenced by management decision-making [170]. According to Leidecker and Burno (1984), CSFs are applied at three levels of analysis: economic/socio-political environment, industry, industry/fi rm-specifi c.
CSFs are generally used in the fi eld of management information systems and business strategy research with various views including strategic planning and decision-making, identifi cation and prioritization in business strategies, market description, and performance models [167, 168, 171].
Comprehensive evaluation of GM-vaccine-CSFs requires investigating both benefi ts and barriers from the fi eld. In this study, the benefi ts of GM vaccines are referred to as the ‘added value’, which GM vaccines introduce over conventional vaccines. It is those CSFs that should make GM vaccines superior over conventional vaccines, thereby defi ning the theoretical potential of GM vaccines. Nev-ertheless, in order for GM vaccines to become successful, barriers need to be overcome. Hence, these barriers play an essential role in successful application of GM vaccines and thus are included in the CSF’s repertoire. Application of this customized concept, combining both the added value and the barriers to describe the CSFs, provides an overview of the market potential of GM vaccines.
39
Table 2.1. Background of the KOLs.
Background Interviews Survey Academia 4 12 Industry 4 8Regulatory 4 1 Other 3 0 Subtotal 15 21 Total 36
2.2. Methodology
This study comprised three data collection stages. Figure 2.1. shows research methods applied in this study and three specifi c data collection moments. First, literature was collected in order to obtain background information on genetically modifi ed (GM) vaccines. Then, exploratory interviews were conducted with key opinion leaders (KOLs), to identify the critical success factors (CSFs) for a suc-cessful introduction of GM vaccines. Finally, a survey was used to quantify, weigh, and prioritize the importance of the collected CSFs.
2.2.1. Literature
A literature study provided specifi c search terms on GM vaccines and the concept of CSFs. Our previous study, which provided a quantitative SWOT analysis about the market implementation of the MVA platform for infl uenza vaccines [160] formed a quantitative basis for evaluating the market potential of all GM vaccines. The collected information, together with data gathered from consulting experts, was used to develop a set of questions for the interviews.
2.2.2. Interviews
In order to attain most recent opinions and views on the market potential of GM vaccines, semi-struc-tured interviews were conducted. The interview candidates were experts and KOLs in the vaccine fi eld. Interview candidates from different backgrounds (academia, industry, regulatory) were pur-posively selected to provide a diverse and comprehensive overview of the market potential of GM vaccines. Additionally, interviews were conducted with ethics-committee-experts and an indepen-dent advisory body (which advises the Dutch government on the risk of the use and production of GMOs on human health and the environment). Table 1 provides background information on KOLs that were approached for the interviews and survey.
40
The semi-structured interviews were conducted to allow for probing in order to gain more in-depth answers. The questions were structured in six categories, which created a context for the questions and guaranteed the completeness of the data gathered. The categories include: ‘vaccine develop-ment’, ‘vaccine manufacturing’, ‘vaccine registration’, ‘hurdles’, ‘societal’, and ‘general questions’ (Appendix). Multiple researchers conducted the interviews through which investigator triangulation was achieved. Data was analyzed anonymously, in order to remove any reticence from the inter-viewees.
Qualitative research requires data collection until reaching a point of data saturation. As before [139, 140] we achieved saturation when the collection of new data does not provide new information onthe research [172, 173]. The saturation curve of this study was constructed based on new CSFs men-tioned during the interviews. To determine the saturation point, the total amount of CSFs was used,irrespectively of the category they belong to. Interviews were conducted until no new CSFs wereobtained in three consecutive interviews. Hence, the saturation determined the research sample size.
All interviews were transcribed, data based, and analyzed in order to gain insight from the data collected to formulate CSFs for GM vaccines. Moreover, their implementation potential mentioned by KOLs from various fi elds with different perspectives was codifi ed. Interview transcripts were open-axial coded according to the grounded theory [174]. By applying the grounded theory, inter-view analysis resulted in 174 open codes. These codes were subsequently categorized into 4 axial codes, which are constructed by means of categorizing open codes identifi ed in the previous step: technical potential, commercial potential, rules & regulations and societal potential.
2.2.3. Ranking Survey
The ranking survey was used to quantify, weigh, and prioritize the CSFs gained from the interviews. Additionally, the survey was used to verify the results of the interviews. The top 10 CSFs in each category were determined using a frequency count on their prevalence in the interviews, and com-piled into a survey. This survey was sent to 87 KOLs around the world, which were selected based on their expertise in the vaccine fi eld. Furthermore, KOLs from different backgrounds were selected (academia, industry, and regulatory) in order to include different perspectives on the market poten-tial of GM vaccines. The KOLs were asked to rank the CSFs based on their importance. This was achieved by allocating 20 points amongst 5 factors in each category. Additionally, the KOLs were asked to indicate whether a CSF is a short-, mid-, or long-term concern.
41
2.2.3.1. Survey AnalysisThe survey developed for this study was based on 4 x 10 CSFs (4 categories, 10 CSF in each cat-egory) in combination with three different priority periods, including short-, mid-, and long-term period. The respondents were asked to indicate the level of importance for each CSF by allocating 20 points amongst 5 factors in each category. During the analysis, the points of each CSF were ac-cumulated, thereby generating an importance level for each CSF. Priority periods were determined using a frequency count for each period of each CSF.
Figure 2.1. Research methods applied in this study. Underlined are the three specific data collection stages.
42
2.3. Results
2.3.1. Interviews
The 4 categories identifi ed in exploratory interviews with the experts and KOLs are presented in Figure 2.2. Subsequently, the interviews were used to extract a top 10 CSFs of each category. Figure 2.2. presents the number of times each category was mentioned and the variety of argu-ments within these categories. The category “technical potential” is mentioned most often, 156 times. Categories “commercial potential” and “societal potential” are mentioned almost equal, 119 and 117 respectively. The category “rules & regulations” is mentioned slightly less, 104 times.
The variety of argument in “technical potential” and “commercial potential” is practically equal, 61 and 58 times, respectively. Comparing these categories to “rules & regulation” (29) and “societal potential” (26) less variety of arguments is identifi ed.
Figure 2.2. Results of the interviews; both the amount of times a category was mentioned and the variety of arguments within the category.
43
Saturation of CFSs, mentioned by the KOLs, was reached after 15 interviews, as indicated in Figure 2.3. The total number of CSFs presented in the saturation curve, 161, differs from the total of the variety in arguments, 174, visualized in Figure 2.2. due to the fact that 13 CSFs were applicable in multiple categories.
Figure 2.3. Saturation curve of the interviews. Cumulative number of new CSF mentioned in the inter-views, irrespective of the category. Saturation was reached at 15 interviews.
2.3.2. Survey
Forty CSFs that were identifi ed in prior exploratory interviews are presented in Figure 2.5. and will further be discussed per category. The name of the CSF will be given in an italic front. The response rate was 24%, well within acceptable limits [139, 140, 146]. Figure 2.4. provides the number of added values and barriers of the top 5 of each category from the survey, identifi ed in exploratory interviews with the experts and KOLs. Furthermore, Figure 2.5. shows the results of the survey in-cluding the total amount of points given to the CSFs by the KOLs, percentage of the total points in the category given to the CSFs, and an indication on each CSF’s priority in the future (short-/mid-/long-term).
44
2.3.2.1. Technical Potential The most important CSF, as indicated by the KOLs, in the category of technical potential is the op-portunity to target previously untargeted diseases. The amount of points given to this CSF was 103 points, representing 25% of the total amount of points. The majority of KOLs indicate this added value of mid-term priority.
The possibilities to produce multi-targeted and safer vaccines are ranked to be the second and third most important factors with 65- and 62 points. It is notable that the possibility to produce multi-tar-geted vaccines is mainly a long-term concern, according to the KOLs. Moreover, developing safer vaccine is indicated to be of a short-term concern. Offers safer vaccines was described as a statement that GM vaccines offer safer vaccines comparing to the conventional vaccines.
Notable, although, the lack of effi cacy was mentioned fi ve times during the in-person interviews, it has not received any scores and is thus not ranked by any of the KOLs in the survey. The top 5 CSFs in technical potential are all added values of GM vaccines (Figure 2.4).
Figure 2.4. Number of added values and barriers of the top 5 of each category from the survey.
45
2.3.2.2. Commercial Potential Commercial potential is prioritized predominantly as short- and mid-term concerns. The new market opportunities is ranked as most important with 76 points, 18% of the total points. According to the KOLs, GM vaccines open up many new markets due to the high unmet need that currently exist. The high market potential is ranked as second important CSF within this category, representing 16% of the points. Furthermore, required fi nancial investments, is not ranked higher, as it was the second most mentioned CSF from the interviews. Also remarkable is that GM vaccines are the future is ranked only with 41 points.
The three highest ranked CSFs in this category are added values, followed by two CSFs which could be assigned as barriers, resulting in a 3:2 ratio of added value against barriers in the top 5 (Figure 2.4).
2.3.2.3. Rules & RegulationsIt is noteworthy that most CSFs in rules & regulations are indicated as a short-term concern. Rules and guidelines are available is ranked as most important with 16% of the points, resulting in 66 points, and indicated as a short-term concern. Second, with 15% of the points (61 points) is fi rst products will be diffi cult, which is indicated as short-term concern. Third is GMO required envi-ronmental assessment and fourth, rules and regulations could be a barrier with 57 and 54 points, respectively. Both are indicated primarily as a short-term priority. Although the highest ranked CSF in this category is an added value, the others in the top 5 are barriers (Figure 2.4).
2.3.2.4. Societal Potential Acceptance is indicated as the most important CSF within this category with 73 points. Acceptance was described as a hurdle in the survey. No alternative vaccines are available, was ranked as the second most important CSF with 65 points, which is 15%. Both CSFs will be in the mid-term future. The third, fourth en fi fth CSFs are closely ranked representing 14%, 13%, and 12%, respectively. These three CSFs are all indicated to be of short-term concern. However, people forgot the need for vaccinations is also indicated to be a long-term concern. It is remarkable that the top 5 of societal CSFs are all hurdles (Figure 2.4).
46
Figure 2.5. Results of the survey. Total is the total amount of points given to the CSF by the KOLs. % of the points means the percentage of the total points in the category given to the CSF. Short-/mid-/long-term gives an indication on the future period of the CSF, the points indicate the amount of KOLs that indicated this peri-od. *Times mentioned in the interviews.
47
2.3.3. Target Market
Figure 2.6. depicts a prediction shift in target market once GM vaccines are introduced in the vac-cine fi eld. Target Market A illustrates the portion of the market of conventional vaccines that could be replaced by better GM alternatives. Target Market B represents the potential new markets that GM vaccines will create once there are vaccines developed for yet untargeted diseases.
Figure 2.6. Shift in Target Market after introduction of GM in the vaccine field. Modified from Blank and Dorf (2012) and applied to conventional and GM vaccines.
48
2.4. Discussion
This study provides a quantitative KOL analysis of the market potential of GM vaccines. Our anal-ysis reveals that CSFs for successful market introduction of GM vaccines can be grouped into four categories: technical potential, commercial potential, rules & regulations, and societal potential. The category rules & regulations requires immediate attention and consideration. Subsequently, the soci-etal potential demands intervention measurements. GM vaccines provide new market opportunities to combat previously untargeted diseases.
Currently certain rules and guidelines are available for GM vaccines. Nevertheless, acquiring the fi rst approval and overcoming the initial obstacles for market introduction remains challenging. Additional requirements and stricter rules and regulations for GM vaccine approvals such as envi-ronmental assessment and additional safety fi les, complicate the registration process, which conse-quently creates a barrier. KOLs consider a central registration procedure (e.g., European Medicine Agency) as a provisional solution. Only for the category rules & regulations all CSFs are short-term prioritized by KOLs. Virtually every CSF within this category deserves immediate attention and consideration. Although a growing body of science on GM vaccines could help to overcome these regulatory hurdles [175], an immediate intervention is required within this category, as many emerging GM vaccines are currently advancing through different clinical trial phases. Furthermore, from a KOL’s perspective, taking actions on the short-term will result in the gradual disappearance of regulatory hurdles.
Currently, many barriers against GM vaccines are allocated to the category societal potential. Al-though no traditional vaccines are available to prevent, treat or cure diseases such as HIV and ma-laria, an adverse opinion exists against GM technologies. As such, awareness needs to be raised and the public needs to be educated about the advantages of GM technologies. A possible approach to increase awareness is emphasizing the successful accomplishments of GM technology in other fi elds. For example, GM techniques are used in production of medicines such as insulin, food such as cheese, and modifi cation of bacteria to perform tasks as making biofuels, cleaning up oil spills, carbon and other toxic waste, and even to detect arsenic in drinking water [176-179]. Vaccines have contributed to a signifi cant reduction of many infectious diseases and the eradication of other dis-eases [9]. However, the general public seems to have forgotten the importance of vaccination. KOLs suggest that occurrence of discussion on GM vaccines is of short-term concern in order to address some of the CSFs in societal potential. Given the sensitive nature of GM, collaboration on multiple levels is required to introduce the subject for discussion.
49
The possibility to target previously untargeted diseases was ranked as the most prominent factor not only within its own category, but also among all other CSFs, irrespectively of the categories. Hence we would advocate that this factor might be the main driver behind research & development and public acceptance in GM vaccine fi eld. Literature has acknowledged the huge scientifi c efforts and promising results concerning GM vaccine development for yet untargeted diseases like, HIV [180], malaria [181], tuberculosis [182], rabies [183], Alzheimer[184], auto-immunity [185], allergies [186], and cancer [38]. This potential added value of GM vaccines contributes to possible reduction in costs in healthcare worldwide. Although development of these vaccines is of high priority, from a KOL’s perspective, developing safe vaccines is still a prerequisite and a short-term priority.
It is remarkable that creating new market opportunities is considered to be a continuous added value and not time dependent. Figure 2.6. illustrates how the GM vaccine market is positioned in comparison to the conventional vaccine market. GM vaccines are complementary to conventional vaccines and the two markets will exist parallel to each other. Nonetheless, according to the KOLs, these vaccines will probably make their fi rst entrance in high-end markets due to fi nancial interest of the companies developing vaccines. Target market B includes the most prominent CSF in technical potential, namely offers opportunities against previously untargeted diseases. This factor is also a required added value in the category commercial potential. Together with no alternative vaccines available from the societal potential category, these CSFs validate the new market opportunities and high unmet need.
In addition to development of vaccines for untargeted diseases, development of multi-targeted vac-cines also has high priority. Furthermore, safety is considered one of the most important CSFs while developing GM vaccines. These vaccines should also save time and provide higher effi cacy than cur-rent vaccines might offer. Other factors to keep in mind include, improved specifi city, cross-protec-tion, and fl exibility. From a KOL’s perspective, developing safe vaccines against untargeted diseases that are time saving is a short-term matter. Remarkably, KOLs considered developing multi-targeted vaccines important, but a long-term concern. Challenging nature of development and production of these multi-targeted vaccines makes them not of short-term interest, as more research is required.
Relating back to the interviews, technical potential was the most prominent category. Regardless of the background of the interview candidates, they were all experts and/or KOLs in the vaccine fi eld and thus possess extensive knowledge and expertise on technical aspects of GM vaccines. It appears that the experts from the industry are required to know the technical details of not only their product but also their competitor’s products. Additionally, experts with an academic background seemed to know the technical details in a more fundamental way, while the regulatory experts must understand technical features to be able to make guidelines and regulations.
50
The specifi c nature of categories commercial and societal potential might be an explanation of the lower occurrence during the interviews. Compared to technical potential, these two categories are more dependent on the background of the interview candidates. However, the candidates, irrespec-tive of their background, know some of the obvious arguments within these categories. The cate-gory rules & regulations was least mentioned by the interview candidates. Although guidelines and regulations are available for GM vaccines, they are constantly updated and sometimes practiced case-specifi c, which creates confusion.
A possible explanation for the high variety of arguments mentioned in the category technical po-tential is the diverse background of interview candidates, as they bring different arguments and perspectives to the table and view these from different angles. Remarkably, the variety of arguments mentioned in technical and commercial potential are comparable. Furthermore, the variety of argu-ments mentioned in rules & regulations are comparable to those from societal potential. This might be due to the fact that technical and commercial arguments are established and well defi ned, thus more tangible, while rules & regulations and societal arguments are more ambiguously defi ned, thus more intangible. Moreover, the rules & regulations and the societal potential arguments are straightforward. While in technical and commercial potential many variables play a role including stakeholder’s involvement, infl uence of various factors at different levels, high interest to be gained by different parties. The stakes are high, both literally and fi guratively.
Interpreting the results, some restrictions apply to this study. A methodological diffi culty was the in-ability to measure success due to the novelty of GM vaccines. Consequently, future research makes it possible to compare successful and un-successful market entries of GM vaccines, and back trace what CSFs were of infl uence, and when these factors played what role on the market.
Although CSFs are generally used to identify key areas of one product or company, the unique customized methodology for CSFs created for this study made it possible to generate a clear over-view of the GM vaccine market potential. Moreover, application of multiple methods during data gathering reinforced the results. Interdisciplinary approach of this study through the involvement of diverse international experts and KOLs forms another strength.
In conclusion, when it comes to the technical potential GM vaccines offer the possibility to target previously untargeted diseases. GM vaccines are the next step in vaccine development and once proven their added value they could replace conventional vaccines. Nevertheless, barriers still ex-ist, mostly in the categories rules & regulations and societal potential. The societal barriers could be overcome by emphasizing the current successful applications of GM technology in other fi elds. Furthermore, general public needs to become aware of the added value of GM and the necessity of vaccination. People tend to forget that it is a matter of life and death. The most profound concerns
51
are rules & regulations, which require immediate attention and intervention. Future research needs to focus on how these regulatory hurdles could be overcome, as many yet untargeted diseases are about to get targeted by emerging GM vaccines. This paper forms a quantitative stepping-stone that shows the immediate attention and intervention required in societal and regulatory parts of GM vaccines development.
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Appendix
Interview Questions1. Vaccine DevelopmentWhat is the technical potential of genetic modification in vaccine development?
2. Vaccine Manufacturersa. What is the large-scale production potential of genetically modified vaccines? Is this different from ‘traditional’
vaccines? b. What is the market potential of genetically modified vaccines? Is this different from ‘traditional’ vaccines?
3. Vaccine Registrationa. What is the registration potential of genetically modified vaccines? Is this different from ‘traditional’ vaccines? b. What is the application potential of genetically modified vaccines? Is this different from ‘traditional’ vaccines?c. Do current rules and regulations cover these novel vaccine technologies?
4. Hurdlesa. What are the hurdles in the development pipeline of genetically modified vaccines? b. How can these hurdles be overcome?
5. Societal a. Do you think that genetic modified vaccines will be influenced by societal factors, which and why? b. What could be a societal consequence/influence of developing genetically modified vaccines?
6. General Questionsa. How come that in contrast to the food sector, where GM is clearly labelled, GM in the vaccine field is rather
anonymous? b. What should be done to make sure that novel vaccine technologies (GMO or using GM) will evolve from ‘best
next thing’ to ‘bench’ to ‘bedside’? c. What are your future perspectives for the role of genetic modification in the vaccine?
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Chapter 3An Interdisciplinary Analysis of Genetically Modified Vaccines: From Clinical Trials to Market
Published as:Ramezanpour, B., Riemens, T., van de Burgwal, L. and Claassen, E. International Journal of Clinical Trials. 2015;2(4). DOI: 10.18203/2349-3259.ijct20151235
56
Abstract
Background: Immunization is considered the most effective strategy for infectious disease control and maintaining global health. Conventional vaccines have successfully targeted a broad spectrum of pathogens. However, a large number of untargeted diseases still remains. Introduction of novel genetically modifi ed (GM) vaccines allow development of new improved vaccines and immuno-therapeutics. Moreover, GM vaccines can also target non-communicable diseases outside the range of infectious diseases, including cancer, autoimmune diseases, and allergies.
Methods: We compiled novel and unique datasets encompassing data from literature, patent doc-uments, clinical trials, and vaccine registers in order to provide a thorough overview of the GM market.
Results: Based on patent data, we found that most patent applications were fi led in North America, Asia, and Europe, which coincides with the locations of the largest companies and institutes. Look-ing at clinical trial data we forecast marketing of two next generation GM vaccines, targeting cancer and malaria. In addition, we calculated phase transition success rates of 82% (phase 1 – 2) and 76% (phase 2 – 3).
Conclusion: These fi ndings indicate viable regions for GM vaccine research and development. Phase transition success rates of 82% (phase 1 – 2) and 76% (phase 2 – 3) predict a relatively high chance of marketing approval. Increased registrations of GM vaccines complemented by rising numbers of patent applications suggest global growth of the GM vaccine market, which currently holds a proportion of nearly 20% of the total vaccine market.
57
3.1. Introduction
Immunization has been an important factor in providing protection and maintaining and improving global health, but its full potential has not yet been reached [1, 2]. Vaccination endeavours have resulted in successful accomplishments, including eradication of smallpox and 99% decrease in polio incidence [3]. In addition to eradication of some communicable diseases, inter alia, a signifi -cant reduction of communicable diseases and a further annual prevention of an estimated 6 million deaths worldwide has been realized [4, 5]. Although, vaccines have been targeting a broad repertoire of infectious diseases, a large number of untargeted diseases remains undeniable, including the “big three”; malaria, tuberculosis, and HIV/AIDS [29]. In addition to infectious diseases, a variety of disorders and non-communicable diseases emphasize the necessity for new and/or improved vac-cines [29, 187]. Conventional vaccines have proven their success, nonetheless, in order to meet the demand of new vaccines, deployment of novel technologies is required. Novel technologies are not only desired for improvements in medical i.e. immunological or clinical outcomes, their con-tribution to societal outcomes are of great value as well [5, 47]. Contributions to society will, for example, consist of health-care cost savings, extending life expectancy, improved quality of life, and equity enhancement [5].
Advanced developments in bioengineering including recombinant technology, sequencing, and cell and tissue culturing techniques contributed to vaccine development and provide many yet unex-plored possibilities in vaccine development against virtually all pathogens [36, 37]. Recombinant technology allows the production of tailor made genetically modifi ed (GM) vaccines and enables targeting diseases such as cancer, autoimmune diseases, allergies, and addictions [29]. GM vaccines allow for both relatively effi cient production and selected increased immunogenic properties in vac-cines. The fi rst recombinant human vaccine, Recombivax HB® was approved in 1986 and was fol-lowed by Flumist®, Flublok®, and IMOJEV® [188-191]. Additionally, a landmark in cancer immu-notherapy was the FDA approval of Dendreon’s prostate cancer vaccine Provenge® in 2010 [192].
Previous studies described changes and trends in the biopharmaceutical and vaccine market, for instance the dramatic decrease in the number of companies that produce vaccines [193]. It should be noted that the GM vaccine market has not been described in detail and prior studies in the fi eld do not provide insights in its current state of global research and development. Furthermore, multiple concerns regarding the vaccine market are expressed in literature, including limited viable markets, intellectual property complications, and the restrictive aspects of rules and regulations [106, 107, 152]. Results from our previous research on one particular GM technique, namely modifi ed vaccinia virus Ankara (MVA) platform, stress the same concerns regarding the total vaccine market [160].
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Considering the changes, developments, and concerns in the fi eld of vaccines, a thorough overview of the current GM vaccine market and a description of its prospects for future growth was needed. In order to achieve this, we developed new and unique datasets for an interdisciplinary analysis of the current GM vaccine market. The unique datasets include data from literature, patent documents, clinical trials, and registered vaccines. Here we present an overview of the global GM vaccine mar-ket, revealing trends in patent applications, vaccine approvals, and additionally next generation GM vaccines forecasting.
3.2. Methodology
The methods applied in this study were performed in different stages to provide a thorough and complete overview of the genetically modifi ed (GM) vaccine market. First a literature study was conducted to obtain search-specifi c-terminology on GM vaccine publications. Subsequently, pat-ents, clinical trials, and registered vaccines were explored and three separate datasets were compiled for the purpose of in-depth analysis.
3.2.1. Literature Search
To confi rm the current knowledge concerning GM vaccines we grouped review papers in multiple online search engines, including Embase, Medline, Cochrane, Web-of-science, PubMed, and Goo-gle scholar. Searches were restricted to English language publications. Medical subject headings (MeSH) combined with Boolean Operators search strategy was employed as the initial basis for syntax development [194, 195]. The fi nal strategy and results were quality controlled by an inde-pendent Biomedical Information Specialist from Erasmus Medical Centre medical library. Appendix A provides supplemental information on coding of the search terms for different search engines. Subsequently, 511 duplicates were removed. Subsequent selection from 1245 remaining papers was done based on the following criteria:
- Only review articles that described vaccine technologies- Only studies in the time frame 2009-2014- Only review articles that described novel vaccine technologies
After deduplicating the obtained data and excluding non-relevant studies 87 literature reviews re-mained for further analysis (Table 3.1).
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3.2.2. Terminology
Although the terms “conventional vaccine” and “GM vaccine” are often used in the vaccinology fi eld, these terms are used inconsistent and interchangeable. We have drafted the following delinea-tion of GM vaccine defi nitions to enable proper selection and interpretation of relevant data (Table 3.3).
Conventional vaccines can be defi ned as vaccines based on the wild type pathogen or a part thereof, be it live-attenuated, inactivated or a single purifi ed antigen [196]. Genetically modifi ed vaccines are categorized based on the following defi nition: vaccines produced and/or developed using genetic modifi cation. For examples: recombinant antigen(s), (self-amplifying) DNA/RNA, and vaccines that consist of genetically modifi ed organisms [2].
3.2.3. Patent Analysis
Data on patents concerning GM vaccines was retrieved from Espacenet, an all-inclusive worldwide database providing access to more than 90 million patent documents. Since patents are classifi ed into various technological classes according to the Cooperative Patent Classifi cation (CPC) system,
Table 3.1. Literature study databases, results, and adopted selection criteria within GM study scope.
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a selected group of three CPC codes was used to focus on GM vaccines (Table 3.2). In order to fo-cus on vaccines, a CPC code indicating “medicinal preparations containing antigens or antibodies” was used, (A61K39/xx). The focus on GM criteria was obtained by using two CPC codes indicat-ing genetic engineering, subsequently including relevant genetically modifi ed vaccines regarding gene therapy (C12N15/xx and A61K48/xx). Search criteria included CPC codes combined with the search terms vaccin* and genetic* OR modif* (Boolean operator). In the search of patent literature all regular subclasses including higher series and relevant subclasses were taken into account to ensure the completeness of patent data. Higher series and subclasses delineate aspects of the regular classes, e.g. technologies, functional features etc.
Table 3.2. Predominant CPC groups in GM patent literature.
Accuracy in patent analysis was assured by comparing patent priority numbers and deduplicating patents falling under the same patent family. Documents were classifi ed as priority documents based on the oldest application and publication data and were then categorized as mother patents. Applica-tion of this methodology resulted in 40,308 unique mother patents worldwide.
For the purpose of investigating market anticipation of companies and institutes, only patents pub-lished in or after 2005 were included and all published documents were extracted from Espacenet, resulting in 15,977 relevant patent documents. Completeness of data was achieved by the iterative methods used in data extraction. CPC codes from key-word-extracted documents were fed back into the database resulting in new hits, which were then deduplicated. The fi nal dataset was quality controlled by an independent biomedical intellectual property specialist from The Netherlands En-terprise Agency (RVO), a part of the Ministry of Economic Affairs.
Subsequently, these 15,977 patent documents were merged based on their geographical location of application. The dataset obtained contained information on patent applicants, date of application, and country codes where patent applications were fi led. Finally, identifi cation of all published docu-
61
ments was done based on their publication number and kind codes. Kind codes function as patent de-scriptor, to distinguish the patent status and indicate the number of times a document was published. Countries were then categorized based on the region they belong to, resulting in the total number of applied and granted patents in the following continents: North America, South America, Europe, Africa, Russia, Asia, and Oceania. The results of this analysis are shown in Figure 3.1. representing continental patent density including both applied and granted patents, and the top 15 companies and institutes that own the most GM vaccine related patents. The color gradient in Figure 3.1. was based on the total number of patents that were fi led in each continent.
GM patent fi ling rates were explored by adopting the same patent data search criteria that were used to make Figure 3.1., as described above. The year 1970 was selected as starting point and patent fi ling dates were grouped per year. The resulting number of patent documents per year was plotted and the timeline is shown in Figure 3.3.
To analyze only the relevant GM vaccine indications that are described in patent literature the search for relevant documents was narrowed by only using CPC code A61K39/xx and C12N15/xx (number 1 and 2 in Table 3.2), and only patent documents fi led in or after 2005 were included (Table 3.4). The GM vaccine indications of patent documents were categorized in infectious disease, cancer, allergy and immune system, genetically related disease, and multi-purpose, based on their CPC codes and in ambiguous cases the patent descriptions. Hereafter, an analysis was conducted to show which com-panies and institutes are involved per indication, based on the number of patents they possess, shown in Figure 3.4. Finally a distinction was made between companies and institutes in order to explore what indications they are currently aiming on, and to explore future indications in the development pipeline. In addition, this analysis was done to illustrate the relatively young nature and growth of the GM vaccine market.
3.2.4. Clinical Trial Analysis
Clinical trials were analyzed in this study to provide an overview of the current development state of GM vaccine technologies and their indications in the different phases of clinical development. Subsequently, clinical trial data collected from clinical trial databases was used as future prediction tool, and enabled us to predict possible future vaccines. This prediction was made based on the frequency of indications in each phase combined with the current phase transition success rates of clinical trial phases.
Data on clinical trials for this study were obtained from the WHO International Clinical Trials Reg-istry Platform, which provides a complete overview of registered clinical trials worldwide [197].
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The WHO International Clinical Trials Registry Platform provides data on exclusively active and on-going medical studies, which was used for dataset compilation. Specifi c search terms on the topic were used in combination with the term ‘vaccine’ to create a dataset related to GM vaccines (Table 3.3), which resulted in 1146 clinical trial records. The clinical trial dataset obtained contains infor-mation on starting dates, development phases, indications and specifi c targets.
Data analysis was conducted on the clinical trial pipeline (phase 1 to 4) for GM vaccine technolo-gies, therapies and treatments registered between November 1st, 1999 and March 5th 2014. The num-ber of clinical trials per development phase was counted and the top fi ve most frequent indications per phase were selected for further analysis. To illustrate a total overview, marketed GM vaccines that proceed testing in phase four were included, and are described in the next part of this method-ology. The results of these analyses are shown in Figure 3.2.
Table 3.3. Clinical trial search terms, results, and dataset variables.
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3.2.5. Registered Vaccines
Data on all currently registered vaccines for human use were primarily gathered from various gov-ernmental databases (Table 3.4). Registered vaccines for human use were obtained from the fol-lowing regions: USA, EU, BRICS countries, Japan, and Australia. Data from India and Russia were excluded from this analysis due to a lack of information on approval dates and the general inacces-sibility of Russian registers. The data search resulted in 821 registered vaccines, approved between 1937 and 2013. According to the dataset the fi rst GM vaccine approval was granted after 1988, consequently selected as starting point for Figure 3.3.
After deduplication the remaining 797 registered vaccines were categorized in two groups ‘con-ventional vaccines’ and ‘GM vaccines’ based on the information provided by the manufacturers. This categorization was conducted in order to illustrate the difference in approval timelines of both groups and the possible increase of GM vaccines approval.
3.3. Results
3.3.1. Patent Literature
In total 15,977 patent documents were included in this study, all fi led in or after 2005. Patent doc-uments were indexed by country code and subsequently grouped. Figure 3.1. illustrates that over the past 10 years most patents were fi led in North America, Asia, and Europe, refl ected by color gradient. Patent documents fi led under country code WO (World Intellectual Property Organization; WIPO) and EA (Eurasian Patent Organization; EAPO) are not included in this fi gure, since they are spread over multiple countries in various regions. WO and EA country codes account for 2713 and 153 numbers of patents, respectively.
The illustrated companies and institutes were identifi ed by analyzing information on patent appli-cants, and were included based on the total number of GM vaccine patents they own, regardless of where the documents are registered. The cut-off point for inclusion was determined to be 99+ patents and resulted in 17 top companies and institutes. Numbers indicate the share of patents in percentage of the total number of patents fi led in or after 2005. We identifi ed GSK (4,9%), Novartis (4,5%), and Merial (2,2%) to be the top 3 companies.
Accompanying Figure 3.1., the top companies and institutes per indication group are shown in Fig-ure 3.4. Indications mentioned in patents were categorized in fi ve groups, based on the information
64
Table 3.4. Registered vaccine databases and results.
provided in the patent descriptions. Only patent documents fi led in or after 2009 were included, and the search terms were narrowed, using only the fi rst two CPC codes (Table 3.2). The ranking is based on the number of patents the companies and institutes own. In this fi gure, purple circles indicate companies and the green circles represent institutes.
3.3.2. Clinical Trials
A total of 1146 clinical trials were included in this study. Figure 3.2. shows the number of active GM vaccine clinical trials per phase. The number of trials is gradually decreasing towards phase 4. Snapshot phase transition success rates are calculated between phase 1, 2, and 3, indicating thepercentage of clinical trials that proceed testing in the next phase. Phase 1 counts 438 clinical trials,and a percentage of 82% is expected to proceed testing in phase 2. Of 358 clinical trials in phase2, 76% is expected to proceed testing in phase 3. The ‘registered’ column represents the number ofregistered GM vaccines that are currently available on the market. Currently, 78 of 124 registeredvaccines are testing in phase 4.
Per clinical trial phase the top 5 most frequent GM vaccine indications were identifi ed and are vi-sualized in phase specifi c pie charts. Cancer indications were present in the top most frequent GM vaccine indications of phase 1 (n=90) and phase 2 (n=106). Malaria indications (n=19) were found to be part of the most frequent GM vaccine indications of phase 1.
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Figu
re 3
.1. P
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66
3.3.3. Registered Vaccines and Patents
Vaccine registration data between 1988 and 2013 and patent fi ling data between 1970 and 2015 were included in this study. In total 797 registered vaccines were analyzed (conventional and GM) and a timeline shows an upward trend in vaccine approvals starting in 2000 (Figure 3.3a). The same trend occurs in both GM vaccine approval and GM vaccine patent fi ling, respectively (Figure 3.3b and 3.3c). GM vaccines were found to represent nearly 20% of the total number of registered vaccines in the year 2013.
In total 40,308 unique patents were included to explore the rate of GM vaccine patent fi ling world-wide. Figure 3.3c. illustrates a rising trend, signifi cantly increasing in the year 2000, which cor-relates with Figure 3.3b. Figure 3.3. illustrates the general growth of the GM vaccine market.
67
Figu
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68
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69Figu
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.4. T
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70
3.4. Discussion and Conclusions
This study provides an interdisciplinary overview of the GM vaccine pipeline, reaching from patents to registered vaccines. Here we demonstrate unexpected high phase transition success rates of GM vaccines in clinical trials, 82% (P1-P2) and 76% (P2-P3). This study also indicates a signifi cant increase of global GM vaccine market share (20%), supported by rising trends in patent applications and vaccine registrations. The most viable regions for GM vaccine markets are North America, Asia, and Europe.
Prior to this study, no comprehensive research was conducted to investigate the current state of GM vaccine fi eld. Therefore, this study was designed to provide a thorough overview of the current state of research and development (R&D) with respect to medical studies, intellectual property protec-tion, and vaccine registrations.
Remarkable high phase transition success rates are revealed from the analysis of clinical trial phases. Comparing to previous studies on biopharmaceuticals, the snapshot phase transition success rates that we present here are relatively high, P1-P2 82% and P2-P3 76% [198, 199]. The stakeholders that are willing to invest in biopharmaceuticals will assess the likelihood of success before making huge investments. Therefore we postulate that the observed high phase transition success rates will create momentum and provide versatile opportunities in GM vaccine R&D and eventually in the vaccine fi eld. Consequently, high rates of market approval may contribute to solving unmet medical needs, which eventually leads to societal benefi ts.
A signifi cant increase of GM vaccine approvals was observed in the period of 1988 to 2013. GM vaccines currently take up 20% of the global vaccine market. Vaccine approval timelines illustrates an upward trend in the number of registered GM vaccines, which is accompanied by an upward trend in GM vaccine patent fi ling. These upward trends indicate the occurrence of several infl uential changes within the GM vaccine fi eld with a starting point of 2000-2001. Literature provides sever-al reasons behind this instant increase, for example, announcement of the Global Fund project by WHO in the beginning of the year 2002, which has resulted in signifi cant increases in funding [200]. Furthermore, the Immunization Vision and Strategy (GIVS) developed by WHO and UNICEF and Bill & Melinda Gates Foundation awards in 2001 to develop drugs and vaccines through public-pri-vate partnerships, which led to increased spending on vaccines worldwide [201, 202]. A decline in GM vaccine share was observed in the period 2000-2001 (Figure 3.3a), which is caused by the exponential increase in conventional vaccine registrations in that same period. The total number of registered vaccines infl ated, which consequently resulted in a smaller GM vaccine share. Overall, the continuous growth of GM vaccine market within the vaccine fi eld indicates an increase in GM
71
vaccine market share.
The most viable GM vaccine markets are located in North America, Asia, and Europe. The regions were compiled of separate countries that emerged from our data (Figure 3.1) and chosen based on the most frequent discussed continental pharmaceutical markets. This could be explained by the fact that the most knowledge and resources are to be found in these regions [203]. Since North America is the leading region in patent possession, most GM vaccine related patents are fi led here, which may be due to the size and capacity of the current pharmaceutical market in the US [204]. Rules and regulations in Russia and Africa make it diffi cult to fi le a patent in these regions, which results in a lower number of observed patent applications. Moreover, combined with unfavorable rules and regulations, a trailing pharmaceutical market could explain the cause for lower numbers of patent applications [107, 205]. Subsequently, the number of patents identifi ed the leading companies and institutes in the fi eld of GM vaccines. GlaxoSmithKline (4,9%), Novartis (4,5%), and Merial (2,2%) were identifi ed as largest stakeholders based on the number of patents they own. Jointly, they are re-sponsible for 11,6 % of the total number of GM vaccine related patents, regardless of where patents were applied. Our analysis reveals that most companies and institutes reside in the United States (Figure 3.1). The involvement of “Big Pharma” companies shows the viability and domineering nature of the GM vaccine market [206]. Companies are found to dominate the indication groups “in-fectious disease” and “allergy and immune system” (Figure 3.4). Institutes and universities seem to dominate the newer indication groups “cancer”, “genetically related disease”, and “multi-purpose”.
Considering the GM vaccine market’s viability and growth, we predict the registration of GM vac-cines targeting cancer and malaria in the coming years. The clinical trial analysis was performed in bulk, which enabled us to accurately forecast future GM vaccines. We assume that a large group of clinical trials targeting a single disease is more likely to receive one or several marketing approvals [199]. New indications, cancer and malaria, were only present among the group of most frequent indications of phase 1 and phase 2.
The fi ndings of this study should be interpreted in the light of several limitations. First, due to the fact that the fi eld of GM vaccines has not been investigated prior to this study, a clear defi nition/delineation of what should be considered a GM vaccine is lacking. Therefore, we designed clear search criteria in this study, based on different defi nitions of GM vaccines found in literature, in order to reduce terminology and defi nition confusion. The search criteria were used to delineate the topic of our study, but might have led to the exclusion of relevant data or studies. To validate our data, multiple certifi ed independent professionals have checked our methodology and the datasets created for this study.
72
Second, patent documents were retrieved from Espacenet by adopting the use of several CPC codes related to GM vaccines. We chose these CPC codes based on the terminology of GM vaccines that is described in literature. We cannot claim completeness of data because we could only apply our search criteria on the public domain of information. Since this concerns a patent database, the more recent patent documents were not included in our dataset because they only become public 18 months after fi ling. Additionally, patent literature is often written in a broad context to avoid being bound to specifi c technologies or indications. The lack of clear indication descriptions led to narrow-ing the search criteria in order to compile a smaller specifi c dataset that was used for construction of Figure 3.4. Only CPC code A61K39/xx and C12N15/xx (Table 3.2) were included, and a period of 5 years was selected.
Finally, clinical trials ought to be removed from the WHO ICTRP database after termination or completion, which is done on a weekly or monthly basis (varies per country). Since the dataset that was used for clinical trial analysis is a snapshot dataset, there is a probability that erroneous clinical trial data has been included in relatively limited amounts.
In conclusion, this study provides evidence on the growth of worldwide GM vaccine market [207, 208]. Advances in research and development and the next generation of GM vaccines can be an-ticipated in the coming years. We forecast the market entry of cancer vaccines and the targeting of malaria by GM vaccines. Additionally, this study identifi ed viable markets for both big pharma-ceutical companies and pioneering institutes. The results of this study point out a compelling need of a clear defi nition of GM vaccines, and future research on GM vaccine production platforms is recommended.
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AppendixEmbase.com 945 ('genetic immunization'/de OR 'DNA vaccine'/de OR 'live vaccine'/de OR 'virosome vaccine'/de OR 'recombinant vaccine'/de OR 'virus like particle vaccine'/de OR (((gene* OR live OR protein*) NEAR/3 (vaccin* OR immuni*)) OR ('virus like' NEXT/1 particle*)):ab,ti OR (('DNA modification'/de OR dna/exp OR rna/exp OR 'genetic recombination'/exp OR 'recombinant protein'/exp OR 'virus vector'/exp OR 'bacterial vector'/de OR virosome/de OR (genetic* OR attenuat* OR enigneer* OR modif* OR DNA OR rna OR vector* OR recombin* OR chimeric* OR virosom*):ab,ti) AND (vaccine/exp OR Vaccination/exp OR immunization/exp OR (vaccin* OR immuni*):ab,ti))) AND ('systematic review'/de OR 'meta analysis'/de OR ((systematic NEAR/3 review*) OR (meta NEXT/1 analy*)):ab,ti)
Medline (OvidSP) 364 (exp "Vaccines, Synthetic"/ OR "Vaccines, Attenuated"/ OR "Vaccines, Virosome"/ OR (((gene* OR live OR protein*) ADJ3 (vaccin* OR immuni*)) OR ("virus like" ADJ particle*)).ab,ti. OR ((exp dna/ OR exp rna/ OR exp "Recombination, Genetic"/ OR exp "Recombinant Proteins"/ OR exp "Genetic Vectors"/ OR Virosomes/ OR (genetic* OR attenuat* OR enigneer* OR modif* OR DNA OR rna OR vector* OR recombin* OR chimeric* OR virosom*).ab,ti.) AND (exp vaccines/ OR exp Vaccination/ OR exp immunization/ OR (vaccin* OR immuni*).ab,ti.))) AND ("meta analysis".pt. OR ((systematic ADJ3 review*) OR (meta ADJ analy*)).ab,ti.)
Cochrane DARE 7 ((((gene* OR live OR protein*) NEAR/3 (vaccin* OR immuni*)) OR ('virus like' NEXT/1 particle*)):ab,ti OR (((genetic* OR attenuat* OR enigneer* OR modif* OR DNA OR rna OR vector* OR recombin* OR chimeric* OR virosom*):ab,ti) AND ((vaccin* OR immuni*):ab,ti)))
Web-of-science 323 TS=(((((gene* OR live OR protein*) NEAR/3 (vaccin* OR immuni*)) OR ("virus like" NEAR/1 particle*)) OR (((genetic* OR attenuat* OR enigneer* OR modif* OR DNA OR rna OR vector* OR recombin* OR chimeric* OR virosom*)) AND ((vaccin* OR immuni*)))) AND ("systematic review*" OR "meta analy*"))
PubMed publisher 8 ((((gene*[tiab] OR live[tiab] OR protein*[tiab]) AND (vaccin*[tiab] OR immuni*[tiab])) OR (virus like particle*[tiab])) OR (((genetic*[tiab] OR attenuat*[tiab] OR enigneer*[tiab] OR modif*[tiab] OR DNA[tiab] OR rna[tiab] OR vector*[tiab] OR recombin*[tiab] OR chimeric*[tiab] OR virosom*[tiab])) AND ((vaccin*[tiab] OR immuni*[tiab])))) AND (((systematic review*[tiab]) OR (meta analy*[tiab]))) AND publisher[sb]
Google Scholar "genetic|DNA|live|attenuated|virosome|recombinant|engineered|modified vaccine|vaccines|immunization|immunisation "systematic review"|"meta analysis"
74
Chapter 4Vector-based Genetically Modified Vaccines:
Exploiting Jenner’s Legacy.
Published as:Ramezanpour, B., Haan, I., Prof. Dr. Osterhaus, A. and Prof. Dr. Claassen, E. Vaccine. 2016 (In press)
76
Abstract
The global vaccine market is diverse while facing a plethora of novel developments. Genetic modifi cation (GM) techniques facilitate the design of ’smarter’ vaccines. For many of the major infectious diseases of humans, like AIDS and malaria, but also for most human neoplastic disor-ders, still no vaccines are available. It may be speculated that novel GM technologies will signifi -cantly contribute to their development. While a promising number of studies is conducted on GM vaccines and GM vaccine technologies, the contribution of GM technology to newly introduced vaccines on the market is disappointingly limited.
In this study, the fi eld of vector-based GM vaccines is explored. Data on currently available, actually applied, and newly developed vectors is retrieved from various sources, synthesised and analysed, in order to provide an overview on the use of vector-based technology in the fi eld of GM vaccine development. While still there is only a single vector-based vaccine on the human vaccine market, there is ample activity in the fi elds of patenting, preclinical research, and different stages of clin-ical research. After the approval of the fi rst vectored human vaccine, based on a fl avivirus vector, vaccine vector technology, especially based on poxviruses and adenoviruses, holds great promise for future vaccine development. It may lead to cheaper methods for the production of safe vaccines against diseases for which no or less perfect vaccines exist today, thus catering for an unmet medical need. After the introduction of Jenner’s vaccinia virus as the fi rst vaccine more than two centuries ago, which eventually led to the recent eradication of smallpox, this and other viruses may now be the basis for constructing vectors that may help us control other major scourges of mankind.
77
4.1. Introduction
Ever since the discovery by Edward Jenner, more than two centuries ago, that vaccinia virus could be used to protect people from variola, vaccines have been of utmost importance in fi ghting in-fectious diseases [209], as they are the most cost effective tools for the prevention of infectious diseases. To date several types of vaccines are available, including live-attenuated, inactivated, sub-unit or split, toxoid, conjugate, DNA, and recombinant vectored vaccines [23]. While conventional vaccines, like live-attenuated or inactivated wild-type, have successfully protected vaccinees from various infectious diseases over the years, they are not available for most infectious diseases and for those who cannot afford them. Conventional vaccine production methods, which predominantly use viruses and bacteria or their products, produced with classical production methods, are labour intensive, expensive, and time consuming, while some of the desired antigens cannot be produced in this way [2]. Furthermore, highly virulent pathogens can only be produced under expensive special safety conditions, while attenuated agents may have a tendency of reverting to their pathogenic form and can usually only be used in fully competent individuals [35].
To overcome the challenges of traditional vaccine production, the development and use of novel generations of vaccines, like those based on GM technologies, are being considered more and more frequently. The advent of these novel technologies may also be expected to create opportunities for the development of vaccines targeting new indications and/or application fi elds. Since there are many major indications for which no or only unsatisfactory vaccines are available, like AIDS, ma-laria, and tuberculosis, the exploitation of novel technologies, like the use of vector-based vaccine candidates or vector-based production of protective antigens, may eventually allow us to fi ll the gap of this unmet medical need. To date several vaccines for humans, based on GM technologies have been licensed (for review see e.g. [210-213]) and a lot of candidates are in the pipeline.
An interesting approach for vaccine development based on GM technology is the use of vectors, which carry selected genes encoding antigens that induce protective immunity. They can either be used as vaccines proper, or for the production of antigens that are incorporated in vaccines. The pres-ent paper only deals with vectors that are actually used as vaccines and not just for the production of immunogens. Vectors can be classifi ed in three different categories: viral, bacterial, and plasmid [214]. Vectors can either be fully replicative or only cause abortive infection, still allowing the ex-pression of the desired immunogens. They can be administered either parenterally or via mucosal membranes [215]. A major advantage of vector-based GM technology, is that the immunogens of in-terest are de novo synthesized, thus not only allowing for the induction of antibody and T helper cell mediated immunity, but also for the induction of protective cytotoxic T cell responses, mimicking a natural immune response against the immunogen. This balanced immune response opens pathways
78
that were previously inaccessible with traditional vaccine technology using ‘non-live’ immunogens. Especially the induction of CD8+ CTL responses may be of particular interest for vaccines against certain virus infections and cancers [83]. Our previous study provides additional insights regarding the strengths, weaknesses, opportunities, and threats of such technology [160].
In the present study, the potential of vector-based vaccines is evaluated. Data obtained from litera-ture, granted patents, and different stage clinical trials are synthesized and analyzed in the light of data from currently registered vaccines providing an overview of the potential of currently used and newly generated vectors in the fi eld of vaccine development. The data suggest that vector-based vaccines may offer a cost-effective alternative for the production of safe vaccines against diseases for which no or less perfect vaccines exist today, thus catering for a huge unmet medical need.
4.2. Methodology
The methods applied in this study have been split in four different stages: evaluation of literature, patents, clinical trials, and registered GM and non-GM vaccines. Each stage was individually exam-ined in detail and the complete data set was compiled. These stages were decided upon in order to provide a complete overview of the genetically modifi ed (GM) vector-based vaccine pipeline and market.
4.2.1. Literature Research
To map the early research stage of emerging vectors, a literature search was performed on avail-able candidate vector vaccine studies. Data was collected on various types of GM vectors and their properties, as mentioned in both research publications and reviews. The search was con-ducted using a combination of Embase, Medline, Web-of-science, Pubmed, Cochrane, and Google Scholar. Medical Subject Headings (MeSH) and Boolean Operators were utilised in or-der to develop a basis for the syntax. The search was restricted to publications/translations in English. This syntax and the search results were analysed by an independent biomedical infor-mation specialist from Erasmus Medical Centre medical library. Additional information on the search terms for different search engines can be found in the supporting information (S1).
A total of 1756 hits were obtained [39]. 511 duplicates were removed, resulting in 1245 publications. Restrictions for further analysis included articles not describing vaccines or vaccine technologies, and articles not describing novel vaccine technologies. Publications were restricted to those pub-lished in the period 2009-2014. The total set contained 87 review articles on GM vaccines.
79
In order to retrieve more papers on vector-based GM vaccine candidates, an additional search was performed on Pubmed including relevant search terms “vaccine”, ”vector” and ”GM”. Reviews were retrieved adding the search term “review” to the previously mentioned terms or by searching for reviews only. Papers dating from the period 1998 to 2014 were collected and 18 new results were added to the previous 87 (Table 4.1).
Table 4.1. Results of literature search.
Database Hits Hits After Deduplication Embase.com 945 940 Medline (OvidSP) 364 97 Web-of-science 323 123 PubMed publisher 8 4 Cochrane DARE 7 2 Google scholar 100 79
Total initial search 1756 1245 Total set after applying restrictions 87 Additional vector search results 18 Final set used for detailed analysis 38
A total of 38 publications, specifi cally on the topic of vector-based vaccines, were selected from this pool and analyzed in detail. The clinical studies and reviews evaluated are shown in Table 4.2., and the results of this literature study can be found in Table 4.6.
Table 4.2. List of clinical studies and reviews evaluated.
Altenburg et al., 2014 Nébié et al., 2014 Arroyo et al., 2001 Nieto et al., 2014 Babu Appaiahgari et al., 2010 Ondondo, et al., 2014 Banchereau et al., 1998 Pandey et al., 2010 Bermudez-Humaran et al., 2013 Paris et al., 2014 Brave et al., 2006 Ploquin et al., 2012 Chin’ombe et al., 2013 Rimmelzwaan et al., 2009 Choi et al., 2013 Robertson et al., 2013 Cottingham, et al., 2013 Rollier et al., 2011 Croyle et al., 2008 Saxena et al., 2013 Dicks et al., 2012 Smith et al., 2011 Dung et al., 2012 Tatsis et al., 2004 Ewer et al., 2013 Tripp et al., 2014 Gomez et al., 2011 Ulmer et al., 2006 Hessel et al., 2011 Ura et al., 2014 Kreijtz et al., 2009 Verheust et al., 2012 Lundstrom, 2014 Weaver et al., 2013 Mooney et al., 2013 Williams et al., 2009 Myhr et al., 2012 Youngjoo et al., 2013
80
4.2.2. Search for Patents
Patents have multiple technology classifi cations based on their claims, and since they are classifi ed in technological classes, patents related to GM vaccines were collected into a database. Patent data concerning GM vaccines was retrieved from Espacenet, which provides access to over 90 million patent documents worldwide [216]. Search terms used were “Medicinal preparations containing antigens or antibodies”, “Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy” and “Mutation or genetic engineer-ing; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, prepa-ration or purifi cation; Use of hosts therefore”, in combination with search words vaccin* (Boolean operator), and genetic* OR modif*, respectively. The results were deduplicated based on the priority numbers. The syntax and search results were analyzed by a patent specialist from the Netherlands Enterprise Agency (RVO) [217], a governmental institution in the department of Economic Affairs. A total number of 40.308 unique patents were found and an original database was created, including all classes and subclasses.
Table 4.3. Patent search.
81
As patent information in the patent database is condensed into Cooperative Patent Classifi cation (CPC) codes, the previous search was repeated, combining the previous search with CPC codes for vectors and search term vaccine*. A total of 96 unique CPC codes were used, resulting in 32.738 vector-based vaccine patent documents. As CPC codes describe the classifi cation in each technical area on various levels, the defi nitions of the CPC codes used were retrieved from Espacenet, and a comprehensive table was created including the CPC codes, their defi nitions, and the number patents containing this specifi c code. All search terms can be found in Table 4.3. and the results are illustrat-ed in Figure 4.1. It should be noted that the method used for this search was iterative, the original data was used to reproduce search terms for the vector search. Because of this iterative method, a complete dataset was collected.
4.2.3. Search for Clinical Trials
Clinical trials data (phase 1, 2, and 3) was gathered from the World Health Organization Interna-tional Clinical Trials Registry Platform, which currently lists 191,038 studies in 190 countries (data retrieved: May 29th, 2015 [218]). Search terms applied can be found in Table 4.4. The results were deduplicated based on the Trial ID number. A total of 1146 unique clinical trials were used to create an original database.
Table 4.4. Clinical trials search.
Database Search Terms Variables WHO International Clinical Trials Registry Platform
“Attenuated NOT Live-attenuated” “Development phase” “Chimeric” (1, 2, or 3) “DNA”“Engineered” “Expression system” “Genetic”“Genetically Engineered” “Indication” “Genetically Modified” “Live” “Production system” “Live-attenuated”“Modified” “Specific target” “Recombinant Protein” “Recombinant” “Technology Class” “RNA”“Vector” “Virosome” “Type of Organism” “VLP”
Total number of vaccines after deduplication 1146 Of which GM vaccines 762 Of which vector-based GM vaccines 226
82
To provide a detailed outlook on the use of viral vectors in GM vaccine trials, the clinical trials database was analyzed in a vector specifi c way. The progress of vector-based vaccines as a share of all GM vaccines was examined, as well as the spread of specifi c vectors and their prevalence for specifi c indications. Data entries on vector trials were sorted by their indication and frequency, and the 10 most prevalent indications were selected to form a new data subset. This subset was analysed on the specifi c types of vectors used per indication, and a comparison was made for these indications with the complete dataset of all GM vaccines. The results are shown in Table 4.7.
4.2.4. Search for Registered GM and non-GM Vaccines
Data concerning registered vaccines was obtained from governmental databases of the following regions; USA, EU, Brazil, India, China, South-Africa, Australia, and Japan (Table 4.5). BRICS countries were selected (only four out of fi ve BRICS countries were included, Russia being omitted due to the general inaccessibility of Russian registers), because of their rapidly growing economies and potential for the industry. Currently, a total number of 821 registered human vaccines are on the market. After deduplication, 797 registered vaccines remained, of which 124 related to GM vaccines. Boolean search terms used to classify vaccines were: “Genet*”, “Modif*”, “Engin*”, “DNA/RNA”, “Recombin*”, “Vector”, “Chimeric”, “VLP/Virus-like” and “Virosome”. In order to analyse the availability of vector-based vaccines on the market, an analysis was performed on this database on vaccines classifi ed as vector-based.
Table 4.5. Registered search.
Region Database Results Reference US US Food and Drug Administration (FDA) 100 [216] EU European Medicines Agency (EMA) 41 [217] Brazil Oswaldo Cruz Foundation (Fiocruz) 9 [218] India Central Drugs standard control
organisation (CDSCO), Medguide India
218 [219, 220]
China China Food and Drug Administration (CFDA)
317 [221]
South Africa South African Vaccination and Immunisation Centre (SAVIC)
37 [222]
Australia Government Department of Health, Register of Therapeutic Goods
75 [223]
Japan Pharmaceuticals and Medical Devices Agency (PMDA)
24 [224]
Total results 821 Total results after deduplication 797 Of which GM vaccines 124
83
4.2.5. Data Convergence
4.2.5.1. Patents and Clinical TrialsIn order to provide an overview on the prevalence of vectors that have been patented and/or regis-tered for clinical trials, two more data analyses were performed. Initially, the comprehensive patent database, that was created as described above, was analyzed for data on the specifi c vector types. This data was then combined with data on vector types from the clinical trial database.
Relevant patent entries were selected from our database based on the presence of CPC codes related to vectors in the patent application and a sub database was created, including 73 different vectors or vector combinations extracted from 10287 unique patents. As many of these vectors only appeared a few times, the top 21 of most prevalent entries was used for further analysis. This resulted in 21 different vectors mentioned in 9088 unique patents.
For the clinical trials analysis, a similar procedure was applied. Instead of searching for CPC codes, data on the technology class of the vaccine was extracted from the previously generated clinical trial database by searching the variable “Expression System”. Relevant data on vectors was extracted, resulting in 17 vectors in 117 phase 1 trials, 14 vectors in 66 phase 2 trials and 2 vectors in 2 phase
3 trials. The results of these analyses are shown in Figure 4.3.
4.2.5.2. Evolution of GM Vaccines: Convergence of all Three DatabasesIn order to visualize the progress of GM vaccines over the years, a timeline was created using data from all available databases (patents, clinical trials, and registered) on the prevalence per indication per year. 16 Indications were selected based on their presence in all databases, and six indications were selected that were present in patents and clinical trials, albeit absent in registered. This resulted in a timeline of vaccine presence per year for 22 indications spanning from 1976 to 2013. Data on registered vaccines from India have been omitted from this analysis, as no information on the dates of application was given in Indian registers. Patents and clinical trials databases comprise of only GM vaccines. The registered database has been used in its entirety, both GM and non-GM vaccines. This visualization is shown in Figure 4.4.
84
Tabl
e 4.
6. M
ain
type
s of v
ecto
rs fo
r G
M v
acci
ne a
pplic
atio
n. S
umm
ary
of p
rope
rties
of v
ario
us v
ecto
rs, t
he in
dica
tions
they
are
ass
ocia
ted
with
and
th
eir a
dvan
tage
s and
dis
adva
ntag
es, a
s ret
rieve
d fr
om li
tera
ture
. In
bold
the
impo
rtant
fam
ilies
of v
iral v
ecto
rs a
re sh
own,
bel
ow th
ese,
in
regu
lar f
ont,
the
subs
eque
nt sp
ecie
s. A
bbre
viat
ions
: HC
V: H
epat
itis C
viru
s, H
IV: H
uman
imm
unod
efic
ienc
y vi
rus,
hMPV
: Hum
an m
etap
neum
oviru
s, hP
IV: H
uman
par
a-in
fluen
zavi
rus,
HPV
: Hum
an P
apill
omav
irus,
JEV:
Japa
nese
enc
epha
litis
viru
s, M
ERS:
Mid
dle
east
resp
irato
ry sy
ndro
me,
ND
V: N
ewca
stle
dis
ease
viru
s, N
OS:
not
oth
erw
ise
spec
ified
, RSV
: Res
pira
tory
sync
ytia
l viru
s, SA
RS:
Sev
ere
acut
e re
spira
tory
synd
rom
e, S
FV: S
emlik
i for
est v
irus,
SIN
: Sin
dbis
viru
s, SI
V: S
imia
n im
mun
odef
icie
ncy
viru
s, TB
: Tub
ercu
losi
s, V
EE: V
enez
uela
n Eq
uine
enc
epha
litis
viru
s.
Pla
smid
DN
A
In
fect
ious
dis
ease
s (N
OS
)
Influ
enza
Eas
y pr
oduc
tion
and
low
cos
ts
S
tabl
e (g
enet
ical
ly, s
helf
life)
Pro
duct
ion
is in
depe
nden
t of c
lass
ical
pro
duct
ion
tech
nolo
gy
In
duce
s bo
th h
umor
al a
nd c
ellu
lar i
mm
une
resp
onse
No
inte
rfere
nce
by p
re-e
xist
ing
imm
unity
Saf
er c
ompa
red
to v
iruse
s
Lo
w im
mun
ogen
icity
Req
uire
s do
se in
crea
ses,
mul
tiple
dos
es o
r ad
juva
nts
R
isk
of in
tegr
atio
n of
vac
cine
DN
A in
hos
t ge
nom
e
Ris
k of
tole
ranc
e in
duct
ion
[34,
81,
228
-231
]
Viru
ses
Ade
no a
ssoc
iate
d vi
rus
(AA
V)
C
edar
viru
s in
fect
ion
H
endr
a vi
rus
infe
ctio
n
HIV
infe
ctio
n
HP
V in
fect
ion
In
fluen
za
N
ipah
viru
s in
fect
ion
In
fect
s a
wid
e ra
nge
of ti
ssue
s
Indu
ces
both
hum
oral
and
cel
lula
r im
mun
e re
spon
se
N
on-p
atho
geni
c
U
nabl
e to
repl
icat
e in
nor
mal
hum
an c
ells
Exp
ress
es tr
ansg
enes
at a
hig
h an
d su
stai
ned
leve
l
Sev
eral
ser
otyp
es a
vaila
ble,
avo
ids
pre-
exis
ting
imm
unity
Flex
ible
mod
ifica
tion
of v
iral g
enes
pos
sibl
e
P
re-e
xist
ing
imm
unity
Low
tite
r pro
duct
ion
H
igh
prod
uctio
n co
sts
Li
mite
d tra
nsge
ne c
apac
ity
La
ck o
f CD
8+ T
cel
l res
pons
es w
ith n
atur
al A
AV
se
roty
pes
Lo
w im
mun
ogen
icity
com
pare
d to
oth
er v
iral
vect
ors
(Ad)
[81,
230
, 232
-234
]
Yel
low
Fev
er v
irus
Y
ello
w F
ever
viru
s in
fect
ion
Ja
pane
se E
ncep
halit
is
D
engu
e
W
est N
ile v
irus
infe
ctio
n
O
nly
vect
or-b
ased
vac
cine
on
the
mar
ket s
o fa
r
Eas
y pr
oduc
tion
and
low
cos
ts
S
ingl
e do
se e
ffect
ive
A
bsen
ce o
f tro
pism
No
pre-
exis
ting
imm
unity
in n
on-e
ndem
ic a
reas
(Nor
th A
mer
ica,
Eur
asia
)
P
re-e
xist
ing
imm
unity
in e
ndem
ic a
reas
(Sou
th
Am
eric
a, A
frica
)
Ris
k of
YFV
ass
ocia
ted
visc
erot
ropi
sm
[235
, 236
]
Ade
novi
ruse
s
Ant
hrax
Can
cer
E
bola
Hep
atiti
s B
HIV
infe
ctio
n
Influ
enza
Mal
aria
Mea
sles
Pla
gue
R
abie
s
SA
RS
TB
E
asy
prod
uctio
n an
d lo
w c
osts
Sta
ble
(The
rmal
ly, s
helf
life)
Infe
cts
a w
ide
rang
e of
hos
ts
G
row
s at
hig
h tit
ers
in c
ell c
ultu
re
C
an b
e m
utat
ed to
rend
er it
una
ble
to re
plic
ate
in n
orm
al h
uman
cel
ls
C
an b
e m
odifi
ed to
circ
umve
nt p
re-e
xist
ing
imm
unity
Can
indu
ce b
oth
muc
osal
and
sys
tem
ic im
mun
ity
S
trong
T c
ell e
ffect
or m
emor
y, li
ttle
T ce
ll ce
ntra
l mem
ory
resp
onse
s (S
uita
ble
for p
rimin
g)
S
ever
al s
erot
ypes
ava
ilabl
e
P
re-e
xist
ing
Imm
unity
Ris
k in
tegr
atio
n of
vac
cine
DN
A in
hos
t gen
ome
R
apid
elim
inat
ion
of tr
ansd
uced
cel
ls in
viv
o
Hum
an a
deno
viru
ses
are
onco
geni
c in
ani
mal
s
[27,
81,
83,
85,
228
-23
0, 2
32, 2
34, 2
37-2
42]
Hum
an s
erot
ypes
(Ad4
, A
d26,
Ad3
5)
C
onsi
dera
bly
less
pre
-exi
stin
g im
mun
ity th
an re
gula
r ser
otyp
e A
d
Gro
ws
at h
igh
titer
s in
cel
l cul
ture
Cro
ss-r
eact
ivity
afte
r im
mun
isat
ion
[242
, 243
]
Sim
ian
sero
type
s (C
hAd6
3, C
hAdO
x1)
E
bola
Hep
atiti
s C
Mal
aria
Lo
w p
re-e
xist
ing
imm
unity
in h
uman
s
Hig
hly
imm
unog
enic
Can
be
mut
ated
to b
e un
able
to re
plic
ate
in n
orm
al h
uman
cel
ls
R
equi
res
boos
ter f
or h
igh
T-ce
ll re
spon
se
[240
, 243
-245
]
Alp
havi
ruse
s
Can
cer
E
bola
Hen
dra
viru
s in
fect
ion
H
IV in
fect
ion
hP
IV in
fect
ion
H
PV
infe
ctio
n
Influ
enza
Mal
aria
Mar
burg
viru
s in
fect
ion
N
ipah
viru
s in
fect
ion
S
FV in
fect
ion
S
IN
TB
VE
E
H
igh
expr
essi
on c
apac
ity
C
an in
fect
den
driti
c ce
lls
In
duce
s ap
opto
sis
in in
fect
ed c
ells
Abs
ence
of p
re-e
xist
ing
imm
unity
in h
uman
s
RN
A v
irus,
una
ble
to in
tegr
ate
in h
ost g
enom
e
C
ytot
oxic
ity
D
iffic
ult p
rodu
ctio
n
H
igh
prod
uctio
n co
sts
P
ossi
bly
inst
able
Rel
ativ
ely
unex
plor
ed in
hum
ans
S
mal
l to
mod
erat
e fo
reig
n an
tigen
load
[27,
81,
85,
229
, 230
, 24
6]
Sem
liki F
ores
t viru
s
Can
cer
C
hiku
ngun
ya v
irus
infe
ctio
n
Indu
ces
both
hum
oral
and
cel
lula
r im
mun
e re
spon
se
H
igh
expr
essi
on c
apac
ity
A
bsen
ce o
f pre
-exi
stin
g im
mun
ity in
hum
ans
B
iosa
fety
issu
es
In
stab
le g
enom
e [2
46]
85
R
NA
viru
s, u
nabl
e to
inte
grat
e in
hos
t gen
ome
E
ncap
sula
ted
parti
cles
pre
vent
vec
tor s
peci
fic im
mun
ity d
ue to
repe
ated
use
S
indb
is v
irus
A
bsen
ce o
f pre
-exi
stin
g im
mun
ity in
hum
ans
R
NA
viru
s, u
nabl
e to
inte
grat
e in
hos
t gen
ome
B
iosa
fety
issu
es
In
stab
le g
enom
e [2
46]
Ven
ezue
lan
Equ
ine
Enc
epha
litis
viru
s
Can
cer
In
duce
s bo
th h
umor
al a
nd c
ellu
lar i
mm
une
resp
onse
Can
indu
ce b
oth
muc
osal
and
sys
tem
ic im
mun
ity
A
bsen
ce o
f pre
-exi
stin
g im
mun
ity in
hum
ans
R
NA
viru
s, u
nabl
e to
inte
grat
e in
hos
t gen
ome
B
iosa
fety
issu
es
In
stab
le g
enom
e [2
46]
Non
segm
ente
d N
egat
ive-
sens
e ss
RN
A v
iruse
s
Influ
enza
Sim
ple
wel
l kno
wn
geno
mes
Sta
ble
geno
me
com
pare
d to
psR
NA
Gro
wn
in h
igh
titer
s in
man
y ce
ll lin
es
C
an in
duce
bot
h m
ucos
al a
nd s
yste
mic
imm
unity
Abl
e to
car
ry la
rge
and
mul
tiple
inse
rts w
hile
mai
ntai
ning
a re
lativ
ely
smal
l gen
ome
G
radi
ent g
ene
expr
essi
on
In
stab
le g
enom
e [2
7]
Mea
sles
viru
s
HIV
infe
ctio
n
Mea
sles
/HIV
com
bina
tion
W
est N
ile v
irus
infe
ctio
n
R
NA
viru
s, u
nabl
e to
inte
grat
e in
hos
t gen
ome
W
ell k
now
n ho
mol
ogou
s va
ccin
e
Can
indu
ce b
oth
muc
osal
and
sys
tem
ic im
mun
ity
P
re-e
xist
ing
imm
unity
Mod
erat
e fo
reig
n an
tigen
ic lo
ad
[27,
81,
230
]
New
cast
le d
isea
se v
irus
/ avu
lavi
rus
A
vian
influ
enza
Can
cer
E
bola
Influ
enza
ND
V in
fect
ion
R
SV
infe
ctio
n
SA
RS
SIV
infe
ctio
n
C
an b
e gr
own
in e
ither
egg
s or
cel
l cul
ture
Gro
ws
at h
igh
titer
s in
Ver
o ce
lls
B
ival
ent v
acci
ne fo
r inf
luen
za a
nd N
DV
for p
oultr
y
Intra
nasa
l or p
ulm
onar
y de
liver
y po
ssib
le
N
o pr
e-ex
istin
g im
mun
ity
A
dmin
istra
tion
both
muc
osal
sur
face
s of
resp
irato
ry a
nd a
limen
tary
trac
ts
N
eedl
e fre
e ad
min
istra
tion
poss
ible
R
isk
of to
lera
nce
indu
ctio
n
Inst
able
gen
ome
[2
7, 2
29]
Par
a In
fluen
za V
irus
5 (P
IV5)
Influ
enza
Vac
cini
a
N
on v
irule
nt
In
fect
s a
wid
e ra
nge
of c
ell t
ypes
Gro
ws
high
tite
rs in
Ver
o ce
lls
G
radi
ent g
ene
expr
essi
on
Fl
exib
le m
odifi
catio
n of
vira
l gen
es p
ossi
ble
A
dmin
istra
tion
both
intra
nasa
lly a
nd in
tram
uscu
larly
No
pre-
exis
ting
imm
unity
N
o cl
inic
al s
afet
y da
ta fo
r use
in h
uman
s av
aila
ble
[27,
247
]
Sen
dai v
irus
H
i gh
imm
unog
enic
ity
[234
] V
esic
ular
Sto
mat
itis
viru
s
E
bola
Filo
viru
s in
fect
ions
Han
tavi
rus
infe
ctio
n
Hep
atiti
s B
Hep
atiti
s C
HIV
infe
ctio
n
HP
V in
fect
ion
In
fluen
za
R
SV
infe
ctio
n
TB
Lo
w s
erop
reva
lenc
e in
hum
ans
In
fect
s a
wid
e ra
nge
of ti
ssue
s an
d ho
sts
S
timul
ates
a s
trong
inte
rfero
n re
spon
se
P
oten
tial t
o pr
otec
t aga
inst
sub
type
s of
avi
an in
fluen
za in
pou
ltry
H
igh
expr
essi
on le
vels
of i
nser
ted
gene
s
Low
pre
-exi
stin
g im
mun
ity
[27,
81,
229
, 23
0]
Poxv
iruse
s
H
IV in
fect
ion
M
alar
ia
R
abie
s
TB
E
asy
prod
uctio
n an
d lo
w c
osts
Sta
ble
(gen
etic
ally
, she
lf lif
e)
B
road
trop
ism
for m
amm
alia
n ce
lls
In
duce
s bo
th h
umor
al a
nd c
ellu
lar i
mm
une
resp
onse
Cyt
opla
smic
site
of g
ene
expr
essi
on
A
ble
to c
arry
larg
e an
d m
ultip
le D
NA
inse
rts
P
re-e
xist
ing
imm
unity
Bio
safe
ty is
sues
Com
petit
ion
for a
ntig
en p
rese
ntat
ion
path
way
s
Rap
id e
limin
atio
n of
tran
sduc
ed c
ells
in v
ivo
Tr
opis
m
[27,
81,
110
, 229
, 230
, 23
2, 2
48-2
50]
ALV
AC
(Can
aryp
ox)
A
vian
influ
enza
Fow
lpox
Influ
enza
HIV
infe
ctio
n
In
duce
s bo
th h
umor
al a
nd c
ellu
lar i
mm
une
resp
onse
Sta
ble
(gen
etic
ally
, she
lf lif
e)
U
nabl
e to
repl
icat
e in
mam
mal
ian
cells
No
pre-
exis
ting
imm
unity
Can
indu
ce s
trong
CD
8+ T
cel
l im
mun
ity
Lo
w e
ffica
cy
[228
, 239
, 249
, 251
]
86
NY
VA
C (V
acci
nia)
Can
cer
H
IV in
fect
ion
In
fluen
za
Ja
pane
se E
ncep
halit
is
M
alar
ia
R
abie
s (a
nim
al)
S
mal
lpox
S
tabl
e (th
erm
ally
, gen
etic
ally
, she
lf lif
e)
R
educ
ed a
bilit
y to
repl
icat
e in
hum
an c
ells
Hig
h le
vel o
f saf
ety
and
gene
exp
ress
ion/
imm
une
resp
onse
Can
indu
ce b
oth
muc
osal
and
sys
tem
ic im
mun
ity
In
duce
s a
dela
yed
antiv
iral r
espo
nse
A
ble
to c
arry
larg
e an
d m
ultip
le D
NA
inse
rts
P
re-e
xist
ing
imm
unity
[2
30, 2
39, 2
48]
Mod
ified
Vac
cini
a A
nkar
a (M
VA
)
Can
cer
C
oron
aviru
s in
fect
ions
(SA
RS
, ME
RS
)
Hep
atiti
s C
HIV
infe
ctio
n
hMP
V in
fect
ion
hP
IV in
fect
ion
In
fluen
za
M
alar
ia
R
SV
infe
ctio
n
Sm
allp
ox
TB
S
tabl
e (th
erm
ally
, gen
etic
ally
, she
lf lif
e)
In
duce
s bo
th h
umor
al a
nd c
ellu
lar i
mm
une
resp
onse
s
Una
ble
to re
plic
ate
in m
amm
alia
n ce
lls
C
an in
duce
bot
h m
ucos
al a
nd s
yste
mic
imm
unity
Indu
ces
both
CD
4+ a
nd C
D8+
T c
ell r
espo
nses
Indu
ces
stro
ng C
D8+
T c
ell c
entra
l mem
ory
over
effe
ctor
mem
ory
(Sui
tabl
e fo
r boo
ster
)
Can
enc
ode
one
or m
ore
fore
ign
antig
ens
(mul
tival
ent v
acci
ne)
In
trins
ic a
djuv
ant c
apac
ities
Rap
id c
lear
ance
Fast
con
stru
ctio
n of
reco
mbi
nant
MV
A (6
-12w
ks)
Li
ttle
pre-
exis
ting
imm
unity
Li
mite
d pr
imin
g ca
paci
ty
V
ecto
r spe
cific
imm
unity
on
repe
ated
use
[2
7, 8
3, 1
10, 2
28-2
30,
234,
239
, 248
, 249
, 25
2-25
5]
Ret
rovi
ruse
s
Long
term
gen
e ex
pres
sion
Gen
erat
ion
of re
plic
atio
n-co
mpe
tent
viru
s
Infe
cts
divi
ding
cel
ls o
nly
[234
]
Lent
iviru
s
Long
term
gen
e ex
pres
sion
Infe
cts
non-
divi
ding
and
div
idin
g ce
lls
H
igh
imm
unog
enic
ity
G
ener
atio
n of
repl
icat
ion-
com
pete
nt v
irus
P
oten
tial f
or tu
mor
igen
esis
[2
34, 2
56]
Bac
teria
La
ctic
Aci
d B
acte
ria
(Lac
toco
ccus
, stre
ptoc
occu
s,
pedi
ococ
cus,
leuc
onos
toc,
la
ctob
acill
us)
A
utoi
mm
une
dise
ases
Nat
ural
ly p
rese
nt in
hos
t
Muc
h sa
fer t
han
tradi
tiona
l atte
nuat
ed v
acci
nes
in c
hild
ren
and
imm
unoc
ompr
omis
ed
peop
le
H
isto
ry in
food
indu
stry
, rec
ogni
sed
as s
afe
P
robi
otic
s, h
ave
heal
th p
rom
otin
g pr
oper
ties
Cap
acity
to s
urvi
ve th
e ga
stro
inte
stin
al tr
act
M
ucos
al a
dmin
istra
tion
coul
d re
duce
trad
ition
al s
ide
effe
cts
Li
mite
d kn
owle
dge
avai
labl
e fo
r use
as
vect
or
vacc
ine
com
pare
d to
vira
l vec
tors
[2
39, 2
57]
List
eria
Can
cer
In
duce
s bo
th C
D4+
and
CD
8+ T
cel
l res
pons
es
N
atur
ally
pre
sent
in h
ost
P
re-e
xist
ing
imm
unity
can
lead
to s
trong
er im
mun
e re
spon
se
M
uch
safe
r tha
n tra
ditio
nal a
ttenu
ated
vac
cine
s in
chi
ldre
n an
d im
mun
ocom
prom
ised
pe
ople
Indu
ce ro
bust
T-c
ell i
mm
une
resp
onse
Can
inva
de a
var
iety
of c
ells
, inc
ludi
ng a
ntig
en p
rese
ntin
g ce
lls
C
an re
side
in th
e cy
topl
asm
Li
mite
d kn
owle
dge
avai
labl
e fo
r use
as
vect
or
vacc
ine
com
pare
d to
vira
l vec
tors
[2
39, 2
58]
Sal
mon
ella
Sal
mon
ello
sis
(in a
nim
als)
Typh
oid
feve
r
HIV
infe
ctio
n
N
atur
ally
pre
sent
in h
ost
P
re-e
xist
ing
imm
unity
can
lead
to s
trong
er im
mun
e re
spon
se
M
uch
safe
r tha
n tra
ditio
nal a
ttenu
ated
vac
cine
s in
chi
ldre
n an
d im
mun
ocom
prom
ised
pe
ople
Indu
ces
robu
st T
-cel
l im
mun
e re
spon
se
In
duce
s bo
th h
umor
al a
nd c
ellu
lar i
mm
une
resp
onse
s
Can
indu
ce b
oth
muc
osal
and
sys
tem
ic im
mun
ity
A
ble
to c
arry
larg
e D
NA
inse
rts
P
re-e
xist
ing
imm
unity
cou
ld s
till b
e a
limiti
ng
fact
or
Li
mite
d kn
owle
dge
avai
labl
e fo
r use
as
vect
or
vacc
ine
[81,
239
, 259
]
87
4.3. Results
4.3.1. Analyzing the Market
Table 4.6. provides information on the most frequently used vectors, as mentioned in literature. In total 21 viral, 3 bacterial and 1 plasmid DNA vectors are presented in this table, covering the most essential vectors of each type for vaccine production or delivery. This table shows data on several upcoming vectors, which are being researched, e.g. new subtypes of poxviruses, adenoviruses, and novel bacterial vectors. Furthermore, the table comprises indications mentioned for these vectors, their advantages and challenges. The viral vector part covers general viral vector species, and sev-eral important main viral families followed by their relevant species. At this point, viral vectors have been researched in more detail than bacterial vectors. Poxviruses and adenoviruses are most frequently mentioned in literature. Moreover, details on the application of these two viral families and several of their species and subspecies, as vectors for vaccine development, are more common.
Figure 4.1. shows the most prevalent CPC codes in vector-based vaccine research. The most prev-alent patent precursors are “Vectors or expression systems specially adapted for eukaryotic hosts - note: This group covers the use of eukaryotes as hosts” (C12N15/79) with 8216 patent entries, “Vi-rus: expressing foreign proteins” (A61K2039/5256) with 5804 entries and “Bacterial cells; Fungal cells; Protozoal cells: expressing foreign proteins” (A61K2039/523) with 1813 entries, respectively.
Notable prevalent viral vectors are “Orthopoxvirus, vaccinia/variola” (C12N2710/24141, 2200 entries), “Mastadenovirus” (C12N2710/10341, 1549 entries), “Nucleopolyhedrovirus” (C12N2710/14141, 1050 entries) and “Poxviridae” (C12N2710/24041, 744 entries).
As demonstrated in Table 4.7., analyzing clinical trials in detail shows that out of 762 GM vac-cine trials, 198 are vector-based. This corresponds to a percentage of 26%. Indications with a high percentage for vector-based GM vaccine trials are variola (89%), epstein-barr (67%), HIV (56%), tuberculosis (TB) (42%), cancer (38%), and malaria (38%). Indications that have very little vec-tor-based trials are infl uenza (3%), human papillomavirus (HPV) (1%), and hepatitis B (1%). The most prominent vectors are the vaccinia virus (modifi ed vaccinia Ankara (MVA) & New York strain (NYVAC), 36.3%) and adenoviruses (17.7%).
88
The cumulative frequency of the aforementioned vectors per year is shown in Figure 4.2. Results from this graph and table illustrate a signifi cant increase in MVA and adenovirus application over the years, while growth of vaccines based on vaccinia virus, ALVAC, and fowlpox virus has stagnated. The results from our registered vaccines search show that the fi rst and currently only vector-based vaccine registered for use on the market is IMOJEV (2010), a Japanese Encephalitis vaccine, based on a yellow fever virus (family Flaviviridae) vector [260].
Table 4.7. Use of viral vectors in GM vaccine Clinical Trials. Types of vectors that are being used for spe-cific indications(top 10 vector vaccine indications) in GM vaccine trials, and a comparison of vector-based vaccine GM trials compared to all GM vaccine trials.
Indication All GM vaccine trials (n)
Vector-based
vaccines (n)
(%)
Type of vector
Adenovirus Vaccinia
(MVA & NYVAC)
Fowlpox ALVAC Fowlpox & vaccinia
Other
Cancer 208 78 38 11 11 12 6 14 24Influenza 157 5 3 1 3 0 0 0 1 HIV 153 86 56 25 43 3 11 0 4HPV 105 1 1 0 1 0 0 0 0 Hepatitis B 82 1 1 0 1 0 0 0 0Malaria 29 11 38 2 8 0 0 0 1 Ebola 4 1 25 1 0 0 0 0 0Variola 9 8 89 0 8 0 0 0 0 TB 12 5 42 0 5 0 0 0 0Epstein-Barr
3 2 67 0 2 0 0 0 0
Total 762 198 26 40 82 15 17 14 30
89
Figu
re 4
.1. P
redo
min
ant C
PC c
odes
for
GM
vec
tor-
base
d va
ccin
e pa
tent
s. Ill
ustra
tion
of th
e C
PC c
odes
pre
sent
in th
e pa
tent
dat
abas
e fo
r GM
vac
-ci
nes.
The
figur
e sh
ould
be
read
from
the
insi
de o
ut, s
tarti
ng w
ith th
e m
iddl
e ci
rcle
, eac
h ad
ditio
nal l
ayer
add
s a n
ew su
bsec
tion
to th
e co
de o
f the
pre
viou
s la
yer.
The
oute
r she
ll co
nsis
ts o
f the
num
bers
beh
ind
the
“/”,
com
plet
ing
the
CPC
cod
e.
90
4.3.1.1. Data ConvergenceThe analysis of the prevalence of specifi c vectors in patents and clinical trials is presented in Fig-ure 4.3. A total of 9088 vector-based vaccine patents were evaluated for the patent database. The orthopoxvirus (vaccinia/variola) is most prevalent with 2200 occurrences, followed by the mas-tadenovirus with 1549 entries. Other frequent vectors were the nucleopolyhedrovirus (1050 en-tries), poxviridae (744), and HIV (407). For clinical trials, a different, less diverse set of vectors was obtained. In Phase 1, MVA is most prevalent, 37 out of 117 trials. Other frequently present vectors are adenovirus (25), vaccinia virus (21), and ALVAC (9). For Phase 2, MVA is again prevalent with 14 out of 66 trials. Other vectors include adenovirus (10) and fowlpox-vaccin-ia combination (10). In phase 3 the use of ALVAC and allogeneic cells are present once each.
The convergence of all databases is presented in Figure 4.4. This fi gure illustrates patent applica-tions and clinical trials for the indications cancer and HIV over the years, yet with plenty of results yet very little success (one registered vaccine for cancer, bladder carcinoma, in 2009) [261]. For indications like Haemophilus infl uenzae (Hib) infection, hepatitis A (Hep A), Japanese encephalitis (JEV), and meningococcus, several vaccines have been registered in the past 20 years. Less patents and clinical trials are present for these indications, compared to HIV and cancer. Infl uenza has a signifi cant amount of both registered vaccines and clinical trials.
Figure 4.2. Cumulative frequency of vectors in clinical trials. Supporting figure for Table 4.2., showing the cumulative frequency of the various vectors used from 1999 until 2013.
91Figu
re 4
.3. P
reva
lenc
e of
vec
tors
use
d in
Pat
ents
and
Clin
ical
Tri
al p
hase
s fo
r G
M v
acci
nes
The
illus
tratio
n in
dica
tes
the
prev
alen
ce o
f var
ious
vec
tors
us
ed fo
r GM
vac
cine
s for
eac
h ph
ase
of re
sear
ch. E
ach
pie
char
t rep
rese
nts t
he c
ontri
butio
n of
eac
h in
divi
dual
vec
tor t
o th
e to
tal a
mou
nt o
f vec
tors
in th
e sp
e-ci
fic d
atab
ase
(Pat
ents
, CT1
, CT2
, CT3
). A
bbre
viat
ions
: HIV
: Hum
an im
mun
odef
icie
ncy
viru
s, A
AV: A
deno
ass
ocia
ted
viru
s, A
LVA
C: C
anar
ypox
viru
s, M
VA:
mod
ified
vac
cini
a Ank
ara.
92
Figu
re 4
.4. E
volu
tiona
ry ti
mel
ine
of in
dica
tions
and
pre
vale
nce
gene
rate
d fr
om v
ario
us d
atab
ases
. The
mot
ion
of in
dica
tions
thro
ugh
time
in th
ree
diffe
rent
pha
ses o
f res
earc
h (P
aten
ts(b
lue)
, Clin
ical
Tria
ls(r
ed),
Reg
iste
red
(Gre
en).
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4.4. Discussion
This study provides an overview of the vector-based GM vaccine pipeline and market, indicating that poxviruses and adenoviruses are among the most prominent vectors in GM vaccine develop-ment. Our fi ndings show that vector-based vaccines comprise a signifi cant part of all GM vaccines (26%) in the pipeline.
To realize data completeness, four different stages of research were conducted and analyzed in de-tail. These stages covered literature, patents, clinical trials, and the registered market of vector-based GM vaccines, generating an idea of evolution these vaccines have gone through over the years. During the start of this project it became clear that GM vaccines have an ambiguous defi nition. Various search terms were often found in literature to defi ne GM vaccines, nevertheless these terms were all used in an inconsistent manner. The defi nition of GM vaccines was narrowed down by de-lineation of search terms found in CPC codes and literature.
Literature widely acknowledged that, compared to bacterial or DNA vectors, viral vectors have been researched in more detail (Table 4.6). Poxviruses and adenoviruses are referenced often and a lot of details are provided on the use of these families as viral vectors. Nevertheless, pre-existing immu-nity is still a major obstacle for most viral vectors (Table 4.6). This is of special concern for the use of adenovirus vectors, although several strategies to circumvent this problem have been developed [240, 244, 245]. Interestingly there are many data suggesting that this seems to be less of a problem for MVA based vaccine candidates.
In comparison with viral vectors, DNA and bacterial vectors show potential in this respect, but this requires more research. Furthermore there are several other limitations to overcome. Viruses are relatively easy to work with, since they have less complex genomes than bacteria [262]. Although several types of bacteria have been mentioned in literature (e.g., Escherichia coli, Vibrio cholerae, Mycobacteria, and Shigella spp.), these are not mentioned in the table due to lack of suffi cient infor-mation on their advantages and disadvantages [239].
The results of the patent search show that the most prominent CPC codes in the patent database on vector-based vaccines cover general information on vectors (C12N15/79, A61K2039/5256, A61K2039/523). These CPC codes do not comprise specifi c vectors but are general indicators for vector-based vaccines. A large variety of different vector types are being patented for vaccine devel-opment (Figure 4.1). According to the patent database, both “mastadenovirus” and “orthopoxvirus: vaccinia/variola” are the most prominent vectors. Human adenoviruses are part of mastadenovirus genus, which in turn is a large genus of the adenoviridae family. It is notable that orthopoxvirus:
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vaccinia/variola as well as poxviridae appear in the patent results. The species vaccinia virus and variola virus are part of the genus orthopoxvirus, which belongs to the family of Poxviridae. The explanation behind this seemingly double occurrence is that CPC codes for both the species and the family are present in Espacenet. There is one CPC code for both vaccinia and variola combined, rather than a separate code for each of these species.
For clinical trials, vector-based vaccines play quite an important part in GM vaccine trials as a whole. 26% of all GM vaccine trials use vector-based candidate vaccines, especially for currently undefeated indications, such as cancer, HIV, TB, and malaria (Table 4.7). Intervention strategies for these diseases represent a large unmet medical need, still causing over a million deaths every year [263]. With limited if any cure available, new methods might provide additional value to vaccine research and development, in hope for a breakthrough. This premise is confi rmed by Figure 4.4. Cancer, HIV, and malaria show a large presence in both patent and clinical trial databases, while Hib, Hepatitis A, and meningococcus show little development in patent and clinical trials stages in recent years. This implies a lower need for new vaccine technologies for these indications, as current vac-cines based on conventional methods are apparently suffi ciently satisfactory [264-266]. Table 4.7. also shows that very little vector-based vaccine trials are present for more or less treatable diseases such as HPV induced neoplasias, hepatitis B, and infl uenza. Apparently there is less medical need for vector-based vaccines for these indications, as vaccine candidates are available based on GM-based and non-GM-based techniques [267-269]. There is, a signifi cant amount of active non-vector-based GM trials for these three indications, demonstrating the variety of GM techniques applied in vaccine development. For infl uenza and hepatitis B vaccine production, the use of recombinant DNA technology is already common practice [211, 270]. Therefore, the focus of research is on optimizing the technology used, rather than on investing in new vector-based technology research.
The increase in MVA vector usage compared to the use of vaccinia virus indicates that MVA has started to replace regular vaccinia virus in vector-based vaccine development, as vaccinia trials have stagnated while MVA trials are increasing rapidly (Figure 4.2). The reasons for this replacement is predominantly related to the safety and effi cacy of MVA, as it only causes an abortive infection, while inducing an abundant expression of the target immunogen, leading to impressive protective immune responses [160]. The prominent use of adenoviruses as viral vectors is probably due to the considerable knowledge on this virus family, the ease of manipulation of the virus for use in vec-tor-based vaccines, and the broad tissue tropism associated with this virus [240, 271]. The consensus that both poxviruses and adenoviruses are important for vector-based GM vaccine research is also strengthened by data shown in Figure 4.3., indicating high prevalence of these vectors in both pat-ents and clinical trials. For patents and the fi rst two phases of clinical trials, both orthopoxviruses vaccinia virus (mentioned in combination with variola virus), and adenoviruses are well represented
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(though in patents adenoviruses are not mentioned directly, these are part of the Mastadenovirus genus).
While analyzing this data set, it is important to keep in mind that the databases used are snapshots of each phase of research and development pipeline. Patents are made public 18 months after submis-sion, but when patents are retracted before this 18 months period, they disappear from Espacenet. Clinical trials only show active and on-going trials (hence the database starts in 1999). Discontin-ued or terminated trials are removed from the database, consequently, making direct correlations between databases unjustifi able. Therefore, the analyses conducted in this study are not directly between databases but each database is seen as an individual snapshot. Even though numerous vec-tors are being studied in different phases of pre-clinical and clinical research, the presence of their majority in phase 1 indicates that the evolution of vector-based vaccines has only just begun. The large amount of vector types being patented, or having reached phase 1 clinical trials, show a lot of promise, as new techniques might lead to a new generation of safer, more effi cient, and cost-effec-tive vaccines.
Comparing the data presented with the literature study we conducted initially, it seems that a lot of new vectors are being patented while little published information is available. This could indicate that some vectors are being patented beforehand, not necessarily in order to start a new study, but in case a method or technique is developed to make them suitable for vaccine production. Without patents, anyone could start developing these vectors without legal consequences, leading to compa-nies competing to sell the vaccine for the lowest price possible. When revenues from vaccine sales eventually do not lead to return on investment for past and future research and development there would be no incentive for the development of new generations of vaccines. Therefore the use of a patent search was considered a valid and valuable approach to gather part of our dataset.
In conclusion, our data suggest that although currently there is only one licensed, vector-based human vaccine on the market and that this fi eld is still in its early days, vector-based vaccines may offer a cost-effective alternative for the production of safe and effective vaccines against diseases for which no or less perfect vaccines exist today. The most promising vectors for vaccine development at this moment appear to be poxvirus and adenovirus vectors. This may be concluded for their abun-dant use in the development of vaccines against diseases like HIV-AIDS, malaria, tuberculosis and different forms of neoplastic disease. It may be expected that the current efforts spent on developing vector-based vaccines, may lead to promising vaccine candidates for these indications and therefore hold promise for current and future unmet medical needs. Therefore, after the recent eradication of smallpox using Jenner’s vaccinia virus as the fi rst vaccine, this and other viruses may now be the basis for constructing vectors that may help us control other major scourges of mankind.
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Chapter 5Cross-sectoral Perspectives of Market
Implementation of the MVA Platform for Influenza Vaccines:
Regulatory, Industry and Academia
Published as:
Ramezanpour, B., Prof. Dr. Osterhaus, A. and Prof. Dr. Claassen, E. Journal of Vaccines & Vaccination. 2016;7(3). DOI: 4172/2157-7560.1000318
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Abstract
This study provides a quantitative multidisciplinary approach to identify and prioritize the main implementation challenges of the MVA platform for novel infl uenza vaccines using a tailor-made prioritization process. Infl uential key opinion leaders (KOLs) in the fi eld of vaccine research, devel-opment, and manufacturing were approached to participate in this study. Semi-structured interviews were performed with 32 KOLs representing the regulatory, industry, and academia fi elds.
The opinions were analyzed quantitatively, through various ranking methods that were integrated and adapted to fi t the purpose of this study, identifying 6 implementation challenges main catego-ries, 21 implementation challenges categories, and 39 implementation challenges underlying caus-es. The most signifi cant barriers are associated with “production & speed” category whereas the least signifi cant are associated with “regulatory” category.
Perspectives among the KOLs proved to be divergent with regard to implementation challenges for the MVA platform. Through comparing these perspectives, useful information on current and po-tential future implementation challenges of novel platforms in general may be expected. Providing an overview and assessment to reveal these challenges may lead to a more substantial situation for all stakeholders involved, given that such an overview allows for the recognition of various imple-mentation challenges from a multidisciplinary perspective, making it possible to identify underlying causes that contribute to the successful implementation of the MVA platform. Remarkably, analysis of implementation challenges resulted in core challenges that resemble similarities between the three perspectives.
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5.1. Introduction
Despite the success of vaccines in disease prevention and control [5], vaccination still has the po-tential to make an even greater contribution to public health on a global scale [1]. Introduction of recent advances and novel approaches in the infl uenza vaccine fi eld provide new opportunities that emphasize the need for adapting/improving state-of-the-art technologies.
With a global annual attack rate estimated at 5%-10% in adults and 20%-30% in children, infl uen-za viruses continue to emerge and re-emerge causing approximately 3 to 5 million cases of severe illness, and 250 thousand to 500 thousand deaths annually [272]. Immunization remains the most effective way to prevent or mitigate infl uenza [27].
Although current annual infl uenza vaccines are relatively effective against epidemic infl uenza in-fections, these vaccines don’t provide protection against pandemic and emerging infl uenza viruses [121]. Moreover, ensuring an adequate and timely supply of vaccines remains challenging due to, inter alia, the limitations of current technologies [27, 109, 116, 273, 274]. For the production of infl uenza vaccines, egg-based and egg-independent technologies are being used [275]. Even though many benefi ts arrive from egg-based infl uenza vaccine production, there are several essential dis-advantages. Upscaling of production to meet the global demand is limited by embryonated chicken egg supplying mechanisms. This can also be affected by the virulence of pandemic strain since these viruses can be lethal to embryonated chicken eggs [27]. Moreover, an increased surge in vaccine demand during a pandemic will generate at least 5-10 fold of the current global seasonal infl uenza vaccine production demand [275].
Egg-independent pandemic infl uenza vaccine approaches include, but are not limited to, cell-de-rived whole or detergent split, recombinant proteins, virus-like particles, DNA/RNA vaccines, and viral vector vaccines [64, 275]. While all these technologies have inherent potential to improve infl uenza vaccines by increasing production capability and providing shorter production time, many are limited by effi cacy and safety concerns. Recent research shows the promise of using viral vector vaccines with certain additional assets, including ability to induce balanced humoral and cellular immune responses and feasibility for large-scale deployment in a short period of time without the safety concerns associated with the production of pathogenic viruses [27, 83, 275].
In recent decades recombinant poxviruses have shown potential as platforms for the development of vaccines that induce protective immunity against various infectious and neoplastic conditions of hu-mans and animals with a good safety profi le [85, 110]. The latter is probably due to their replication, which is largely restricted to avian cells. Despite the availability of a series of attenuated poxviral
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vaccine vectors with a good safety profi le, modifi ed vaccinia virus Ankara (MVA) is among the most advanced and widely used attenuated vectors in clinical trials [86, 87].
In our previous study, we have quantifi ed the strengths, weaknesses, opportunities, and threats that come with the MVA platform [160]. Here we present implementation challenges of this platform. Furthermore, although different vaccinia virus vectors are being used in many clinical trials against various diseases, such as HIV [94-96], hepatitis [97], infl uenza [98], malaria [99, 100], tuberculosis (TB) [101], and cancer [102], MVA vectors have proven to be relatively safe as compared to other vaccinia virus strains [104, 105].
An increasing number of novel development/production approaches including viral vector-based techniques shows its potential added value to develop new vaccines that address an unmet medical need. Nonetheless, lack of proper rules and regulations and stringent regulatory requirements act as obstacles in bringing a vaccine candidate to the clinic [2]. International and national regulato-ry agencies require stringent experiments to address concerns regarding the introduction of novel vaccines. The present study shows that involvement of regulatory, industry, and academia worlds contributes to streamline and improve required regulations, possible biosafety issues, and MVA-vec-tor-associated risks.
The vaccine licensure process prior to vaccine approvals plays a decisive role for manufacturers to expand their engagement in development and manufacturing of novel vaccines [276]. Although demonstration of added value of novel generation vaccines contributes to their successful registra-tion and implementation on the market, providing convincing clinical data appears to be challenging for manufacturers [27]. Furthermore, dependency on external factors discourages industry to invest in development of novel vaccines.
In the present study, we uncover market implementation challenges of the MVA platform [160] by performing semi-structured interviews with the KOLs representing the golden triad; regulatory, in-dustry, and academia. Quantifying expert’s opinions regarding market implementation challenges of the MVA platform through various ranking methods (integrated assessment (IA) approach, perspec-tive method, and rank-frequency and importance frequency methods) provides a unique overview from a multidisciplinary perspective, making it possible to identify foremost underlying causes that contribute to the challenges novel vaccines have to face before successful market implementation.
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5.2. Methodology
A comprehensive analysis of our previous study indicated the added value of diverse perspectives that exist among the KOLs with different backgrounds [160]. A multidisciplinary approach has been used to represent the most infl uential stakeholders in the fi eld of vaccine research, development, and manufacturing, namely; regulatory, industry, and academia.
Data collection consisted of a literature study on the topic of this research and interviews with KOLs. Semi-structured qualitative interviews serve as a tool to further identify the main implementation challenges in the fi eld of infl uenza vaccine [277]. The prioritization process was based on several quantitative ranking methods that were integrated and adapted to fi t the purpose of our research: in-tegrated assessment (IA) approach [278-283], perspectives method [284, 285], and rank-frequency and importance frequency methods [286, 287]. The results from all analyses are integrated to create a RCA tree [50, 51] (RCA applied top-down) visualizing all three perspectives.
Table 5.1. Study design.
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5.2.1. Descriptive Study Design
5.2.1.1. Root Cause Analysis (RCA)Root cause analysis is an approach designed to identify the underlying causes of events, in this case MVA implementation challenges on the infl uenza market. Identifi cation of underlying causes enables to reveal different effective options for solutions. The RCA is a four-step process including data collection, causal factor visualization, root cause identifi cation, and generation of the most ef-fective recommendation to overcome the challenges [288, 289].
5.2.1.2. InterviewsThe interview candidates were purposively selected using the snowball method [290, 291] to pro-vide a diverse and complete overview from the fi eld of infl uenza. The interviewees were asked a standardized set of questions in order to make the results comparable. The results from the inter-views were subsequently used for further analysis.
5.2.1.3. Integrated Assessment (IA) ApproachIntegrated assessment (IA) approach provides the opportunity to integrate knowledge and perspec-tives from several domains into a single framework. This research approach pursues scientifi c un-derstanding of complex issues based on combining, interpreting, and communicating knowledge from different disciplines in such way that a cause-effect chain of an issue can be evaluated from different perspectives [278-283]. In contrary to conventional research analysis, IA is very effective in not only unveiling problems and their underlying causes, but at the same time providing relations between these causes. Complex problems have several causes that sometimes interact across multi-ple domains, consequently, requiring application of inter- and trans-disciplinary approaches.
Table 5.2. Interviewee’s background.
Background Interviewees Response rate
Regulatory 9 23%
Industry 18 100%
Academia 5 39%
Total 32 48%
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5.2.1.4. Perspective MethodTogether with the aforementioned approach, the perspectives method focuses on the interaction and interrelation between regulatory, industry, and academia KOLs in a multi-disciplinary way. The perspective method classifi es, interprets, and analyzes these different perspectives [284, 285]. We developed a set of questions and conducted interviews with the KOLs from the fi eld of infl uenza as part of the perspectives method to analyze the current perspective on the implementation of MVA platform among the experts with different backgrounds. Subsequently, a dimensional perspective construction was created providing insight into differences and similarities between the three stake-holders. This construction plays an essential role in identifi cation of reasons behind discrepancies and demonstrates inherent challenges at different levels.
5.2.1.5. Rank-frequency and Importance-frequency MethodsThe rank-frequency method cross-tabulates the frequency of an item with its appearance ranking. This method consists of two indicators: the frequency of a factor and its appearance ranking. The importance-frequency method replaces the appearance ranking criterion with an importance ranking criterion [287].
5.3. Results
A total of sixty-two peer-reviewed publications, divided in scientifi c reviews (12), scientifi c publi-cations (30), and governmental guidelines (3) were evaluated in order to attain more insight into the topic of this study (Table 5.3).
Policy making on implementation of a vaccine development/production platform involves diverse fi elds of expertise. To assess the MVA market implementation challenges under different perspec-tives, 32 KOLs from the vaccine fi eld were interviewed. As a result, three distinctive perspectives on implementation of MVA platform emerged, each led by its own established view in a different discipline and each with a predominant emphasis on specifi c set of underlying causes (Figure 5.2). The analysis of interview transcripts reveals 6 main categories of implementation challenge, which subsequently are divided into 21 categories of implementation challenges. These categories are fur-ther subdivided into 39 underlying causes.
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5.3.1. Dimensional Perspective Construction; Three Perspectives, their Similarities and Differences
Mapping the implementation challenges in a dimensional perspective construction visualizes dif-ferences and similarities between KOL’s responses (Figure 5.1). This fi gure illustrates the core im-plementation concerns associated with each perspective. According to the KOL’s multidisciplinary perspectives, following implementation categories are ranked as top three and thus are essential: challenging to provide convincing clinical data, external dependency, and need for new production platforms/facilities. Furthermore, analysis of the obtained data made it possible to identify several other important categories by KOL’s perspectives: fl exibility requirements, regulatory construct, licensable vaccines, and challenging to demonstrated effi cacy, respectively (Figure 5.1).
From the regulatory, industry, and academia perspective, it is challenging to demonstrate effi cacy in clinical trials and therefore diffi cult to provide compelling data. According to the KOLs, external dependency on factors such as strain reference and reagents emphasizes the necessity for new pro-duction platforms/facilities, which consequently contribute to a more rapid production process and hopefully translating to faster market entry. Flexibility is a prerequisite in every step of the process in order to eventually produce licensable vaccines and acquire regulatory approval.
According to the KOLs from the regulatory authorities and industry, infl uenza market is viable,
Table 5.3. List of total evaluated reviews, publications, and governmental guidelines.
Reviews Publications Governmental
Guidelines
Altenburg et al. 2014 Andre et al. 2008 Hanton et al.2002 Kaper et al. 2005
Chan et al. 2013 Baarda et al. 2005 Offermans et al. 2012 WHO et al. 2014
Cherp et al. 2011 Bakari et al. 2011 Osterhaus et al. 2011 WIPO et al. 2012
Choi et al. 2013 Bejon et al. 2007 Ramezanpour et al. 2015
Cottingham et al. 2013 Berthoud et al. 2011 Rotmans et al. 1998
Krammer et al. 2015 Cavenaugh et al. 2011 Schneider et al. 1997
Lee et al. 2014 Dany et al. 2015 Sheehy et al. 2012
Mooney et al. 2013 De Ridder et al. 2007 Smits et al. 2009
Pandey et al. 2010 Draper et al. 2013 Suter et al. 2009
Perdue et al. 2011 Edenhofer et al. 2005 Tameris et al. 2013
Rimmelzwaan et al. 2009 Ferenc et al. 2003 Ulmer et al. 2006
Rollier et al. 2011 Garcia et al. 2011 Valkering et al. 2009
Goodman et al.1961 Verheust et al. 2012
Gomez et al. 2011 Verschuren et al. 2010
Greenwood et al. 2011 Zeng et al. 2014
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large, and complex. Industry emphasizes the importance of demonstrating added value of a product in comparison to other competitive products. Providing compelling data is necessary to validate this added value and make a product more appealing to the eyes of different stakeholders. Moreover, an extensive intellectual property (IP) profi le is a requirement in this fi eld. According to the regulatory authorities, providing knowledge and quantitative assessments might be one of the most essen-tial compelling factors helping the acceptance of MVA platform by various stakeholders including public, politicians, and governments. From the academia perspective, the effects of pre-existing immunity against vaccine vectors in the human population may represent a barrier in successful implementation of such platforms. Furthermore, public acceptance towards vector-based vaccines is one of the profound challenges in successful market implementation of MVA.
Both regulatory and academia KOLs indicate that the industry needs to be incentivized to make further investments in the development of novel technologies. Complex territorial regulations and requirements complicate translating vaccine candidates into actual vaccines. Furthermore, imple-mentation of MVA platform might interfere with ongoing projects in the pipeline. A good business model is required to ensure application sustainability of this platform, from an industry perspective. Application of an advance-purchase-agreement can support sustainability and helps risk sharing for development of pandemic vaccines.
5.3.2. RCA Tree
Implementation challenges of the MVA platform are assigned to six main categories: production and speed, technical, immunogenicity, competitors, pre-pandemic/ mock-up, and regulatory. These categories are further classifi ed and ranked according to their importance into 21 implementation challenges categories. Underlying causes, a total of 39, related to each challenge are also illustrated in Figure 5.2.
5.3.2.1. Production and SpeedComparing to other implementation main categories, the main category “production & speed” has the highest overall score. External dependency challenges, posed predominantly by industry KOLs, are a predominant implementation challenge of the MVA platform. The foremost underlying causes for delay in the production process are unpredictable global demands, external factor including reagents and reference strains provided by the WHO, and rules & regulations. Moreover, advanced production platforms and proper facilities are required to speed-up the process of market entry and validation.
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5.3.2.2. TechnicalThe main category “technical” is ranked to possess the second highest scores. Within this category fl exibility requirements to match antigenic changes in circulating viruses appeared to be essential. Nevertheless, lack of knowledge to provide quantitative assessments regarding cross-reactivity and required protection immunity remains a challenge. Consequently, technical challenges and unpre-dictable market dynamics and demands are considered to be of high risk to manufacturers when deciding to invest in novel technologies.
5.3.2.3. ImmunogenicityWithin this main category, challenges related to provide convincing clinical data are the foremost mentioned challenge, in particular from a regulatory perspective. The main underlying causes are the lack of clinical data on immunogenicity, cross-protection, safety, and effi cacy. Additionally, comparison to the current standard of care raises the bar even higher (Figure 5.2).
5.3.2.4. CompetitorsDue to the large and complex nature of the infl uenza market and many comparable competitive products available in late stage development, demonstrating added value assures competitive advan-tages in gaining market share and public acceptance. Furthermore, the public needs to be educated on the value of vaccinating with a virus, MVA, against another virus, infl uenza.
5.3.2.5. Pandemic/Mock-upMock-up dossiers are regulatory constructs to make advance-purchase-agreements with govern-ments due to unattractive nature of pandemic vaccines during peacetime. Moreover, mock-up vac-cines facilitate and increase the chance of getting proof of concept vaccines into clinical trials. This business strategy will ensure sustainability and therefore increase the chance for development of licensable vaccines by the industry.
5.3.2.6. RegulatoryAccording to the regulatory authorities, lack of incentives for vaccine manufacturers and complex requirements and regulations for novel vaccines complicates the translation of pandemic candidates into actual vaccines.
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Figure 5.1. Dimensional perspective construction. Three perspectives on MVA platform implementation have their roots in separate disciplines; regulatory, industry, and academia. They differ with respect to their focus on various domains. The implementation-challenge-categories are situated in the center of the diagram address the concerns of all three perspectives. Each additional layer represents a different perspective illustrated by color. And each color represents a separate main category of implementation challenges. The outer shell represents the main KOL’s perspective.
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Figure 5.2. RCA tree. Integration of the overall results: root-cause analysis (RCA), rank-frequency method, integrated assessment (IA) approach, and perspectives method of MVA platform implementation.
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Figure 5.3. Importance frequency, ordered according to all results of implementation challenges catego-ries from the regulatory, industry, and academia perspective.
5.3.3. Importance Frequency
Results presented here indicate the most important implementation challenges, main categories/ categories/ underlying causes, ranked according to each perspective.
From the perspective of the regulatory authority and academia KOLs, providing convincing clinical data with the purpose of vaccine approval remains the most challenging factor for the implementa-tion process of MVA platform. External dependency is experienced as the most essential implemen-tation barrier that the industry has to face in order to get the MVA vaccine development/production platform on the market. All three perspectives consider these challenges as predominant barriers, however with variable importance degrees depending on their backgrounds.
There are also some implementation-challenge-categories solely mentioned by one perspective. Regulatory authorities indicate public/politicians/governments acceptance to play an essential role in the future after implementation of this platform. According to the industry KOLs, sustainability of such platform with respect to time-bound properties of these pandemic vaccines and importance of having a solid business strategy to remain successful is going to be a profound challenge. From the perspective of the academia KOLs, public acceptance of such platform must also be taken into consideration while discussing the challenges.
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5.4. Discussion and Conclusions
The current study evaluates the market implementation potential of MVA platform to generate next-generation infl uenza vaccines, which will provide superior immunogenicity, safety profi le, and shorter production time. Our study reveals that implementation barriers of the MVA platform can be grouped into six main categories (ranked according to importance): “production & speed”; “techni-cal”; “immunogenicity”; “competitors”; “pre-pandemic/mock-up” and “regulatory”. It is notewor-thy that the top three categories, when ranked according to the rank-frequency as well as importance frequency, coincides with the top three categories shared by all three perspectives. Approaching KOLs representing industry, regulatory, and academia shows how complex the acceptance of an MVA based infl uenza vaccine production platform can be.
Visualization of integrated results shows that dependency on external factors such as reagents and reference strains requires immediate attention based on the fact that this category is related to the most important main category, “production & speed”. Regulatory and academia commonly rec-ommend making less complex and more streamlined regulations that consequently will, inter alia, incentivize the manufacturers to develop vaccines instead of vaccine candidates (Figure 5.2). There-fore, it is noteworthy that the main category “regulatory” is not as highly ranked as it is generally assumed to be [292]. This state of discrepancy between KOL’s perspectives highlights ambiguity regarding novel vaccines regulations and stresses the need for custom-made rules, regulations, and guidelines.
At present, many of the core implementation challenges overlap between the three perspectives with a remarkably high level of resemblance on required immediate attention for the top two challenges. This not only reveals that the solution to these challenges must be an integrated effort, but it also em-phasizes the importance of breaking the barriers by working together. This new way of collaboration between various stakeholders will eventually redefi ne their relationship.
High level of urgency for new production platforms/facilities requires speeding up the search for novel platforms that meet the requirements. Consideration of combining novel technologies with conventional production platforms and vaccine formulations is necessary to speed up the production of vaccines and reduce the time gap between the emergence of new infl uenza viruses and vaccine availability.
Successful introduction and registration of a new vaccine (platform) is based on and infl uenced by various factors including provision of suffi cient information to decision makers, demonstration of added value compared to existing products, increased public acceptance of the vaccines by demon-strating safety, effi cacy, sustainability, and cost-effectiveness.
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Industry KOLs indicate establishing a sustainable business model as a prerequisite to turn a relative commercially unattractive platform into a success. Depending on market dynamics and uncertain-ties, manufacturers can be confronted with various unexpected events, such as technological/de-velopmental failures and technological/logistical and regulatory challenges, which all contribute to the risks manufacturers have to face in order to realize developing novel pandemic vaccines [274]. Providing compelling data representing added value of novel technologies and demonstrating com-petitive edge to many existing products on the market is deemed very important both by regulatory and industry KOLs. Hence, it is essential to explore application of this platform for both seasonal and pandemic infl uenza as well as other infectious diseases [160]. Moreover, alternative route of immunization such as oral, needle-free skin delivery, nasal, and sublingual must be considered as well [274].
Integration of different perceptions and collaboration of different stakeholders working with differ-ent paradigms offering different insights results in benefi cial decision making and helps reaching consensus when interactive complexity plays a predominant role. Furthermore, public attitude and public acceptance towards vector-based vaccines such as MVA is one of the profound challenges that must be surmounted aided by the application of clear guidance and regulations by relevant au-thorities. Although, acceptance issues associated with novel vaccines are not limited to an increased level of public education, it might have a positive impact on the acceptance if the public is aware of the value of vaccinating with a virus, MVA, against another virus, infl uenza.
Finally, practical challenges of establishing MVA platform on the market and ensuring effective long-term sustainability of this platform require collaboration from different stakeholders. Our study indicates that once regulatory, industry, and academia understand each other’s perspective and come to the realization that they jointly can anticipate market implementation barriers in a collaborative manner that will lead to a strategic dialogue and consequently increased chance of reaching a con-sensus. This will be benefi cial for each and every party involved and will further make an enormous contribution not only to public health but also to the economy.
The future of vaccines is unpredictable due to, inter alia, high complexity, uncertainty, and ambi-guity of its market dynamics. In such an uncertain situation, the threats such as regulatory and po-litical fl uctuations, innovative and disruptive technologies, and unforeseeable economic and social consequences could be simultaneously barriers and advantages. Identifying, analyzing, quantifying, prioritizing of implementation challenges from different perspectives provide the opportunity to explore different views, evaluate various options, minimize inherently uncertain risks and barriers, consequently anticipate future challenges and be prepared for future threats.
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Chapter 6Market Implementation of the MVA Platform for Pre-pandemic and Pandemic Influenza Vaccines:
A Quantitative Key Opinion Leader Analysis
Published as:
Ramezanpour, B., Pronker, E.S., Kreijtz, J.H.C.M., Osterhaus, A.D.M.E. and Claassen, E. Vaccine. 2015;33(35), 4349-4358. DOI: 10.1016/j.vaccine.2015.04.086
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Abstract
A quantitative method is presented to rank strengths, weaknesses, opportunities, and threats (SWOT) of modifi ed vaccinia virus Ankara (MVA) as a platform for pre-pandemic and pandemic infl uenza vaccines. Analytic hierarchy process (AHP) was applied to achieve pairwise comparisons among SWOT factors in order to prioritize them. Twenty-four key opinion leaders (KOLs) in the infl uenza vaccine fi eld were interviewed to collect a unique dataset to evaluate the market potential of this platform.
The purpose of this study, to evaluate commercial potential of the MVA platform for the develop-ment of novel generation pandemic infl uenza vaccines, is accomplished by using a SWOT and AHP combined analytic method. Application of the SWOT-AHP model indicates that its strengths are considered more important by KOLs than its weaknesses, opportunities, and threats. Particularly, the inherent immunogenicity capability of MVA without the requirement of an adjuvant is the most important factor to increase commercial attractiveness of this platform. Concerns regarding vector vaccines and anti-vector immunity are considered its most important weakness, which might lower public health value of this platform. Furthermore, evaluation of the results of this study emphasizes equally importance role that threats and opportunities of this platform play.
This study further highlights unmet needs in the infl uenza vaccine market, which could be addressed by the implementation of the MVA platform. Broad use of MVA in clinical trials shows great prom-ise for this vector as vaccine platform for pre-pandemic and pandemic infl uenza and threats by other respiratory viruses. Moreover, from the results of the clinical trials it seems that MVA is particularly attractive for development of vaccines against pathogens for which no, or only insuffi ciently effec-tive, vaccines are available.
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6.1. Introduction
Vaccines are the most cost-effective tools for controlling the spread and impact of infectious dis-eases in both humans and animals [86]. Vaccines generally work by harnessing the host’s adaptive immune system against infectious pathogens, by exposing it to an inactivated, live-attenuated, sub-unit or recombinant version of the wild-type pathogen or parts thereof [32, 293]. Furthermore, ap-propriately managed vaccination campaigns have completely eradicated two devastating infectious diseases of humans and animals: smallpox and rinderpest, respectively. This accomplishment has not been equalled by any other medical or veterinary interventions [6-8]. Unfortunately, interven-tions for most viral diseases still represent a signifi cant unmet medical need. Reasons include, but are not limited to absence of safe and effective vaccines, lack of vaccine availability, accessibility, and affordability [32]. State-of-the-art technologies may be used to overcome at least some of these limitations. This paper largely focuses on the issue of vaccine availability to combat human pan-demic infl uenza.
Expression systems may be used to express genes encoding immunogens of pathogens in order to directly induce protective immune responses in the human or animal host [78, 79]. Vectors applied for this type of vaccine delivery include plasmid DNA, RNA, viral and bacterial vectors [78]. Sev-eral viral vector-based vaccine platforms exist, such as adeno-, pox-, parainfl uenza-, and alphavi-rus-based expression systems. Those and the others allow the establishment of vaccines for heterol-ogous pathogens [32, 78, 82] and all have their inherent advantages and disadvantages.
In the recent decades recombinant poxviruses of mammals and birds have shown potential as plat-forms for the development of vaccines that induce protective immunity against various infectious and neoplastic conditions of humans and animals [86-88]. Despite these supportive data and the apparent potential of poxvirus-based platforms and their current use in animal vaccines, there is still no recombinant poxvirus based vaccine registered for use in humans [83]. Nevertheless, several incremental improvements, such as techniques allowing for better quantitative and qualitative target antigen expression characteristics, prime-boost regimens, as well as viral vector manufacturing and purifi cation technology, justify the expectation that several poxvirus vector-based vaccine candi-dates for humans are approaching their fi nal stages of development [83, 86, 93].
Modifi ed vaccinia virus Ankara (MVA) is among the most advanced and well-characterized recom-binant vaccine vectors currently in human clinical trials [103]. MVA is a highly attenuated strain of vaccinia virus, originating from chorioallantois membrane produced vaccinia virus Ankara after more than 570 serial passages in primary chicken embryo fi broblasts (CEF). This serial passaging of MVA resulted in a loss of virulence and immune evasion genes as well as its ability to replicate
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in most mammalian cells [90, 91]. Currently, European Medicine Agency (EMA) has approved a vaccine against smallpox containing a non-replicating live form of the MVA virus, which implies effectiveness and safety of this vaccine platform technology as an entity suitable for addressing a wide variety of infectious diseases [110, 294].
Altenburg et al. elaborate on the advantages and disadvantages of MVA as viral vector platform for vaccines against infl uenza and other viral respiratory diseases in their reviews. They describe unique properties of MVA as viral vector vaccine including its biological safety profi le, relative easy production process for large-scale manufacturing, and potential to effi ciently express a plethora of foreign genes either alone or in combination enabling the use of MVA as a versatile and multiva-lent vaccine [88, 110, 111]. Moreover, MVA has immunostimulatory capacities to induce protective immune responses against many infectious agents. In particular targeting the innate in addition to the adaptive immune system obviates the use of an adjuvant [88]. Replication defi ciency of MVA is confi rmed in various in vivo mammalian models including animals with severe immunodefi ciencies [110]. Furthermore, recombinant MVA viruses can be used under conditions of biosafety level 1 in most countries. These features provide advantages compared to replication competent poxvirus vectors and other viral vectors [110].
Pre-existing anti-vector immunity may hamper the effectiveness of vectored vaccines. Nonetheless, also in the presence of pre-existing anti-vector immunity, protective immunity against for instance infl uenza could be induced [87, 88, 110]. Although several infl uenza virus proteins have been shown to induce different levels of protective immunity, in the current study we took the approach that an MVA based vaccine against pandemic infl uenza should primarily express the hemagglutinin (HA) gene [98, 113-115, 295].
Limitations associated with other production platforms also apply to MVA viral vectored vaccine candidates. Considering that MVA has the potential to express multiple foreign antigens of interest, each new recombinant MVA virus is considered a new biological entity and thus requires proper quality assessment. Furthermore, heterologous prime-boost vaccination strategies will complicate the regulatory approval process [110]. These issues need to be addressed prior to successful im-plementation of this platform for use against pre-pandemic and pandemic infl uenza and other new emerging pathogens. More data on effi cacy in humans would also contribute to success of this platform.
In the present study we have evaluated the commercial potential of MVA vector-based vaccine tech-nology for pre-pandemic and pandemic infl uenza by approaching key opinion leaders (KOLs) in the fi eld of infl uenza vaccine development, in order to obtain a balanced view on its strengths, weak-
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nesses, opportunities, and threats using the SWOT-AHP combined analytic method [296-298]. Ap-plication of analytic hierarchy process (AHP) method helps construct a multi-criteria decision-mak-ing process, identify decision-making factors, and determine the reciprocal importance of these factors [299]. AHP method provides the possibility to quantify and prioritize subjective, qualitative, and intangible factors into numeric values. Moreover, this approach is an effective decision-making method especially when subjectivity might exist [297].
In doing so we provide an empirically validated contemporary industry view of MVA as a vaccine technology platform. We demonstrate that MVA is considered a suitable platform for vaccine devel-opment, and argue that there is a future for MVA-based vector platforms to develop not only pre-ventive, but also therapeutic vaccines to address unmet public health needs in the fi eld of infectious diseases.
6.2. Methodology
The methodology used is built-up into three data collection moments. First, collecting background information from the literature, which subsequently enabled us to develop a balanced set of inter-view questions. Next, quantifi cation of the qualitative data generated from interviews with KOLs by means of SWOT-AHP application. Finally, drawing conclusions by integrating the two previous steps, Table 6.1.
Table 6.1. Study design. SWOT: Strengths, Weaknesses, Opportunities and Threats.
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6.2.1. Literature Reviews & Interviews
A literature study was conducted to gain more insight into the MVA platform and its potential for infl uenza vaccine development, learn more about the industrial players in the market, and develop a validated set of interview questions. Market potential of a new production platform for infl uenza vaccine development, such as MVA, is best evaluated by KOLs specialized in the fi eld of infl uenza intervention strategies. In order to determine SWOT of the MVA platform for infl uenza vaccines, semi-structured interviews with KOLs were performed.
Fifty out of a total number of sixty-three (79%) articles that were selected based on topic relevance were published after 2010. Only thirteen (21%) did not meet this criterion. This study used a combi-nation of Pubmed, Google Scholar, ScienceDirect, Web of Science, applying relevant search terms on the subject including virus vectored vaccine, modifi ed vaccinia virus Ankara (MVA), infl uenza
virus, pre-pandemic and pandemic vaccine, vaccine technology platform, and vaccine production platform.
6.2.1.1. Interview Participants KOLs, who include a range of infl uential individuals with extensive knowledge and experience in the fi eld of infl uenza (e.g., US Department of Health and Human Services (HHS), CEOs and Se-nior managers from large companies in the fi eld of infl uenza, World Health Organization (WHO), National Institute of Infectious Diseases (NIAID)), wish to remain anonymous due to confi dential-ity concerns. Participants were approached to contribute in interviews representing industry, (non) governmental, and public research institutions. This selection was based on their expertise in the infl uenza vaccine fi eld. Twenty-four out of ninety KOLs agreed to participate in the study (response rate of approximately 30%). In this research we subdivided them into two groups: industry and non-industry. Eighteen participants from industry and six, non-industry participants contributed in the study.
6.2.1.2. Exploratory Interviews The participants were contacted, informed about the nature of the study, and invited to take part. Two pilot interview sessions were conducted prior to implementation of 60 minutes semi-structured interviews.
6.2.1.3. Interview Questions Interview questions (Appendix) were developed focusing on the infl uenza fi eld, in particular MVA virus vector vaccines, and their implementation potential. In essence, the interviews were de-signed to gather data on how KOLs perceive the current pandemic vaccine fi eld, possibilities to
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increase the commercially attractiveness and public health value of infl uenza vaccines, reciprocal competition in the infl uenza vaccine market, and SWOT of MVA platform for infl uenza vaccines.
6.2.2. SWOT Analysis
SWOT analysis is a commonly used business analysis tool to evaluate external and internal envi-ronmental factors, which could impact the strategic planning process. The purpose of SWOT ap-plication in decision-making is to develop and implement a strategy resulting in a good fi t between internal and external factors. Internal factors to the theme are usually classifi ed as strengths and weaknesses, and those external to the theme are classifi ed as opportunities and threats, Figure 6.1. [296-298, 300].
6.2.3. AHP Analysis
AHP is a multi-criteria decision analysis tool that helps express the general decision process by deconstructing a complicated problem into a multilevel hierarchical structure [299]. Furthermore, AHP method is applied as prioritization mechanism to accomplish pairwise comparison of factors representing the relative importance of the criteria determined by the joint judgments of the experts. The team of experts provides their preferences by comparing two given factors. The question is which of the two factors has a greater value and how much. The comparisons are made using a scale of absolute numbers that represents which of the two factors has a greater weight in the choice and how much. In AHP, pairwise comparisons are based on a standardized comparison scale of 1-9, Table 6.2. The whole number is entered in its appropriate position and its reciprocal in the transpose position [299, 301, 302].
Figure 6.1. SWOT analysis framework. Environmental scan provide two different analysis; Internal factors and External factors. This study comprises; Internal factors: Strengths (8 factors), Weaknesses (3 factors); External factors: Opportunities (5 factors), Threats (6 factors).
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Pairwise comparisons are separately made for each SWOT group. In the next step relative weights of factors are calculated where W1, W2,…, Wn are the weights obtained by the comparisons. Sub-sequently, multiply together the elements in each row of the matrix, and then take the nth root of that product. “W” is called an “eigenvector” of order n. The sum of the nth roots is used to normalize the eigenvectors to add to 1, Table 6.5.
Table 6.2. AHP scale. Pairwise comparison scale.
Each eigenvector is normalized by multiplying the matrix of judgments by eigenvectors of each element, providing a new vector. Relative importance values are obtained by using the eigenvalue techniques to obtain “λ”. “λ” is called an “eigenvalue”. λ is calculated by dividing each new vector by the corresponding eigenvector element. The mean of these values is the estimated λ max. If the pairwise comparisons are consistent, the λ max=n.
The quality of the AHP is related to the consistency of the pairwise comparison judgments. There-fore, it is important to judge the consistency of the decision-making. The Consistency Index (CI) is calculated using the following equation:
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Consistency Ratio (CR) can conclude whether the evaluations are suffi ciently consistent. According to Random Index (RI), if the number of CR exceeds the value of 0.1, the evaluation procedure has to be repeated to improve consistency, Table 6.3. A CR of 0.1 or less is generally stated to be accept-able. The AHP method applied in this study is based on research method developed by Saaty [299, 301] and used by Görener, Lee, and Kahraman [297, 298, 303].
Table 6.3. Random Index.
6.2.4. SWOT-AHP Analysis Models
Here, we provide quantitative means for SWOT analysis. One of the main limitations of the classical SWOT analysis is that the importance of each factor cannot be quantifi ed. Therefore, it is diffi cult to assess the mutual effect on factors and each factor on the decision [297]. In order to circumvent this inadequacy, the SWOT framework is designed into a hierarchic structure and the model is integrated and analyzed using the AHP.
In this study SWOT factors are identifi ed by KOLs from industry, (non) governmental, and public research institutions. All pairwise comparisons are accomplished by the joint judgment of a team of experts representing the relative importance of the criteria. Expert team is constituted from four members with expertise in the fi eld of infl uenza and analysis skills [297].
Quantifi cation of the SWOT frame via AHP provides the opportunity to calculate priorities for the groups and factors analyzed. The inconsistency ratios represent whether the experts are consistent with themselves while assigning the scores in the pairwise comparison matrixes. This method is used to determine relative priorities on absolute scales from both discrete and continuous paired comparisons in multilevel hierarchic structures. Furthermore, AHP is an effective decision-making method especially when subjectivity might exist [297].
In this study, the result of the AHP-SWOT model application was divided into three parts: Goal, the SWOT groups and the factors included within each SWOT group, Figure 6.2. The goal of this study
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is identifi cation and quantifi cation of MVA’s strengths, weaknesses, market opportunities, and po-tential threats to provide insight into the potential and critical issues that impact the overall success of implementation of this novel platform.
Figure 6.2. Hierarchical structure of the SWOT Matrix.
6.3. Results
Results of the literature study on the MVA platform and its potential for infl uenza vaccine develop-ment in comparison to alternative infl uenza pandemic vaccine production methods are presented in Table 6.4.
Analyzing the SWOT groups and factors from the interview transcripts resulted in 8 strengths, 3 weaknesses, 5 opportunities, and 6 threats tabulated in a SWOT matrix, as presented in Table 6.5. Subsequently, quantifi cation of the SWOT group by means of AHP offers the possibility to calculate the priorities for each group and factors within these groups. Pairwise comparisons of the SWOT groups are determined by asking the question of which of the two groups has a greater weight in the choice and how much. Each preference is converted into a numeric value based on 1-9 Saaty’s AHP scale [299]. All pairwise comparisons were performed by a team of experts in the fi eld. Multiplying the entries in each row of the matrix together and then taking the nth root of that product provide the eigenvector (Importance Degree). Subsequently, the nth roots are summed and the sum is used to normalize each eigenvector number to add to 1. (Example strengths from SWOT group (Table 6.5): product of the row; 20, nth root; 2.12, sum of all nth roots; 4.59, importance degree; 2.12/4.59=0.46)
Table 6.5. demonstrates that the strengths far outdistance (46%) the opportunities, threats, and weaknesses of MVA platform, respectively. The strengths are 4.48 times more important than weak-nesses (0.461/0.103) and 2.11 times more important than opportunities and threats (0.461/0.218).
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Table 6.4. Alternative influenza pandemic vaccine production methods beyond phase I. Pro’s and con’s in relation to the MVA platform. (3. Sub-unit: Influenza virus-derived; purified essential antigens (e.g., hemag-glutinin (HA) and neuraminidase (NA) that stimulate immune system, Vector-derived; expression system for gene encoding antigens/delivery system for genes/antigens to generate desired immune response) [69, 247, 304-321].
AlternativeProductionMethods
1. Whole inactivated virus (WIV)
Advantages Disadvantages Ref.
Established technology Side effectsHigh dose/ Adjuvant required
304-307
1. Split virus Established technologyLess side-effectscompared to WIV
Influenza virus derived
High dose/Adjuvant required
304, 309
3. Sub-unit (HA/NA/...)
Established well-defined technologyLess side-effects compared to WIV and Split Virus
High dose/Adjuvant required
308-310
Vector derived (e.g. baculovirus)
Rapid productionLess side-effects
High dose/Adjuvant required
69
VLP Rapid production Less side effects
Complex technology High level purification
311-313
4. Vectored subunit (e.g. Adenovirus)
High dose productionpossibilityCross-reactive
Pre-existinginterfering immunity
247, 308, 314
5. Live-Attenuated
Established technologyLow/ single dose requiredNeedle free application
Temperaturesensitive
315-316
6. DNA vaccines
No pre-existing interfering immunity
Limited efficacy 308, 319-321
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6.3.1. Descriptive Results, Strengths
The eight main strengths are determined as follows:
• Non-adjuvanted MVA is commercially more attractive. This is due to safety con-cerns that adjuvants still raise. The benefi ts from adjuvants have to be balancedwith the risks of adverse reactions.
• Good immunogenicity and broad protective effi cacy of MVA offer excellent com-mercial attractiveness. Convincing human clinical trials data have to be provided.
• Non-adjuvanted MVA provides more public health value. This is due to safety con-cerns.
• High immunogenicity and reasonable pricing make MVA commercially more at-tractive. Although the vaccine market is competitive, providing vaccines withhigh immunogenicity and reasonable pricing creates a competitive advantage inthe market.
• Public health value of MVA is sustainable. This is due to high value of immunoge-nicity in a public health point of view.
• MVA’s commercially attractiveness is sustainable. MVA is an excellent backbone,safe, and effective.
• MVA has a high public health value. In case of equal safety and effectiveness ascurrent vaccines.
• Good immunogenicity and broad protective effi cacy of MVA provide public healthvalue. Convincing data have to be provided on vaccine superiority for scientifi ccommunity and public.
6.3.2. Descriptive Results, Weaknesses
The three main weaknesses are determined as follows:
• Low public health value. Doubts are expressed concerning vector vaccines and anti-vectorimmunity.
• MVA’s commercial attractiveness might be very sustainable, but without seasonal productionfacility, no one is going to bear the development costs.
• Non-adjuvanted vaccines: offer fewer doses, fewer people get vaccinated, slower marketreach.
6.3.3. Descriptive Results, Opportunities
The fi ve main opportunities are determined as follows:• MVA can be presented as pre-pandemic and mock-up vaccines. Mock-up can be employed for
regulatory construct to make advance agreements with government.• Competition of other non-adjuvanted H5N1 vaccines is not relevant. Infl uenza market is large.
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There are still opportunities for entry and growth for vaccines companies.• Non-adjuvanted vaccines offer more opportunities in some markets (e.g., USA). This is due to
strict regulations for the human use of adjuvants than those applied for veterinary vaccines.• Regulatory approval of non-adjuvanted MVA will make it commercially more attractive.• Sustainability of MVA’s commercial attractiveness depends on quality, availability, and cost.
6.3.4. Descriptive Results, Threats
The six main threats are determined as follows:• Commercial attractiveness of non-adjuvanted MVA is antigen dependent. Dependent on the
virulent of emerging pandemic infl uenza virus.• Public health value of non-adjuvanted MVA depends on vaccine acceptance by public and
suffi cient coverage. It is challenging to convince people to get vaccinated against infl uenzavirus with another virus (MVA).
• Adjuvanted vaccines offer more doses.• Commercial attractiveness of non-adjuvanted MVA depends on public acceptance/perception.• Adjuvant can make a difference between protection and no protection and provides cross-re-
activity.• Many competing products are in late stage clinical trials. MVA has to have profound compet-
itive advantages to compete on the same market for same customers.
Subsequently, AHP was used to perform pairwise comparisons to derive relative importance degrees of the factors within each group. As demonstrated in Table 6.6., in the comparison matrix the sum of vector is 1, and the vector represents the relative importance among the factors compared. Com-parison of various factors within the strengths group illustrates that S1 and S2 are considered to be equally infl uential in this group. Table 6.6. exemplifi es the comparison matrix applied to determine the importance degrees of each SWOT group. The priority degrees of the SWOT factors within the groups have been visualized in Figure 6.3. The most infl uential factors within the SWOT groups are: S1/S2, W1, O1, T1/T2.
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Figure 6.3. The priority degree of the categorized factors from strengths, weaknesses, opportunities and threats. S1/S2-W1-O1-T1/T2 are the most influential factors within the SWOT groups.
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Table 6.5. SWOT Matrix; Importance degrees within SWOT group. Comparing the importance degrees of the SWOT group, strengths appear to be the most outstanding property of MVA (Example; strengths from SWOT group: product of the row; 20, nth root; 2.12, sum of all nth roots; 4.59, importance degree; 2.12/4.59=0.46).
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129
Figure 6.4. Illustration of overall priority of SWOT factors per group. Strengths, opportunities, and threats are the three determining group in the MVA market, respectively.
Last, the overall priority scores of the SWOT factors were calculated by multiplying the importance degrees of SWOT groups, as shown in Table 6.5., by the priority degrees of the factors within the groups as shown in Table 6.7. The overall priorities of the most infl uential SWOT factors were: strengths, 0.111 (e.g., 0.461 x 0.241 = 0.111); weaknesses, 0.043; opportunities, 0.085; threats, 0.045. The fi nal stage was to calculate the consistency ratio in order to fi nd out how consistent the judgments have been relative to large samples of purely random judgments. The number 0.1 is the accepted upper limit for consistency ratio (CR) [297]. The fi nal CR of all the pairwise comparisons is within the limit.
Figure 6.4. visualizes the graphical interpretation of overall priority of the SWOT group within the fi eld of MVA according to the KOLs. 46% of the MVA market is assigned to the strengths of this platform. Opportunities, threats, and weaknesses constitute 22%, 22%, and 10% of the market, re-spectively.
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Table 6.7. Inconsistency ratio of the SWOT group and priority of the factors within the groups have been illustrated. Overall priority of each factor is resulted from multiplying the priority of the group with priority of the factor within the group.
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6.4. Discussion
This study provides unique quantitative data to support studies suggesting that MVA meets the un-met needs of the current vaccine platform for pandemic infl uenza vaccine development [83, 86-88, 90, 103]. The fi ndings show the following ranking of each SWOT group priority: Strengths (Impor-tance Degree (ID), 46.1%), Opportunities and Threats (ID, 21.8%), and Weaknesses (ID, 10.3%). These results indicate that the KOLs evaluated strengths of the MVA platform outweigh weaknesses, opportunities, and threats. This indicates that safety, good immunogenicity, and broad protective effi cacy are overall the most important considerations for successful implementation of this vaccine platform. Furthermore, literature describes various (pre) clinical trials and studies demonstrating immunostimulatory capacities that make MVA induce protective immune responses against many infectious agents [88, 90, 111, 295, 322, 323].
This study was designed to explore the commercial potential of the MVA platform for the develop-ment of novel generation pandemic infl uenza vaccines. Results from both literature study and KOL’s perspectives helped us understand the current strengths, weaknesses, opportunities, and threats for implementation of this platform. Furthermore, the quantifi ed data helped in assessing the reciprocal effect within each SWOT group and effect of each factor within each group on the strategic planning process.
Since conversion from qualitative to quantitative scales is based on untested assumption, critics argue the existence of possible inconsistency in pairwise comparisons. The use of pairwise com-parison, however, simplifi es the expert’s judgmental tasks to focus each time on a part of the issue. Furthermore, AHP method automatically carries out an inherent inconsistency check by requiring more judgments to be made than it is needed to establish a set of weights [324, 325]. Critics have also questioned whether the AHP method can represent KOL’s preference given the quantitative representations of these judgments and the mathematical method applied. It is important to realize that deconstructing important factors during decision-making process allows simplifying a complex problem into a multi-criteria decision-making, which consequently contributes to the main purpose of any decision; creating insights and understanding rather than fi nding the right answer.
Literature has widely acknowledged that MVA has advantages over currently used vaccines and vaccine platforms in development [86, 90, 111, 326]. Under the strength group, immunogenicity related factors were rated as the most infl uential strength to be considered with an approximately 0.5 total priority of factors within this group and a 0.23 as overall priority. Subsequently, immunogenic capabilities of MVA without the need of an adjuvant are the second most infl uential subject in this group with a 0.34 priority rate within the group and a 0.16 overall priority rate. Finally, factors relat-
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ed to safety and effectiveness of this platform are considered to be important assets of this platform with a priority rate of 0.17 within the groups and an overall priority rate of 0.078. From a KOL’s per-spective, factors related to immunogenicity and without an adjuvant need, increase the commercial attractiveness and public health value of this platform. Moreover, factors related to immunogenicity and safety and effectiveness of this platform increase its sustainability value in the vaccine market. According to the KOLs, providing human data on MVA’s capability to induce enhanced immunoge-nicity and broad protective effi cacy will further increase commercial attractiveness of this platform
Furthermore, these properties provide the opportunity of getting regulatory approval in particular in some markets where adjuvants are not being accepted due to safety concerns. Industry represen-tatives indicate that using the MVA platform creates opportunity to invade other as yet unreached markets. Furthermore, the use of mock-up dossiers approved for regulatory authorities may help in negotiating advance agreements with governments, ensuring industries future cash fl ow. In case of novel vaccines, safety of the vaccine is the fi rst consideration. Safety data from the MVA’s clinical trials show great promise [91]. At the same time, KOLs emphasize the fact that MVA’s capability to induce such immunogenicity could be largely dependent on the antigen used. According to the literature, much research is dedicated to emerging novel and alternative vaccine strategies over the last decade. Research in vaccine fi eld emphasizes emergence of the poxviral vaccine platforms as a profound delivery platform [86, 88, 327].
KOLs indicate that one of the main challenges that MVA-vectored vaccines are facing is the ac-ceptance of this platform by the lay public in the vaccine fi eld. This challenge is contradicted by our literature search results. Application of poxvirus vectors for the expression of foreign genes of interest is becoming more attractive than other viral vectors [91, 110]. Despite the fact that there are no licensed poxvirus vector-based human vaccines on the market yet, there is an increasing amount of clinical trials of poxvirus vector vaccine candidates for infectious diseases [83]. This discrepancy might be an indication that there is a perception change towards the vector vaccines. In this context it is important to recognize that MVA, as a modifi ed live form of the vaccinia virus, has already been approved as a backbone vector system in a vaccine against smallpox [294].
A key unmet need of the current infl uenza vaccines are speed and scalability resulting in production of suffi cient vaccine dosages within the required time frame. KOLs indicate the same unmet need as one of the threats MVA might be encountering. Recently, large-scale production of MVA has been shown to be possible for four million doses of non-recombinant MVA-smallpox-vaccine. Moreover, two companies have developed cell lines suitable for MVA manufacturing to avoid the need for embryonated eggs [87]. Non-industry representatives consider issues related to quality, safety, avail-ability, and reasonable pricing of vaccines essential for MVA’s commercial sustainability. Moreover,
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they indicate that public vaccine acceptance will likely be a key factor to simultaneously increase public health value and commercial attractiveness of the MVA platform.
This study indicates that the sustainability of the MVA platform can be assured by exploring this platform for use in both seasonal and pandemic infl uenza as well as other infectious diseases in particular those caused by newly emerging viruses [87]. Some KOLs stress the challenge of having many competitors in the infl uenza market fi ghting for the same costumers. In 2011, the global in-fl uenza vaccine market was valued at over three and a half billion dollars and is predicted to grow annually about 6% over the next seven years to reach over fi ve billion dollars in 2018 [328].
The most favorable feature of this platform is its proven immunogenicity, broad protective effi cacy without the requirement of an adjuvant, and its relatively easy scalability which make MVA the vaccine platform of choice for many so far unmet vaccine needs. Thus, MVA’s specifi c properties stress the great potential of this platform. Although the public acceptance of such vaccines can be challenging, providing safety data in human trials could result in a change in perception. The infl u-enza market offers suffi cient opportunities for MVA to be implemented as a novel vaccine platform with broad protection against seasonal and pandemic infl uenza viruses. Despite the fact that poxviral vector platform holds a great promise for market implementation, more collaboration is required between academia, vaccine industries, and the regulatory authorities [88].
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Pre-pandemic/Pandemic Vaccines
To what extent do you think there is room left on the current vaccine market for a new mock-up, (pre) pandemic vaccine candidate? What is your opinion regarding currently available (pre) pandemic candidate vaccines considering virus strain, immunogenicity, price, production capacity and speed? What are their shortcomings? What (realistic) characteristics should a (pre) pandemic vaccine have to obtain public health value? To be commercially attractive? What are the primary limitations to develop new (pre) pandemic vaccines? How could these limitations be overcome? To what extent are you willing to invest in a new vaccine even when you are not the market leader?
MVA Platform
What are strengths and weaknesses of MVA platform? What could be opportunities and threats of such a platform in your opinion? Considering the advantages and disadvantages of such a platform, to what extent do you think it has a sustainable market value? Is such a platform commercially attractive to invest in?
MVA-based H5N1 Vaccine
What should be the best manner to bring the MVA-based H5N1 non-adjuvanted vaccine candidate into the market: as a pre-pandemic and/or mock-up vaccine? Comparing non-adjuvanted MVA based vaccine candidates to adjuvant vaccines, what are the strengths and weaknesses as it comes to commercial attractiveness? Comparing non-adjuvanted and adjuvanted vaccines to each other in general, what is your opinion regarding an MVA based non-adjuvanted vaccine candidate as it comes to commercial attractiveness? The production process of an MVA-based vaccine candidate is relatively easy; it can be produced on biosafety level 1 conditions. What is your opinion regarding commercial attractiveness? MVA-based H5N1 vaccine candidate shows a good immunogenicity and broad protective efficacy, what is your opinion concerning the public health value/ commercial attractiveness? MVA-based H5N1 vaccine candidates show a good safety profile, good immunogenicity, independent of embryonated chicken eggs. What is your opinion as it comes to commercial attractiveness? Baxter has approval from the EMA for their non-adjuvanted H5N1 pandemic mock-up vaccine produced on vero cells. To what extent do you think this will influence commercial attractiveness of the MVA-based H5N1 non-adjuvanted vaccine candidates? Considering all strengths, weaknesses and competitors of this MVA-based H5N1 non- adjuvant vaccine candidate, to what extent do you think this product has a public health value? And sustainable commercial attractiveness?
Appendix
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Chapter 7Emergency Deployment of Genetically
Engineered Veterinary Vaccines in Europe
Published as:Ramezanpour, B., de Foucauld, J. and Kortekaas J. Vaccine. 2016 (In press)
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Abstract
On the 9th of November 2015, preceding the Word Veterinary Vaccine Congress, a workshop was held to discuss how veterinary vaccines can be deployed more rapidly to appropriately respond to future epizootics in Europe. Considering their potential and unprecedented suitability for surge pro-duction, the workshop focussed on vaccines based on genetically engineered viruses and replicon particles. The workshop was attended by academia and representatives from leading pharmaceutical companies, regulatory experts, the European Medicines Agency and the European Commission. We here outline the present regulatory pathways for genetically engineered vaccines in Europe and describe the incentive for the organization of the pre-congress workshop. The participants agreed that existing European regulations on the deliberate release of genetically engineered vaccines into the environment should be updated to facilitate quick deployment of these vaccines in emergency situations.
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7.1. Introduction
The fi rst vaccination in Europe took place in the 18th century, when Europe was plagued by severe outbreaks of rinderpest, a disease caused by the deadly rinderpest virus (RPV). A Dutch farmer and cattle trader named Geert Reinders (1737–1815) observed that calves born from cows that had survived rinderpest were less susceptible to the disease. We now know that this so-called “passive immunity” resulted from the intake of maternal antibodies via colostrum. Moreover, Reinders de-scribed that once these calves were inoculated with virulent RPV, they developed only mild clinical symptoms and subsequently became immune to the virus. These fi rst vaccination experiments were described in letters directed to the Royal Society of London in 1776. Twenty-two years later, Ed-ward Jenner (1749-1823) reported that humans could be protected from the highly deadly smallpox (variola) virus by “variolation” with the cowpox virus, a close relative of the variola virus that is non-pathogenic to humans [329]. Later, cowpox was replaced by the related vaccinia virus. The discoveries by Reinders and Jenner contributed to the development of live vaccines that ultimate-ly facilitated the global eradication of two devastating infectious diseases of human and animals; smallpox in 1980 and rinderpest in 2010 [6-8]. Today, after more than two centuries of vaccine research and development, numerous viral diseases can be controlled by vaccination and some are even targeted for global eradication, such as polio encephalomyelitis in the human fi eld [330] and sheep and goat plague (peste des petits ruminants) in the veterinary fi eld [331].
Live-attenuated vaccines against viral diseases of livestock are classically developed by carrying out passages of the viruses in heterologous hosts or cell culture, resulting in the accumulation of at-tenuating mutations or deletions in the viral genomes. Although numerous vaccines were developed using these methods, the safety of such vaccines needs to be determined empirically and is often not understood at the molecular level. Consequently, these vaccines may suffer from concerns about genetic stability and reversion to virulence. The availability of reverse genetics systems to introduce precisely defi ned mutations into viral genomes is therefore considered a milestone in veterinary medicine. Already in the early 90’s, genetic engineering was used to create a vaccinia virus express-ing the rabies virus glycoprotein. After this vaccine was found to be stable and safe for target and non-target animals, it was successfully applied as a bait vaccine in an extensive open fi eld trial [332, 333]. Around the same time, genetic engineering was used to attenuate Suid herpesvirus 1, the caus-ative agent of the economically important Aujesky’s disease of swine [334]. The resulting vaccine virus was successfully used to eradicate Aujesky’s disease from The Netherlands [335].
Genetic engineering also enabled the development of multivalent vaccines. A virus that was used for such approach is the herpesvirus of turkey (HVT) [336, 337]. HVT is an apathogenic virus that protects chickens against Marek’s disease virus, which is caused by the related herpesvirus Gallid herpesvirus 2 and was used to develop bivalent vaccines that also protects against infectious bursal
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disease virus [338], Newcastle Disease virus [339, 340], infectious laryngotracheitis virus [341] or infl uenza A virus [342-345]. A fi nal example of a multivalent vaccine is based on an attenuated myxomavirus that expresses the capsid protein gene of the calicivirus rabbit hemorrhagic disease virus. This vaccine provides protection from myxomatosis and rabbit hemorrhagic disease, two highly deadly diseases of rabbits [346]. Another highly successful vaccine platform is based on the Canarypox virus (family Poxviridae, genus Avipox). Examples of commercially registered vaccines include vaccines for the protection of horses against infl uenza and West Nile virus, cats from rabies and feline leukaemia virus and dogs and ferrets from canine distemper virus [347].
Until today, two vaccines based on genetically engineered RNA viruses were registered in Europe, which are both based on genetically engineered Bovine virus diarrhoea viruses (BVDV). The fi rst vaccine contains two genetically engineered BVD viruses and can protect cattle from BVDV types I and II [348]. The second vaccine that was recently marketed comprises an attenuated BVDV virus that expressed the E2 protein of CSF virus [349]. Of note, the latter vaccine nicely exemplifi es how genetic engineering can be used to develop vaccines that enable Differentiating Infected from Vac-cinated Animals (DIVA).
Apart from veterinary vaccines that are already registered, numerous genetically engineered vi-rus-based vaccines are currently in development in Europe. This not only includes live viruses, but also so-called “replicon” particles [350, 351]. Replicon particles phenotypically resemble the viruses from which they were derived, but lack (part of) a gene that is necessary for the production of progeny particles [352]. These particles are capable of infecting target cells of the vaccinated animal, but are incapable of spreading from the initial site of infection. By this feature, replicon particles are aimed to combine the effi cacy of live vaccines with the safety of inactivated vaccines. Recently, replicon particle-based vaccines targeting Porcine Epidemic Diarrhea virus or avian in-fl uenza virus were developed and were recently granted conditional licenses in the US [353, 354].
The availability of platform-based vaccines that are registered in Europe would suggest that these platforms could be used to respond to epizootics within months or even weeks after onset of an out-break. For example, an incursion of a highly pathogenic and fast-spreading strain of avian infl uenza virus could be effi ciently counteracted by a vaccine based on HVT expressing the hemagglutinin (HA) protein [342]. Preferably, the HVT, or similar vaccine vector, expressing a given infl uenza virus HA protein is already registered in Europe, which can be updated to fi t a novel outbreak strain in a well-defi ned fast-track process. Unfortunately, within the current legislation, such as emergency response is not possible.
To discuss which innovations are needed in regulatory procedures to enable emergency vaccination with genetically engineered vaccines in Europe, a workshop entitled “From Agent Identifi cation
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to Vaccine Supply” was organised preceding the World Veterinary Vaccine Congress of 2015, in Madrid, Spain. The workshop was attended by sixty-six scientists involved in veterinary vaccine development, representatives from leading pharmaceutical companies, regulatory experts and rep-resentatives from the European Medicines Agency (EMA) and the European Committee (EC). The use of existing platforms that are already registered in Europe was discussed as well as promising novel technologies. To enable rapid deployment of these vaccines in response to future epizootics, signifi cant innovations in European regulations are required. We here review the status quo of the European regulatory arena by evaluating the current knowledge and performing a literature search. Furthermore, a workshop attended by different stakeholders (representatives from: academia, lead-ing pharmaceutical companies, regulatory, European Medicines Agency, and European commission) enabled us to propose innovations in regulatory procedures to enable surge vaccine deployment in response to rapidly spreading epizootics in Europe.
7.2. Current European Regulations for Genetically Engineered Vaccines
Since the late 1980’s, the European Union (EU) has provided regulations for new technology-based vaccines, including genetically engineered vaccines, starting with Council Directive 87/22/EEC of 22 December 1986. This directive covered the approximation of national measures relating to the placing on the market of high-technology medicinal products, particularly those derived from bio-technology [355]. Later, in 1990, a more specifi c directive was issued (90/220/EEC of 23 April 1990 [356]), that dealt with the deliberate release into the environment of genetically modifi ed organ-isms (GMOs) for human and veterinary vaccines. This directive was fi nally replaced by Directive 2001/18/EC, which describes regulations regarding the release of genetically engineered organisms into the environment [357]. Of note, this directive was amended by Directive 2008/27/EC [358]. The scope of Directive 2001/18/EC, as amended, covers all “…organism, with the exception of hu-man beings, in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination”, where organism means “…any biological entity capable of replication or of transferring genetic material”. Furthermore, the processes used to modify (al-ter) the genetic material must use: (1) recombinant nucleic acid techniques involving the formation of new combinations of genetic material by the insertion of nucleic acid molecules produced by whatever means outside an organism, into any virus, bacterial plasmid or other vector system and their incorporation into a host organism in which they do not naturally occur but in which they are capable of continued propagation; (2) techniques involving the direct introduction into an organism of heritable material prepared outside the organism including micro-injection, macro-injection and micro-encapsulation; (3) cell fusion (including protoplast fusion) or hybridisation techniques where live cells with new combinations of heritable genetic material are formed through the fusion of two
142
or more cells by means of methods that do not occur naturally (same directive Annex I.A. part 1). The interpretation of these defi nitions is a matter of debate. For example, a virus or virus particle resulted from these processes, even when it is replication-defi cient in the target cells of vaccinated animals, might fall within the scope of this directive as it brings (or ‘transfers’) genetic material to the host cell, allowing the expression of antigen(s) that will trigger a protection against specifi c disease(s). Canarypox-based mammalian vaccines fall under the scope of Directive 2001/18/EC; it could therefore be the case for replicon particle-based vaccines. On the other hand, DNA vaccines were considered as ‘out of scope’.
The directive gives all instructions to applicants to request a permit for carrying out fi eld trials need-ed for the registration procedure. For this, the applicant company must prepare a dossier containing a technical fi le with information relating to: (1) vaccine construct, (2) conditions of release of the vaccine and the target receiving environment, (3) interactions between the vaccine and the specifi ed environment, (4) how to manage the vaccine once introduced into the fi eld with respect to control, remediation methods, waste treatment, and emergency response plans. In addition, an environmental risk assessment must be carried out by the applicant, following prescribed guidelines (Annex II, III and VII of Directive 2001/18, Commission Decision 2002/623/EC [359]). Furthermore, a summary document should be provided (Same Directive and Council Decision 2002/813/EC [360]).
The dossier is submitted in the country or countries where the applicant desires to test the vaccine in the fi eld. Subsequently, the vaccine will be assessed by the national competent authorities of each country, which are usually represented by a specifi c committee of experts in genetically engineered organisms; this committee is a separate entity from the veterinary regulatory authorities. The EC and all other member states are kept informed during this procedure and are entitled to intervene if nec-essary. Furthermore, the assessment includes consultation of the public. Once this permit is granted by the committee, the applicant can request the other permit needed for testing any veterinary vac-cine in the fi eld, which is granted by the veterinary registration authorities. Subsequently, comple-tion of the fi eld trials and fi nalizing the registration dossier are the fi nal steps prior to submission of the European-wide registration procedure to the EMA. Indeed, all vaccines falling under the scope of Directive 2001/18/EC, follow a EU-wide market authorization process through the EMA (regula-tion 726/2004/EC, [361]). More than 19 different live genetically engineered veterinary vaccines or vaccine components were registered under these different directives [362-380].
It is worthwhile to note a few points from this process. Although the fi nal registration process is directly handled by the EMA, the risk of vaccine release into the fi eld is fi rst assessed by the na-tional committees of each relevant country where the vaccine needs to be tested in the fi eld. In the current situation, only a few EU countries were involved and took this responsibility for veterinary
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vaccines; this includes Belgium, France, Germany, Hungary, the Netherlands and Spain [381]. Since the national committee usually manages all matters concerning genetically engineered organisms (including plants), it is comprised of members with various background (e.g. plant, human, and vet-erinary experts) with only a few directly involved in the veterinary fi eld. The risk assessment for the national fi eld release focuses solely on safety data, no effi cacy data are required at this stage. Only later during the registration process, the European authorities will be able to carry out the general benefi t/risk assessment, based on all quality, safety and effi cacy data, which is the basis for granting a marketing authorization.
The complex nature of the different dossiers and procedures for genetically engineered veterinary vaccines, contributes to a quite lengthy timeline for the completion of the process. It requires ap-proximately 18 to 24 months to build the fi eld release request dossier from the established master seed and subsequently 9 to 10 months to get both fi eld release and fi eld trial permits. Furthermore, an additional 18 to 24 months are needed to prepare the fi nal registration dossier for the European Medicines Agency. The central registration procedure itself takes an average of 18 months to be completed. Overall, this is 9 to 18 months more than for conventional vaccines.
7.3. Opportunities for Fast-track Deployment of Vaccines Within the Bound-aries of Current Legislation
There are a few improvement opportunities concerning the current regulations associated with the scientifi c assessment and registration procedure, which may allow shortening the timeline for vac-cine availability. Considering approaches to reduce the amount of testing in order to obtain a fi eld trial permit, article 7 of Directive 2001/18 could be applicable to vaccines as well, although they are not explicitly mentioned in Annex III referred to in this article. This implies that the assessment can be based on the existing data from a previously approved product (in this case platform vaccines and technologies, e.g. vector vaccines and replicon particles), data that can be called ‘precursor data’ or ‘mock-up’ dossiers. It is our understanding that this was used already, at least informally, for the canarypox vector platform used for the development of several mammalian vaccines [382]. A guideline should be developed providing clear limits on data assessment raised from platform vaccines and technologies. It should indicate and clarify the data requirements once these platforms/technologies are used to create new constructs in case of an emergency situation (for example, sup-porting a faster update of the HA gene sequence of infl uenza vaccines based on a vector platform using the same insertion site and promoter). Still focusing on the fi eld trial authorisation, European authorities should encourage national authorities to accept a positive assessment for a fi eld release request dossier, made by an expert committee from another country. When a disease is present in
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different countries, these ‘mutual recognitions of assessment’ would speed up the arrival of the vac-cine into different markets (especially if an emergency use permit is granted according to Article 8 of Directive 2001/82/EC, [383]).
Indeed, another possibility within the current legislation is provided by Article 8 of Directive 2001/82/EC. This directive on veterinary medicinal products, provides the opportunity to get a pro-visional fi eld permit to use a vaccine in the target animals/farms affected by an infectious disease for which there are no vaccines or cure. Three conditions are to be met for the authorities to grant this authorisation: (1) information from the fi eld confi rms the emergency need for a vaccine; (2) the vaccine has been granted a permit for deliberate fi eld release according to Directive 2001/18 and (3) the veterinary registration authorities assess that the benefi t/risk balance is positive, taking all cir-cumstances and available data provided by the applicant, as well as from other relevant sources, into account. After the permit has been granted, meanwhile the vaccine is being used and monitored for its behaviour in the fi eld, the applicant must undergo the normal regulatory process, which includes completing the laboratory and fi eld trials ‘data package’, the registration dossier, and the EMA reg-istration. It is our suggestion that European authorities confi rm that the article 8 of Directive 2001/82 as amended, can be used for vaccines which are in the scope of Directive 2001/18.
It is also worthwhile to mention a human fl u vaccine named Fluenz Tetra, which was registered in Europe in 2013 [384]. Fluenz Tetra is the fi rst and only four-strains live-attenuated infl uenza vac-cine for intranasal application available in Europe. This vaccine contains two attenuated infl uenza A strains, H1N1 and H3N2, and two attenuated infl uenza B strains. The vaccine strains are pro-duced by reverse-genetics and laboratory reassortment between a wild-type infl uenza virus and a cold-adapted master strain. Each year, the production strains are updated through the same technol-ogy, using the latest wild type strains recommended by World Health Organization (WHO) based on anticipated circulating infl uenza strains for the coming season. The European Medicines Agency has agreed that the step of annual update of the master seeds does not require a new registration process as the European law would normally require, but through a rather light variation procedure [385]. This regulatory path for applying the gene updates in this vaccine could certainly inspire authorities to apply it for veterinary vaccines.
Still looking at opportunities in the current legislation, a more strategic approach involves the possi-bility for the EU and other stakeholders to launch global projects on vaccines (or vaccine platforms if the disease is caused by different serotypes) against already probable and identifi ed threats. In this case, a data package could be prepared in advance of the emergency situation. Some success factors for such approach include but are not limited to: funding from the EU commission, fruitful liaison with the EMA (through the procedure for scientifi c advice and with the help of their newly
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established task force, ADVENT) and with national fi eld release committees. The latter would allow the experts to compose a list of actions-to-take prior to fi nalized safety risk assessment and a list of remaining prerequisites in case of the threat’s emergence.
7.4. Longer-term Opportunities: New Ways to Fast-track Deployment of Live Genetically Engineered Vaccines in Europe
Besides looking at possibilities within existing legislation, need ideas need to be explored that could lead to a real fast-track registration system for genetically engineered vaccines. One opportunity is the “mock-up” procedure, in which a vaccine is developed and authorized in advance of an unex-pected event. Authorization of fi eld deployment of these vaccines can be fast-tracked, since most of the information required for fi eld release is assessed in advance.
The extremely high safety profi les of canarypox and HVT platforms could be used as the basis for facilitating the development of “mock-up” dossiers, such as currently exist for human and veteri-nary vaccines based on inactivated infl uenza, foot-and-mouth disease, and bluetongue viruses [386]Bluetongue (BT. Such dossiers could for example describe vaccine vectors expressing HA genes of any infl uenza virus, the way to update the construct, and data needed for the marketing authorization procedure. Alternatively, “mock-up” dossiers could be developed that describe the use of replicon particles for specifi c purposes. Although this technology is not yet registered in Europe, the USDA has set a specifi c regulatory path for replicons and other replication-defi cient genetically engineered vaccines allowing a very fast issuance of the marketing authorization [387]. In the light of the suc-cess stories from the existing examples, when compared to the risks of not vaccinating, this new regulatory tool would enable the European authority in the veterinary fi eld to carry out better and
faster benefi t/risk balance assessment.
7.5. Recommendations to Amend Directives 2001/18/EC and 2001/82/EC
As a fi rst step towards innovation of European regulatory pathways, Directive 2001/18 should be reviewed. Relevant changes should be made to Annex III to incorporate the technological advances of genetic engineering since this document was written more than 15 years ago. More precise guide-lines are required, as is now the trend in the USA, to facilitate the arrival of promising novel tech-nologies such as those based on replicon particles. In addition, clarifi cation should be provided in
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the directive on the use of ‘precursor data’ with purpose of reducing the testing of the candidate con-struct. It should also set a mutual recognition procedure for the national fi eld release assessments. Since the same directive also indicates the placing on the market procedure, it should clearly empha-size that national fi eld release permits can be applied by registration authorities to grant exceptional use permits. Finally, the interest and signifi cance to have a European fi eld release committee should be discussed. Article 8 of Directive 2001/82 as amended, could also be reviewed to clearly include vaccines, which are in the scope of Directive 2001/18.
7.6. Conclusions
In the current regulatory arena, it is not possible to fast-track registration of genetically engineered vaccines. Although some National Authorities have authorized the deployment of such vaccines in emergency situations under provisional fi eld permits, innovations in regulatory procedures are required to enable surge vaccine deployment in response to future epizootics. As a fi rst step, Direc-tives 2001/18 and 82 should be reviewed and updated to describe novel technologies and ideally describe fast track procedures for these vaccines. In addition, guidelines for “mock-up” dossiers for genetically engineered vaccines should be developed. Last, but certainly not least, public and politicians’ perceptions towards genetically engineered vaccines and associated innovations in leg-islation should be taken into account by scientists, vaccine manufacturers, and the authorities. All stakeholders must be convinced that the benefi t of these vaccines to bring successful solutions to the fi eld is not associated with signifi cant risks, but rather strong and obvious benefi ts, brought by the technology itself. Research on how to overcome barriers and ameliorate approval procedures in an emergency situation is required during peacetime, which might contribute to gradual disappearance of some currently existing regulatory barriers, thereby facilitating future emergency responses to epizootics.
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Chapter 8Conclusions and Discussion
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8.1. Introduction
Here, we provide a summary of the main conclusions of each study performed in this dissertation. Furthermore, this chapter discusses how each of the studies contributes to existing literature by providing new insights on GM vaccine candidates into the vaccine fi eld. The aim of this dissertation inter alia is to evaluate the market potential of next generation GM vaccines as market driver for disruptive innovation to target unmet vaccine needs. To meet this aim the approach to investigate the market potential is multidisciplinary, encompassing regulatory, industrial, and academic disciplines. Furthermore, these studies combine both qualitative and novel quantitative approaches to investi-gate the market potential evaluating literature, patents, clinical trials, and registered vaccines from various data sources with the intention of forecasting the future trends in the vaccine fi eld.
Data on successful market entry of GM vaccines can be used as a measure, which in turn is used to indicate the CSFs, for market introduction of these vaccines. Nevertheless, identifi cation of CSFs is only a fi rst step. Current and future prospects of global GM vaccine market were investigated in-volving transition from clinical trials towards the market, generating a landscape of next generation GM vaccines for the coming decennia. As an extension of those studies, the need is pointed out to defi ne the GM vaccines, GM vaccines technologies, and GM vaccines production platforms to fi t vaccine R&D specifi cally. Subsequently, market implementation potential of GM vaccine market approval are discussed.
Such an overview allows for holistically examining the main challenges from a multidis-ciplinary perspective, making it possible to identify several causes that contribute to the barriers that these novel platforms have to face for successful market implementation.
The ranking of these unmet implementation barriers in these studies is dependent on the preferences of KOLs, which in turn might infl uence the perception of reality. Demand articulation might there-fore be infl uenced by the somewhat ‘hidden agendas’ of different stakeholders involved such as the industry, regulatory authorities, and academia. These inherent inconsistencies have been corrected by the application of a tailored analysis methodology based on consistency ratios. Further analysis was designed to explore the commercial potential of the MVA platform for the development of novel generation vaccines, in particular for pandemic infl uenza vaccines.
In essence, the level of success of any future vaccine is hard to predict due to among others high complexity, uncertainty, and ambiguity of its market dynamics. Such uncertain market dynamics necessitate continuous evaluation of the current vaccines available, unmet medical needs, targeted diseases, the threats like regulatory and political fl uctuations, innovative and disruptive technol-
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ogies, future breakthroughs in studies identifying correlates of immune mediated protection and pathogenesis and unforeseeable economic and societal consequences, which could act as a complex mix of barriers and opportunities.
Once a vaccine has been awarded market approval, and is accessible to the general public, dynamics such as public perception towards GM vaccines of the market landscape may change.
In terms of CSFs of GM vaccines, Figure 8.1. provides a schematic overview of the most signifi cant success factors assembled in bundles based on their association to a particular theme. In addition, this fi gure illustrates three different layers of perspectives that can infl uence each individual factor within these bundles and can be mutually infl uenced by these factors. As demonstrated, the main themes of this overview are: prerequisite successful market, extrinsic assets novel technologies, in-trinsic assets novel technologies, potential next generation novel technology, and vaccine landscape. Furthermore, identifi cation of these CSFs and implementation challenges throughout this disserta-tion resulted in the following prerequisites for successful market entry, Figure 8.2.: rules & regula-tions, collaboration, providing compelling data, perception change, increased fi nancial investments, and sustainability novel platforms.
Finally, several avenues for further research are suggested, focusing on future R&D of GM innova-tion networks, the role of different stakeholders, strengths, weaknesses, opportunities, and threats of novel vaccines for successful market entry, and institutional factors that could contribute to adoption of new innovations to meet unmet vaccine needs.
8.2. Summarizing Conclusions and Contributions
The studies presented in this dissertation provide fi ndings contributing to existing literature on the subject of disruptive innovation by GM technology in the vaccine fi eld. Specifi cally, they reveal CSFs for the successful market introduction of GM vaccines, current and future trends of global GM vaccine market R&D, current state-of-the-art and newly generated vector-based technologies, and market implementation and market commercial -potential of the MVA platform. In essence, chapter 2, 5, and 6 were designed to capture the CSFs, market implementation barriers, and SWOT of GM vaccine fi eld. Furthermore, these chapters evaluate market elements for successful implementation of novel technologies in general with an in-depth focus on one of the most advanced novel GM technologies: introduction potential, commercial potential, implementation potential, and successful entry. Other chapters of this dissertation focus on the journey from bench to vaccination site and on one of the most advanced novel GM technologies.
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Figure 8.1. Significant critical success factors for successful market implementation of GM vaccines. The breadth of each baulk represents its relative importance compared to the other critical success factors.
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Figure 8.2. Principal and interconnection between key prerequisite factors for successful market imple-mentation of GM vaccines.
Prerequisites Succesful Market
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In terms of the GM vaccines, Figure 8.3. provides an overview of the most signifi cant objectives that are revealed and evaluated in this dissertation. It illustrates similarities and overlaps in terms of internal links between and within the respective chapters (Figure 8.3a). In addition, priority degrees of GM essential assets, according to two priority degrees (Medium and High), in combination with their time urgency, according to three priority periods (Short-, Mid-, and Long-term), are visualized in a matrix (Figure 8.3b). As demonstrated, the main components of this overview are: prerequisites successful market, extrinsic assets novel technologies, intrinsic assets novel technologies, potential next generation novel technology, and vaccine landscape. Each chapter of this dissertation explores different dynamics within the GM fi eld with mutual link between different factors.
Chapter 2 endeavours to uncover CSFs affecting successful market entry of novel vaccines. Opting to capture the most recent opinions and views to identify the CSFs for market introduction of GM vaccines, exploratory interviews were conducted with the key opinion leaders (KOLs) representing the regulatory authorities, industry, and academia. Although the market potential of conventional vaccines has been evaluated in detail [162, 388], that of the GM candidate vaccines differs due to their novelty and specifi c characteristics [389-391]. This chapter therefore contributes to the vaccine fi eld in general, and relating to GM vaccine market in particular. Since GM vaccines are consid-ered the next step in vaccine development [40], gaining knowledge about their market potential is essential [392, 393]. Moreover, many new GM vaccines may be expected to enter the market in the near future [28]. Quantifi cation and classifi cation of the results revealed that CSFs could be sorted into 4 categories: technical potential, commercial potential, rules & regulations, and societal. The application of a unique and effective weighted-ranking technique in combination with three differ-ent priority periods, short-, mid-, long-term, contributes to and validates the primary and existing methodology as conducted in different studies [140, 141, 172-174, 208]. Furthermore, ranking the top 10 CSFs within each category, based on their importance, reveals that the category rules & regulations require immediate attention and consideration. Additionally, societal potential category demands intervention measurements, as both these categories included highly prioritized factors. This study also reveals that GM vaccines not only provide new market opportunities against previ-ously untargeted diseases, but also create the possibility for research, development, and production of multi-targeted vaccines. Therefore, this chapter emphasizes the essence of providing insights in the current and future prospects of global vaccine market.
Chapter 3 provides an interdisciplinary overview of the GM vaccine pipeline, reaching from pat-ents to registered vaccines. This chapter describes the necessary chronological phases required to develop a product concept up to the point of market entry. For the purpose of this dissertation, phase transition success rate of clinical trials phases (1, 2, 3) is defi ned by the percentage of successful transition of vaccine candidates from one clinical phase to the next clinical phase. With the intention
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Figure 8.3a. Schematic overview of the most significant objectives that are revealed and evaluated in this dissertation.
of forecasting a trend in the fi eld of GM vaccine market, our dataset implicates a success rate of 82% (phase 1-2) and 76% (phase 2-3) and emergence of vaccines against cancer and malaria in the coming years. Additionally, this study identifi ed North America, Asia, and Europe as viable markets for GM vaccine R&D for both “Big Pharma” and pioneering institutes. In conclusion, chapter 3 indicates a signifi cant increase of global GM vaccine market share (20%), providing evidence on the growth of worldwide GM vaccine market supported by rising trends in patent applications and vaccine registrations [207, 208]. To the best of our knowledge, prior to this study, no data supported comprehensive research conducted to investigate and provide insights in the current state of the global GM vaccine market R&D in detail. This study shows that advances in R&D and the next
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Figure 8.3b. Priority degree of GM essential additional assets to the vaccine field; according to two priority degrees (Medium, High), in combination with their time urgency, according to three priority periods (Short-, Mid-, Long-term).
generation of GM vaccines can be anticipated in the coming years. In addition to these insights, chapter 3 adds to the existing body of innovation literature by providing a thorough overview of the current state of R&D with respect to medical studies, intellectual property protection, clinical trials, and registration of vaccines. Moreover, this chapter indicates that combining different databases (patents, literature, clinical trials, registered vaccines) and application of various analysis techniques is an effi cient method of technological forecasting. As such, this dissertation points out a compelling need for a clear defi nition of GM vaccines, and future research on GM vaccine production platforms is recommended.
Chapter 4 explores state-of-the-art and newly generated vector-based technologies in the fi eld of vaccine development. To start off with, this chapter reveals that vector-based vaccines comprise a signifi cant part of all GM vaccines (26%) in the pipeline. Considering that currently there is only one licensed, viral vector-based human vaccine on the market (Sanofi ’s IMOJEV), a vaccine against Jap-anese encephalitis [109, 394, 395] and that this fi eld is still in its early days, vector-based vaccines may offer a cost-effective alternative for the production of safe and effective vaccines. Moreover, this chapter suggests that these vaccines can be used against diseases for which no or less suffi cient vaccines exist today, thus catering for a huge unmet medical need. Furthermore, this study provides an overview of the vector-based GM vaccine pipeline and market, indicating that poxviruses and
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adenoviruses are among the most prominent vectors in GM vaccine development. This may be concluded from their abundant use in the development of vaccines against diseases like HIV-AIDS, malaria, tuberculosis, and different forms of neoplastic disease. Completeness of data in this chapter has been realized by involving four different stages covering literature, patents, clinical trials, and registered vector-based vaccines. Moreover, it provides the evolutionary path that these vaccines have gone through over the years [211, 261, 264, 265, 267-270]. Chapter 4 evaluates vector-based vaccines and thereby adds depth to the vaccine fi eld by providing an overview of these vaccines. In addition, this study reveals that inconstant and confusing terminology is often found in literature to describe GM vaccines. The data therefore contribute to delineation of the GM vaccine fi eld by narrowing down the search terms found in patent CPC codes and literature. In addition the studies validate that recent activities in the fi elds of patenting, preclinical research, and different stages of clinical research could be used as an analysis tool to thoroughly examine and explore the fi eld of vector-based GM vaccines.
The study presented in Chapter 5 uncovers market implementation challenges of the MVA plat-form. Opting for a qualitative methodology, KOLs were approached representing industry, regula-tory authorities, and academia. In essence, the need to involve different disciplines and perspectives within the vaccine fi eld, in this research, confi rms how complex the acceptance of novel vaccines and novel vaccine production platforms can be. Chapter 5 adds depth to the perspective of KOLs by providing a qualitative and quantitative prioritization analysis of the MVA platform market po-tential, including associated market implementation barriers. Correspondingly, quantifying expert’s opinions regarding market implementation challenges of the MVA platform through various ef-fective weighted-ranking methods provides a unique and novel overview from a multidisciplinary perspective, making it possible to identify foremost underlying causes that contribute to the chal-lenges novel vaccines face before market implementation. This study reveals that implementation barriers of the MVA platform can be grouped, according to their importance, into six main catego-ries: production & speed, technical, immunogenicity leading to protective effi cacy, competitors, pre-pandemic/mock-up, and regulatory. Subsequently, the implementation barriers are plotted in a dimensional perceptive construction to visualize the overlaps, similarities, and differences in KOL’s perspectives. An in-depth analysis into the interview transcripts reveals underlying reasons for these identifi ed resemblances and discrepancies. Moreover, the study indicates that the delay in vaccine development and production is predominantly initiated by dependency on external factors such as rules and regulations required by regulatory authorities as well as, in case of infl uenza, reference stains and reagents provided by WHO. Moreover, both chapters 2 and 5 suggest that introduction of centralized procedures and more streamlined rules and regulations could play a predominant role in contributing to meet the challenges for successful market introduction.
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Chapter 6 can be seen as an extension of the previous chapter, by offering insights in, and specifying the market implementation potential of novel generation vaccines in general with a special focus on infl uenza vaccines. Furthermore, identifying the favorable and unfavorable internal and external factors help provide an empirically validated contemporary industry view of MVA as a vaccine tech-nology platform. This study was designed to explore the commercial potential of the MVA platform for the development of novel generation pandemic infl uenza vaccines. Essentially this chapter high-lights the necessity of four factors to be taken into consideration prior to realizing unmet vaccine needs with the purpose of developing novel vaccines or platforms including SWOT analyses.
Given the present economic climate, it is believed that identifying the factors that are par-ticularly relevant to determine commercial potential of novel vaccines could have a posi-tive effect on the likelihood of successful introduction of such new vaccines.
In addition, this study provides the fi rst quantitative data and thereby contributes to studies suggest-ing that MVA addresses the unmet needs of the current vaccine platform for pandemic infl uenza vac-cine development [86-88, 90, 92, 103]. MVA’s specifi c properties stressed in Chapter 6, in particular its safety, good immunogenicity, and broad protective immunity, demonstrate the great potential of this platform. Moreover, the KOL studies indicate that strengths of the MVA platform outweigh weaknesses, opportunities, and threats. Furthermore, literature describes various (pre-) clinical trials and studies demonstrating immunostimulatory capacities that make MVA induce protective immune responses against a plethora of infectious agents [88, 90, 111, 117, 295, 322, 323].
The vaccine market offers suffi cient opportunities for MVA to be implemented as a novel vaccine platform with broad protection against seasonal and pandemic infl uenza viruses. Broad application possibilities might eventually contribute to a sustainable long-term busi-ness opportunities provided by such platforms.
Chapter 7 reviews the current European regulatory arena and proposes innovations in regulatory procedures to enable surge vaccine deployment in response to rapidly spreading epizootics in Eu-
rope.
8.3. Urgency of Addressing Unmet Vaccine Needs
This dissertation presents a disquisition on a sensitive topic in the contemporary world; genetic mod-ifi cation [396-406] with an exclusive focus on GM technologies applied for novel vaccine develop-ment against as yet untargeted diseases. Furthermore, the journey of introduction-, implementation-,
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and commercial potential of GM vaccines from bench to vaccination site and from patent to patient is explored.
Presently, different investigations and evaluations on GM products in general, conducted by various bodies from different countries worldwide, have not been conclusive and have proven to be contro-versial. Moreover, debates on this important subject have not been consistently grounded on evi-dence-based facts and are rather based on strong emotions and beliefs. Although empirical research, confi rmed by global governmental authorities including EC, has revealed no sign of environmental or public health damage, misperceptions regarding GM continue to govern [407-409]. Consequent-ly, here we reveal and enforce a suitable equilibrium between potential risks and benefi ts of GM technology as a driver towards target unmet vaccine needs, for the benefi t of public health. Until now, no comprehensive quantitative studies on this subject have been undertaken incorporating re-lated scientifi c literature knowledge, patents, clinical trials, and registered vaccines data.
8.4. Prerequisites Successful Market
Although the studies presented in this dissertation have identifi ed several essential prerequisites, which could infl uence the successful implementation process of novel GM vaccines, intrinsic and extrinsic assets of GM technology seem to play a superior role towards their successful market entry (Figure 8.1). Currently, these inherent properties have proven their value during different phases of clinical trials with a high success transition rates. Nevertheless, the market implementation of GM vaccines is inexcusably far behind its technological possibilities due to different hurdles at different levels with different underlying causes. Measures and hurdles have to be taken to bridge a valley of death that seems to exist between clinical trial phases and market entry of vaccines based on GM technology.
Hence, identifi cation of key factors for successful market implementation of GM vaccines has the fi rst priority, regardless of whether one perceives these as critical factors for success or challenges that have to be overcome to achieve success. Moreover, three relevant stakeholders in the vaccine fi eld, namely regulatory, industry, and academia have also recognized these factors to be signifi cant determinants of success. It is of importance to note and understand that these factors could be of in-terest and advantageous to a broader scope of stakeholders (e.g., patients, policy makers, investors) than the three emphasized in this dissertation. Furthermore, they aid to screen, detect, address, and cover a broad horizon of solutions to balance strengths, weaknesses, opportunities, and threats of such platforms.
Regulatory authorities are responsible for protecting public health by ensuring safety, effectiveness,
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quality, and security of vaccines. These regulatory bodies continue to oversee the production of vac-cines after the vaccine and the manufacturing processes are approved, in order to ensure continuing safety for the benefi t of public heath [410]. Ultimately, the success of GM vaccines is determined by their regulatory approvals followed by introduction into the market. The market authorization is granted by regulatory authorities responsible for exercising extended evaluation of data collected during vaccine development and clinical trials regarding vaccine safety and effi cacy. Due to the high degree of complexity, regulatory issues are an often-occurring hurdle for novel-GM-technologies. Furthermore, it seems that regulatory hurdles increase with the novelty and complexity of a technol-ogy due to their uncertain technical-, societal-, commercial-, and public health potential in particular during the initial stages of development. This famous bottleneck can be overcome primarily by providing compelling data demonstrating, inter alia, improved safety, effi cacy, immunogenicity, and added value in comparison with existing products. Furthermore, providing future-oriented business models ensuring long-term sustainability of such novel platforms contributes to disappearance of some of the regulatory concerns. From an industry perspective, establishing a sustainable business model is a prerequisite to turn novel platforms into a success. Based on the high variety of stake-holders involved and the benefi ts they could gain from the gradual disappearance of regulatory chal-lenges, it seems like the most obvious and logical option that solution to these challenges must be an integrated effort between these stakeholders in the vaccine fi eld. It must be taken into account that the extent to which stakeholders are willing and able to collaborate is dependent on several factors. For example: individual advantages to be gained, long-term consequences, level of transparency, and risk-return trade-off. The latter can be achieved through, inter alia, application of advance-pur-chase-agreements and pre-estimated risk-benefi t ratio [411-413].
As stated throughout this dissertation, the vaccine fi eld consists of many stakeholders who contrib-ute their area of expertise with individual diverse and divergent interests and concerns regarding successful implementation of novel vaccines. Achievement of this common goal requires collabora-tion of individual yet interdependent disciplines through interrelation and interaction in a multidisci-plinary way. Studies throughout this dissertation show several existing similarities, differences, and overlaps between different stakeholders.
Confl icting interest recognized between the internal preferences of each perspective may contribute to some of the existing hurdles at different levels, which may result in delayed market implementa-tion of novel vaccines. It must be realized that the required unique way of collaboration can only be accomplished through redefi ning the relationship between different stakeholders in a groundbreak-ing, simultaneously, mutually benefi cial and satisfactory way which consequently contributes to a long-term sustainable cooperation.
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The sooner the collaboration in the development cycle of novel vaccines is implemented, the sooner the existing hurdles could disappear and consequently the faster market entry success rate can be achieved.
Furthermore, we reveal that collaboration through public-private-partnerships leads to increased spending in the vaccine fi eld worldwide. Increase in funding and investments is observed to be a key driver of instant increase in research activities within the vaccine fi eld and therefore within the GM vaccine fi eld. Hence, both regulatory and academia KOLs propose initiatives, with an exclusive emphasis on less complex and more streamlined regulations, which could incentivize the industry to make more investments in vaccine R&D and eventually develop vaccines in addition to vaccine candidates. Furthermore, a growing body of science, not only in the GM technology arena but also in the fi eld of identifying correlates of immune mediated protection and pathogenesis, contributes to broader development, production, and application possibilities of this platform consequently con-tributing to long-term sustainable application strategies.
Noteworthy, our studies reveal that all the above-mentioned-factors could infl uence general public’s understanding and perspective of dynamics within the vaccine landscape. Although the importance of immunization is not up for debate, the general public, paradoxically, seems to have largely for-gotten the benefi ts of vaccination. As such, according to the KOLs, awareness needs to be raised and the public needs to be educated about the benefi ts and added value of GM technologies. Public acceptance entails a high level of complexity and requires more interventions than just increased level of public education. Furthermore, empirical research has shown that there is no direct asso-ciation between increased levels of scientifi c knowledge leading to an increased public acceptance [414]. There is a need for a two-way communication between different stakeholders on the one hand and the public on the other hand which is based on, inter alia, mutual respect, openness, and trans-parency. Furthermore, a proposed approach to increase awareness is emphasizing the successful accomplishments of GM technology by different stakeholders in other fi elds including production food (e.g., cheese [176]) and medicine (e.g., insulin [179]), bacterial modifi cation to perform tasks as making biofuels, cleaning up oil spills, toxic waste, and even to detect arsenic in drinking water [178, 179]. Consequently, this should all contribute to gradual change in public perception and atti-tude towards emerging GM based vaccines.
8.5. MVA Vectored Vaccines: A Next Generation Technology
The signifi cant role of providing compelling data on GM vaccines has been a stepping-stone for further advancement of these novel technologies in different studies. Furthermore, from a regulatory
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and industrial standpoint, providing data representing added value of these technologies and demon-strating competitive edge to many existing products on the market are deemed to contribute to their successful market introduction.
Currently, a signifi cant portion of GM vaccine candidates (20%) in the global vaccine development market share shows their worldwide increasing growth in the vaccine fi eld. With the intention of forecasting a trend in the GM vaccine market and subsequently predicting the potential next gener-ation novel technologies, databases on clinical trials and patents, as well as on registered vaccines, have been evaluated.
Technical advances in vaccine R&D and the next generation GM vaccines can be anticipated in the coming years supported by data refl ected in upward trends perceived in both numbers of GM vaccine patent fi lings and registered vaccines. In addition, compared to biopharmaceuticals, we identifi ed remarkable high phase transition success rates (P1-P2 82% and P2-P3 76%) confi rming the forecasted market opportunities provided by GM vaccines. Complementary to these fi ndings, we provide insights into increasing number of novel development/production approaches and their potential added value to develop new vaccines that address unmet vaccine needs. Both literature and studies carried out in this dissertation suggest that vector based platforms, with a focus on MVA platform, have advantages over currently used vaccines and vaccine platforms in development [86, 90, 111, 326].
Currently, a signifi cant portion (30%) of all GM vaccine trials in the pipeline can be allocated to vector-base technologies with a special emphasis on currently undefeated indications such as can-cer, HIV, TB, and malaria. In the light of the rising trends that are observed from data on patent applications, vaccines registration, and currently registered vaccines, a prediction can be made that the coming decade will see the emergence of vaccines against cancer and malaria. These insights imply the important part GM vaccines, in particular vector-based vaccines, play in the vaccine fi eld. In contrast to described increasing trends, there is currently only one licensed vector-based human vaccine on the human vaccine market. This discrepancy between ample activities in the fi eld of patenting, preclinical-, and different stages of clinical research, and the fact that there is currently only one approved vector-based vaccine, implies an increased chance of more GM based vaccines obtaining market authorization in the coming years. In this context it can be argued that this discrep-ancy might be an indication that there is already a perception change towards the novel vaccines in the vaccine landscape.
Both literature research and studies presented here confi rm emergence of poxvirus based vaccine platforms as a successful delivery platform. Despite the fact that there are no licensed poxvirus
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vector-based human vaccines on the market yet, there is an increased number of poxvirus-vec-tor-based vaccine candidates against various infectious diseases in different clinical trial phases. In comparison to other vectors, the MVA vector shows to be the most frequent and fast growing candidate in the vaccine clinical trials. Moreover, literature provides various (pre) clinical trials and studies demonstrating immunostimulatory capacities of MVA providing protective immune re-sponses against many infectious agents. This increased usage and broad application possibilities are predominantly related to intrinsic properties such as safety, effi cacy, and defi cient susceptibility to pre-existing immunity, as MVA only causes an abortive infection in human cells, while inducing an abundant expression of the target immunogen, leading to impressive protective immune responses. Moreover, KOLs from the vaccine fi eld reveal that strengths of the MVA platform compensate its weaknesses, opportunities, and threats.
MVA has begun to distinguish itself in vector-based vaccine trials, as other vectors have stagnated while MVA trials are increasing rapidly, consequently qualifying MVA as candi-date for novel, safe, and stable vaccines, especially for diseases that have an unmet medical need.
8.6. Intrinsic/Extrinsic Assets Novel Technologies
This dissertation reveals that regardless of challenging hurdles GM vaccines have to face for suc-cessful market implementation, the main focus must be laid on valuable assets these technologies have to offer where the current state-of-the-art technologies fail or are inadequate to complete the task. Novel technologies hold the promise of providing additional values to vaccine R&D in hope for a breakthrough. The most profound added value of these novel technologies is the scientifi c and technological opportunities they provide to develop vaccines against previously untargeted diseases. Moreover, an important intrinsic added value of GM technology in the future is the ability to create the possibility for research, development, and production of multi-targeted vaccines. Consequently, these assets may contribute to solving unmet vaccine needs, which will eventually lead to societal and commercial benefi ts.
As stated throughout this dissertation, versatile opportunities will be initiated with GM vaccine market introduction including new possibilities in vaccine R&D, which hold promise to target cur-rent and future unmet vaccine needs. These market opportunities are fuelled by several ingredients: e.g. technical advantages, broad repertoire of previously untargeted diseases, high unmet medical and societal needs, commercial and societal benefi ts, invading new markets, and remarkable mar-ket growth rate in the future. It is noteworthy that novel technologies aid to open sealed doors to
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yet unreached markets. Reasons for this inaccessibility include, but are not limited to: divergent national/international rules and regulations, geographic-specifi c-diseases, and high costs of vaccine development/production.
As revealed in studies presented in this dissertation inherent features of GM technologies together with ample technological innovations in the vaccine fi eld are of high societal, commercial, and in particular public health importance. Consequently, intrinsic and ex-trinsic assets of these novel technologies contribute to target unmet vaccine needs in the vaccine fi eld in general, and in the GM vaccine market in particular.
8.7. Vaccine Landscape
In the light of the occurring shift in the vaccine landscape, incentivized by GM technology introduc-tion, a partial replacement of conventional vaccines by GM technology based vaccines and addition of a new portion to the current target market against yet untargeted diseases, may be anticipated. These new market opportunities attract and incentivize different stakeholders aside from vaccine industry and established manufacturers to invest in these novel vaccines. In the competitive vaccine landscape of today with different types of involved stakeholders and where resources in general are limited, combination and/or parallel use of novel technologies with conventional production plat-forms and vaccine formulations have to be taken into account prior to any vaccine R&D attempts. Furthermore, the insights regarding the emerging market dynamics allow different stakeholders such as policy makers, vaccine developers and manufacturers, and investors to anticipate and consider important parameters before making any strategic and fi nancial decisions.
Although a lot of investments being made in novel technologies with the purpose of targeting unmet vaccine needs, results from different studies reveal that more investments can lead to increased vac-cine R&D, target untargeted diseases, save more lives, and eventually save a great deal of money. The stakeholders that are willing to invest in biopharmaceuticals and vaccines will assess the likeli-hood of success before making any huge investment. Two important parameters that often infl uence their decision-making include the cost of investment and the statistical chance of a product entering the market.
In this context, this dissertation indicates that the currently most viable GM vaccine markets (North America, Asia, Europe) coincide with the locations of the largest companies and institutions. This is, inter alia, due to the fact that the most knowledge and resources are to be found in these regions. Furthermore, involvement of “Big Pharma” is a self-explanatory evidence of the current viability and domineering nature of the GM vaccine market. Contrary to companies that play a dominating
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role in the fi eld of infectious diseases, allergy and immunological disorders, scientifi c institutes and universities seem to focus more on the newer indication groups such as cancer, genetically related disease, and multi-purpose (e.g., chlamydia, HIV, HSV, gonorrhea, and trichomonas). The latter im-plies increasing market opportunities for the industry with respect to new R&D fi elds in the future.
Furthermore, an in-depth market analysis revealed that in 2010 only 3% of the global pharmaceu-tical market could be allocated to vaccine revenues. In the meantime, the global vaccine market increased in value from $5 billion in 2000 to almost $24 billion in 2013. Eventually, global vaccine sales were estimated to be $29.6 billion in 2014. In addition, with a spectacular growth of global vaccine market of 10-15% at an average annual rate, nearly double, as compared to 5-7% of the global pharmaceutical market, the global vaccine market is becoming an engine for the pharmaceu-tical industry and is expected to reach $100 billion by 2025 (Figure 8.4). Hence, it seems more prof-itable for the investors, e.g. industries and venture capitalists (VC’s), to invest in vaccines instead of small molecules and biopharmaceuticals. Vaccines require a lower investment and have a higher chance of market entry as commercial products, which consequently result in potentially higher return on investments [415-417].
The growth of the “Biotech” vaccines is rapidly outperforming “Pharma” and small mol-ecules.
Current state-of-the-art and future next generation technology prospects, as well as the occurring transitions and transformations in global vaccine market, together with the observed high phase transition success rates of GM vaccine candidates advancing throughout clinical trials phases will create momentum and provide versatile opportunities for investors to invest in the novel and emerg-ing GM vaccine fi eld.
Discussion on conversion of natural to GM has remained controversial in society. There are different angles from which to look at this issue. It is essential to shift the focus from negative non-scientif-ic-based aspects of this technology towards the positive and signifi cant properties of this technolo-gy. It is noteworthy that GM-specifi c- (de) merits in the vaccine fi eld have generated more than its fair share of attention in the society while the most GM activities occur in the food and agriculture industry. In essence, the subject of GM technologies is one that generates discrepancies even in a signifi cant and world-renowned industry such as food industry with food sovereignty principles. It is remarkable that the food industry has generated both the most debated (corn, 1994) and the most successful (cheese, late 1980s) GM products.
GM-vaccine-communication can benefi t from lessons learned from the food industry.
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Considering crises that we will have to face in the decades that lie ahead including worldwide pop-ulation growth, increased pressure on water, energy, and food supply, and not in the last place the continuing trend of emerging infections from the animal world (pandemic infl uenza, AIDS, SARS MERS, Ebola, Zika) it would be inevitable to make use of novel technologies, building on new science driven insights in pathogenesis and correlates of immune mediated protection and patho-genesis.
Figure 8.4. Current global market sales. The left y-axis represents the global pharmaceutical sales and the right y-axis indicates the global vaccine sale. Furthermore, the figure illustrated on the top-left corner indicates the annual percentage change of global growth rate total sales for both pharmaceuticals and vaccines.
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8.8. Suggestions for Future Vaccine Research
The work presented in this dissertation, focuses on GM technologies and GM vaccines, highlights an ambiguity in the way GM vaccines are termed and defi ned across the vaccine fi eld. Various search terms were often found in literature to defi ne GM vaccines. Nevertheless, these terms were all used in an inconsistent manner. Although this defi nition was narrowed down in this dissertation by delin-eation of search terms found in patents and literature, a proposed research topic would be to even-tually provide a consensual terminology and a pragmatic operational defi nition throughout the vac-cine fi eld. A concise series of chronological steps is required to reduce terminology and defi nition confusion and accomplish consensus: address the applied terminologies, discuss the distinguishing features of GM technologies in various defi nitions, conclude with a proposition of consensual GM terminology and a pragmatic operational defi nition [418].
A second proposed research topic includes the focus on regulatory hurdles, especially since regula-tory hurdles have been identifi ed as one of the most profound barriers infl uencing the registration process and successful implementation of GM vaccines. In the view of the changing GM regulatory landscape and the apparent existing gap between clinical phases and market entry of GM vaccines, a rules and regulations impact-assessment with a primary focus on features which contribute to bridge this gap deems to be a critical area for further research.
Furthermore, although discrepancies remain regarding the rules and regulations of GM vaccines and specifi cally delineating the boundaries of acceptance between factors such as safety, effi cacy, immu-nogenicity, public health value, and cost-benefi ts, the signifi cant unmet vaccines need for untargeted diseases raise the pressure to take immediate measures. In this context, an angle for further research would be to aim at understanding the capabilities, fl exibilities, and feasibilities in different steps of regulatory processes in order to face unmet medical needs in the market. Further research could explore ways in which regulatory authorities can best create a customized approach specifi cally for GM application purposes. A proposed tailor-made approach is to compare the infl uence of both in-dividual continuous iteration adaptations (e.g., minor changes; case-by-case) and pivots adaptations (e.g., substantive changes; rules and regulations centralization) separately to an integrated version of these through long-term exploitation. This approach may slightly differ depending on the territorial scope, and may therefore be adjusted as such.
Finally, if we want to profi t optimally from the newly emerging GM vectored vaccine technolo-gy, generating knowledge and insights in the fi eld of interactions between the target organism and the host, and more specifi cally in the correlates of immune mediated protection and pathogene-sis, should go hand in hand with GM vector research. Understanding of how our immune system functions in particular antigen recognition and presentation by the immune system, details in the
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pathogenic organisms’ behavior and their interaction with the host at a molecular level are essential keystones that must be explored to generate knowledge which will lead to new possibilities in the fi eld of vaccine development.
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Summary
In essence, this dissertation evaluates the disruptive innovation that has been started in the vaccine market by the introduction of GM technology with the purpose of targeting unmet vaccine needs. The studies aim to identify challenges that novel technologies have to meet to reach for success-ful market implementation. Main implementation barriers, together with their different underlying causes, are identifi ed and evaluated from three different perspectives; regulatory, industry, and aca-demia. The fi ve research chapters (chapters 2 to 6) present new fi ndings describing and evaluating the dynamics of these innovation barriers for successful market implementation. Where chapters 2 and 5 evaluate the dynamics relating to market potential of GM vaccines from a multidisciplinary perspective, distinguishing between critical success factors (chapter 2) and market implementation potential (chapter 5), chapters 3 and 4 present a more in-depth look at the current and future pros-pects of the global GM vaccine market (chapter 3) and the current state-of-the-art and newly gener-ated vector-based technologies (chapter 4). Chapter 6 gives a KOL’s perspective on the strengths, weaknesses, opportunities, and threats that are essential in order to defi ne determining factors for strategy-oriented-planning and decision-making-processes in the future.
The eight chapters show that GM technology offers new technical opportunities for vaccine devel-opment against previously untargeted diseases. Simultaneously, novel technologies provide exten-sive opportunities at different levels where the current technologies fail or are insuffi cient to fulfi ll the task. Furthermore, the studies evaluate the existing valley of death between clinical phases and market introduction of GM vaccines. The primary reason for this occurrence is identifi ed to be the complex and additional rules and regulations required for the authorization of these vaccines. Note-worthy, the high societal, commercial, and public health value offered by innovative technologies implies an increased market transition demand in the regulatory landscape with respect to novel GM vaccines. Subsequently, on the basis of this premise, other barriers within the context of successful market implementation of GM vaccines will gradually be overcome in order to target unmet vaccine needs for the benefi t of public health.
In essence, the key element and, simultaneously, one of the most challenging hurdles turns out to be the crucial collaboration between different stakeholders, with their different perspectives work-ing with different paradigms offering different insights resulting in benefi cial decision-making and accomplishing consensus when interactive complexity plays a predominant role. Various stakehold-ers at different levels must understand each other’s perspective and come to the realization that only jointly they can anticipate market implementation barriers in a collaborative manner that will eventually lead to a strategic dialogue. Consequently this will be leading to an increased chance of reaching a consensus, an enormous contribution to public health, and economical benefi ts for
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each and every stakeholder involved. The three relevant disciplines involved in the studies of this dissertation are in one way or another interdependent and have to interact and interrelate to achieve the common goal of vaccine availability from bench to bed. In essence, such outcomes are desirable with the purpose of increased novel vaccine development that will, without a shadow of doubt, be realized in the near future.
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Samenvatting
In essentie evalueert deze dissertatie de disruptieve innovatie in de vaccin markt die is begonnen door de introductie van GM technologie, met als doel zich te richten op de onvervulde medische behoeften (‘unmet vaccine needs’). De doelstelling van de studies van deze dissertatie is om uit-dagingen te identifi ceren waaraan innoverende technologieën moeten voldoen om een succesvol-le marktimplementatie mogelijk te maken. De voornaamste implementatie barrières, met diverse onderliggende oorzaken, zijn geïdentifi ceerd en geëvalueerd vanuit verschillende perspectieven: de regulatoire autoriteiten, de industrie en de academische wereld. De vijf onderzoeksgeoriënteerde hoofdstukken (hoofdstuk 2 tot 6) presenteren onderzoek naar de introductie van nieuwe uitvinding-en, die de dynamiek van deze innovatie barrières bij succesvolle marktimplementatie beschrijven en evalueren. Daar waar hoofdstukken 2 en 5 de dynamiek gerelateerd aan het marktpotentieel van GM vaccines evalueren vanuit een multidisciplinair perspectief, met een onderscheid tussen kritische succesfactoren (hoofdstuk 2) en marktimplementatiepotentieel (hoofdstuk 5), bieden de hoofdstuk-ken 3 en 4 een analyse van de actuele stand van zaken en toekomstperspectieven van de globale markt van GM vaccines (hoofdstuk 3) en de huidige state-of-the-art en nieuw gegenereerde technol-ogieën gebaseerd op vectoren (hoofdstuk 4). Hoofdstuk 6 geeft een overzicht weer van de meningen van belangrijke opinieleiders (KOLs) in de vorm van sterkten, zwakten, kansen en bedreigingen die een essentiële rol spelen in het defi niëren van bepalende factoren voor strategiegerichte planning en besluitvormingsprocessen in de toekomst.
De acht hoofdstukken van deze dissertatie tonen aan dat GM technologie nieuwe technische mo-gelijkheden biedt voor vaccin ontwikkeling tegen unmet medical needs. Tegelijkertijd bieden deze innovatieve technologieën nieuwe mogelijkheden voor verschillende niveaus waar huidige tech-nologieën falen of ontoereikend zijn om de bestaande problemen op te lossen. Bovendien wordt de bestaande ‘valley of death’ tussen de klinische fases en de marktintroductie van GM vaccines in de studies geëvalueerd. Het voornaamste knelpunt, blijkt te liggen in de complexe en aanvullende regels en voorschriften die voor een vaccinautorisatieproces zijn vastgesteld. Opmerkelijk is dat de hoge maatschappelijke, commerciële en volksgezondheidspotentie die de innovatieve technolo-gieën bieden leiden tot een hogere markttransitievraag in de regelgevingsmêlee die van toepassing is op nieuwe GM vaccines. Bovendien zullen, uitgaande van deze premisse, andere barrières voor de succesvolle marktimplementatie van GM vaccines geleidelijk worden overwonnen om aan un-met medical needs tegemoet te komen. Het meest majeure knelpunt, en tegelijkertijd ook een van de meest uitdagende obstakels, blijkt de noodzaak tot samenwerking tussen stakeholders met heel diverse perspectieven en paradigma’s te zijn, stakeholders waarvan een samenwerking juist nieu-we inzichten biedt resulterend in gunstige besluitvorming en het bereiken van consensus wanneer interactieve complexiteit een overheersende rol speelt. Verschillende stakeholders op verschillende niveaus moeten elkaars perspectieven begrijpen en zich realiseren dat ze gezamenlijk op een coöper-
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atieve manier de marktimplementatie-barrières die uiteindelijk zullen leiden naar een strategische dialoog kunnen slechten. Bijgevolg leidt dit tot een verhoogde kans op een consensus, een enorme bijdrage aan stand van de volksgezondheid en tot aanmerkelijke economische voordelen voor alle betrokken stakeholders. De drie relevante disciplines, betrokken in de studies van deze dissertatie, hebben een onderlinge afhankelijkheid en moeten met elkaar interactie en interrelatie aangaan om hun gemeenschappelijk doel (het beschikbaar maken van vaccines, van het lab tot op de markt) te realiseren. Deze samenwerkingsrelaties zijn essentieel voor de door alle betrokkenen gewenste toename van nieuwe vaccin ontwikkelingen en zullen, zonder enige twijfel, in de nabije toekomst worden gerealiseerd.
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Abbreviations and Glossary of TerminologiesAcute respiratory infections ARI Adeno Associated Viruses AAV Analytic hierarchical process AHP Bovine virus diarrhea virus BVDV Chicken embryo fibroblast CEF China Food and Drug Administration CFDA Consistency Index CI Cooperative Patent Classification CPC Critical Success Factor CSF Deoxyribonucleic acid DNA Differentiating Infected from Vaccinated Animals DIVA Eurasian Patent Organization EAPO European Committee EC European Medicines Agency EMA European Research Council ERC European Union EU Food and Drug Administration FDA Genetic modification / Genetically modified GM Genetically modified organism GMO Global Immunization Vision and Strategy GIVS Health and Human Services HHS Hemagglutinin HA Herpesvirus of turkey HVT Importance Degree ID Integrated Assessment IA Intellectual Property IP Japanese Encephalitis JEV Key Opinion Leaders KOL Modified Vaccinia virus Ankara MVA National Institute of Infectious Diseases NIAID Neuraminidase NA New York vaccinia virus NYVAC Para Influenza Virus 5 PIV5 Pharmaceutical and Medical Devices Agency (PMDA) Random Index RI Replication-defective canarypox ALVAC Research and development R&D Ribonucleic Acid RNA Root Cause Analysis RCA Served Available Market SAM South African Vaccination and Immunization Centre SAVIC Strength, Weakness, Opportunity, Threat SWOT Target Market TM Total Addressable Market TAM Tuberculosis TB Whole Inactivated Virus WIV World Health Organization WHO World Intellectual Property Organization WIPO Venture Capitalist VC
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About the Author
Bahareh Ramezanpour was born on May 5th 1985 in Karadj, Iran. She completed her primary and partial-ly her secondary education in Iran. Together with her family she immigrated to The Netherlands at the age of 16. After completing her pre-university education focused on Nature & Health, she continued to pursue a Bachelor of Science (BSc.) degree in Biomedical Sciences at the Vrije Universiteit Amsterdam in 2011. After receiving her Master of Science (MSc.) degree (Cum Laude) in Infectious Diseases and Manage-ment, Policy-Analysis and Entrepreneurship (MPA) in Health & Life Sciences at the the Vrije Universite-it Amsterdam in 2013, Bahar started a PhD research program at ViroNovative BV. In order to strengthen
her intellectual capacities and skills and to enable her to drive innovation, Bahar started her PhD in the fi eld of vaccinology and its market (implementation) potential, in particular vaccines developed/produced based on novel and genetically modifi ed technologies.
Under the supervision of Prof.dr. Eric Claassen and Prof.dr. Ab Osterhaus, she conducted research on the topic of disruptive innovation by genetically modifi ed based vaccines as a market driver to target unmet vaccine needs. In addition to her PhD research program, Bahar had the opportunity to work at ViroNovative BV, Erasmus MC Vlieland BV, and Sovalacc BV as Director Business Development and worked on several life sciences related consultancy projects. With a background in infectious diseases, infl uenza vaccination (Erasmus MC Department of Viroscience), and MPA, Bahar possesses both practical and academic experience in the areas of business development in the fi eld of life sciences and Biotech, market related activities, networking, negotiation, recognizing/generating new business leads, IP related contracting as well as licensing.
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Dankwoord
Het voelt als de dag van gisteren dat ik samen met mijn moeder en zusje naar Nederland kwam. Wat is het allemaal toch snel gegaan, of komt het doordat ik nooit de tijd heb genomen om even stil te staan en terug te blikken?
In een nieuwe omgeving aangekomen besloot ik de uitdaging aan te gaan en me te willen assimil-eren in deze nieuwe cultuur. Ik heb me snel de taal eigen gemaakt en heb me ingezet om een goede opleiding te kiezen die me perspectieven gaf en aan mijn behoefte aan uitdaging tegemoet kwam.
Het voelt soms alsof ik op de automatische piloot in een soort survival mode leef. Ik ben zo kritisch naar mezelf dat er niks goed genoeg is en alles altijd beter kan. Er is nooit sprake geweest van een mijlpaal in mijn leven! Het was voor mij vanzelfsprekend dat ik de taal binnen no time onder de knie moest hebben. Het was vanzelfsprekend dat ik binnen no time mijn eigen plek heb moeten vinden in een vreemd land. Het was vanzelfsprekend dat ik ging studeren. Het was vanzelfsprekend dat ik cum laude afstudeerde. Zo bijzonder was het allemaal niet.
Desondanks, het behalen van mijn doctoraat doet me toch stilstaan en terugblikken. Niet alleen ter-ugkijken naar hoever ik gekomen ben, maar meer nog hoe ik zover gekomen ben, wie ik onderweg tijdens mijn journey allemaal heb mogen leren kennen en wat hun bijdrage is geweest aan mijn persoonlijke ontwikkeling. Sommigen blijken ook vrienden voor het leven te zijn. Ze hebben me door alles bijgestaan. Ze hebben me door moeilijke tijden heen geholpen en ze zijn me zo dierbaar geworden dat ik ze als familie beschouw. Mijn nieuwe familie in een vreemd land. Vreemd? Vreemd is het allang niet meer. Ik zal altijd hoe dan ook een Iraniër blijven, maar toch voel ik me ook een Nederlander. Ik voel me ook bevoorrecht dat ik het beste van twee werelden heb mogen ervaren, een wereldburger!
Een van deze mensen die zichzelf onmisbaar heeft gemaakt in mijn leven is tegelijkertijd ook mijn promotor Eric Claassen. Eric, ohhhh Eric hoe kan ik jou ooit genoeg danken. De woorden schieten me tekort en de tranen schieten in mijn ogen als ik dit schrijf. Als eerste mijn grootste bewondering omdat je mij tijdens mijn PhD periode hebt kunnen overleven. Ik ben niet de makkelijkste en toch heb je mij altijd weten te kalmeren, adviseren en laten zien hoe ik wijze lessen uit elke situatie kan halen! Ik prijs me dan ook meer dan gelukkig dat ik jou in een educatieve sfeer, als promotor, in een zakelijke sfeer, als CEO, en in een persoonlijk sfeer, samen met je dierbare gezin, heb mogen ervaren. In alle gevallen heb je me altijd bij belangrijke gesprekken en in belangrijke situaties mee laten beslissen. Dank voor het vertrouwen dat je altijd in me hebt gehad. Dat heeft mij gevormd tot de onafhankelijke, toegewijde, en leergierige persoon die ik vandaag ben. Voor mij ben je een
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rolmodel, een leermeester, een adviseur, een vaderfi guur die mij in verschillende situaties altijd heeft bijgestaan. Natuurlijk heb je een hele sterke vrouw naast je staan, Conny Kruyssen (ook bekend als mijn Japanse moeder), die ik ook zeer dankbaar ben.
Iemand anders die zich ook onmisbaar heeft gemaakt in mijn leven is Ab Osterhaus, mijn tweede promotor. Ik zal nooit onze eerste ontmoeting vergeten. Ab, je stelde natuurlijk een zeer interessante vraag, een typische Ab vraag: “waarom kies je voor virologie en niet bacteriologie?”. Natuurlijk kon ik je geen reden geven om het me nog lastiger te maken, dat gaat op een of andere manier van-zelf, dus zonder enige twijfel antwoordde ik “omdat ze zo dynamisch zijn”. Op dat moment wist ik niet dat ik mijn tijd met jou aan het beschrijven was. Misschien had ik meer moeten laten zien hoe essentieel je bent geweest en hoe je me op verschillende manieren op verschillende vlakken hebt geholpen. Bij deze wil ik hier graag mijn grote waardering uitspreken voor jou als persoon, voor je professionele prestaties, voor je tijd die je ondanks lange vluchten in de vroege ochtenden of late avonden altijd vrij hebt gemaakt, voor je adviezen die onmisbaar waren en een zeer waardevolle bijdrage hebben geleverd aan de kwaliteit van deze dissertatie. Ook al leverden onze discussies soms wat frustraties op, steeds gaf je me toch het gevoel dat je naar mijn argumenten luisterde. Maar ook al wisten we het allebei beter, uiteindelijk wint Ab!
Ik voel me bevoorrecht dat ik vanaf het allereerste moment door twee internationaal gerenommeerde personen ben begeleid. Ik was me er ook vanaf het begin van bewust dat de verwachtingen anders liggen en dat mijn PhD journey resulteert in een dissertatie waarop ik trots mag zijn.
Verder wil ik me met dit dankwoord richten op iedereen die mij op wat voor manier dan ook heeft bijgestaan bij het tot stand komen van deze dissertatie.
Een bijzondere dank aan mijn collega Rob Posthumus die altijd voor me klaar staat en mij in verschillende situaties heeft bijgestaan en gesteund. Door met een objectieve blik mij te adviseren en alle mogelijke opties en scenario’s voor me uit te beelden, heb je me altijd meer dan je denkt ge-holpen. Ik moet vaak met plezier terugdenken aan onze memorabele trip naar Japan. Ook gaat mijn dank uit naar Jacqueline Broerse voor haar scherp analytisch inzicht en opbouwende kritiek die een waardevolle bijdrage hebben geleverd aan de kwaliteit van deze dissertatie.
De leden van de kleine commissie Prof.dr. J. Broerse, Prof.dr. R. Kort, Prof.dr. G. Rimmelzwaan, Prof.dr. L. Hellebrekers dank ik voor het kritisch lezen en beoordelen van mijn dissertatie. De leden van de grote commissie Prof.dr. Justin Jansen and dr. Joost Kreijtz wil ik bedanken voor het voeren van oppositie tijdens de promotie ceremonie.
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Verder zou ik graag een paar collega’s en vrienden willen danken voor hun steun, kritische blik, brainstorm sessies en waardevolle discussie die allemaal ontzettend hebben bijgedragen aan mijn studies.: dr. Kenneth Fernald, Linda van de Burgwal, dr. Esther Pronker, dr. Manon Cox, Peter van Dongen, Dik van Harte, Ewit Roos, Pamela Browne, Anne Nevel, dr. Maurits van den Nieuwboer, dr. Rory de Vries, Hadil Es-Sbai. Ingrid Haan, Tommy Riemens en Pim Kamphuis, dank voor jullie inzet tijdens je stage. Verder zou ik ook graag mijn co-authors dr. Joost Kreijtz, dr. Esther Pronker, dr. Jeroen Kortekaas en dr. Jean de Foucauld willen bedanken. Ook de collega’s en met name de dames van de secretariaat afdeling Viroscience Erasmus MC (Loubna Bouzyd, Simone Slabbe-koorn-Romijn, Maria Silva, Anouk Gideonse) bedankt omdat jullie altijd maar dan ook altijd voor me klaar hebben gestaan met veel bereidheid, steun en liefde.
En natuurlijk mijn paranimfen, mijn beste vrienden Alex de Ruiter en Viran Tilakdharie. Ik wil jullie in het bijzonder danken voor je grenzeloze liefde, steun, ontzettend boeiende gesprekken op late avonden en voor wie jullie zijn. Jullie halen het beste in mij naar boven. Daarvoor mijn dank, waardering en onvoorwaardelijke liefde. Verder wil ik graag Lieneke Pool danken die ondanks onze afstand toch me altijd het gevoel geeft dat ze dichtbij me is. Ik kan altijd bij je terecht!
Last but defi nitely not least, mijn familie, vrienden en in het bijzonder mijn moeder Afsaneh Heydar Taeme en mijn zusje Shekoufeh Ramezanpour. Hoe kan ik jullie ooit danken voor alles wat jullie tot nu toe voor me hebben gedaan? Jullie grenzeloze geduld, onvoorwaardelijke liefde en eeuwige vertrouwen in mij zijn van ongekende waarde geweest. Mam, je ben one of a kind. Door jou ben ik de persoon geworden die ik vandaag ben. Je bent mijn voorbeeld! Je geeft het begrip onvoorwaar-delijke liefde en opoffering een nieuwe betekenis. Ik prijs mezelf dan ook meer dan gelukkig dat ik door jou groot ben gebracht. Dank dat je er bent!
Deze mijlpaal had ik niet kunnen bereiken zonder jullie. Mijn bijzonder dank en waardering!
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