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Optimmunize: imprOving the beneficial effects Of vaccines 19 - 21 february 2020
ABST
RACT
BO
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Name:
Optimmunize: Improving the
beneficial effects of vaccines
Wellcome Genome Campus Conference Centre, Hinxton, Cambridge, UK
19-21 February 2020
Scientific Programme Committee:
Christine Stabell Benn
University of Southern Denmark, Denmark
Rebecca Chandler
Uppsala Monitoring Centre, Sweden
Nigel Curtis
The University of Melbourne, Australia
Eleanor Fish
University of Toronto, Canada
Sabra Klein
Johns Hopkins University, USA
Tweet about it: #optimmunize20
@ACSCevents /ACSCevents /c/WellcomeGenomeCampusCoursesandConferences
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Scientific Programme Committee
Christine Stabell Benn
University of Southern Denmark, Denmark
Rebecca Chandler
Uppsala Monitoring Centre, Sweden
Nigel Curtis
The University of Melbourne, Australia
Eleanor Fish
University of Toronto, Canada
Sabra Klein
Johns Hopkins University, USA
Wellcome Genome Campus Scientific Conferences Team:
Jemma Beard
Conference and Events
Organiser
Nicole Schatlowski
Scientific Programme
Officer
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Dear colleague,
I would like to offer you a warm welcome to the Wellcome Genome Campus Advanced Courses and
Scientific Conferences: Optimmunize: Improving the beneficial effects of vaccines. I hope you will find
the talks interesting and stimulating, and find opportunities for networking throughout the schedule.
The Wellcome Genome Campus Advanced Courses and Scientific Conferences programme is run on a
not-for-profit basis, heavily subsidised by the Wellcome Trust.
We organise around 50 events a year on the latest biomedical science for research, diagnostics and
therapeutic applications for human and animal health, with world-renowned scientists and clinicians
involved as scientific programme committees, speakers and instructors.
We offer a range of conferences and laboratory-, IT- and discussion-based courses, which enable the
dissemination of knowledge and discussion in an intimate setting. We also organise invitation-only
retreats for high-level discussion on emerging science, technologies and strategic direction for select
groups and policy makers. If you have any suggestions for events, please contact me at the email
address below.
The Wellcome Genome Campus Scientific Conferences team are here to help this meeting run
smoothly, and at least one member will be at the registration desk between sessions, so please do
come and ask us if you have any queries. We also appreciate your feedback and look forward to your
comments to continually improve the programme.
Best wishes,
Dr Rebecca Twells Head of Advanced Courses and Scientific Conferences [email protected]
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General Information
Conference Badges
Please wear your name badge at all times to promote networking and to assist staff in identifying you.
Scientific Session Protocol
Photography, audio or video recording of the scientific sessions, including poster session is not
permitted.
Social Media Policy
To encourage the open communication of science, we would like to support the use of social media at
this year’s conference. Please use the conference hashtag #optimmunize20. You will be notified at
the start of a talk if a speaker does not wish their talk to be open. For posters, please check with the
presenter to obtain permission.
Internet Access
Wifi access instructions:
Join the ‘ConferenceGuest’ network
Enter your name and email address to register
Click ‘continue’ – this will provide a few minutes of wifi access and send an email to the
registered email address
Open the registration email, follow the link ‘click here’ and confirm the address is valid
Enjoy seven days’ free internet access!
Repeat these steps on up to 5 devices to link them to your registered email address
Presentations
Please provide an electronic copy of your talk to a member of the AV team who will be based in the
meeting room.
Poster Sessions
Posters will be displayed throughout the conference. Please display your poster in the Conference
Centre on arrival. There will be two poster sessions during the conference.
Odd number poster assignments will be presenting in poster session 1, which takes place on
Wednesday, 19 February, at 18:00 – 19:00.
Even number poster assignments will be presenting in poster session 2, which takes place on
Thursday, 20 February, at 18:00 – 19:00
The page number of your abstract in the abstract book indicates your assigned poster board
number. An index of poster numbers appears in the back of this book.
Conference Meals and Social Events
Lunch and dinner will be served in the Hall, apart from lunch on Wednesday, 19 February when it will
be served in the Conference Centre, alongside registration. Please refer to the conference
programme in this book as times will vary based on the daily scientific presentations. Please note there
are no lunch or dinner facilities available outside of the conference times.
All conference meals and social events are for registered delegates. Please inform the conference
organiser if you are unable to attend the conference dinner.
The Hall Bar (cash bar) will be open from 19:00 – 23:00 each day.
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Dietary Requirements
If you have advised us of any dietary requirements, you will find a coloured dot on your badge.
Please make yourself known to the catering team and they will assist you with your meal request.
If you have a gluten or nut allergy, we are unable to guarantee the non-presence of gluten or nuts in
dishes, even if they are not used as a direct ingredient. This is due to gluten and nut ingredients being
used in the kitchen.
For Wellcome Genome Campus Conference Centre Guests
Check in
If you are staying on site at the Wellcome Genome Campus Conference Centre, you may check into
your bedroom from 14:00. The Conference Centre reception is open 24 hours.
Breakfast
Your breakfast will be served in the Hall restaurant from 07:30 – 09:00.
Telephone
If you are staying on-site and would like to use the telephone in your room, you will need to
contact the Reception desk (Ext. 5000) to have your phone line activated – they will require your
credit card details to do so.
Departures
You must vacate your room by 10:00 on the day of your departure. Please ask at reception for
assistance with luggage storage in the Conference Centre.
Taxis
Please find a list of local taxi numbers on our website. The conference centre reception will also be
happy to book a taxi on your behalf.
Return Ground Transport
Complimentary departure transport from the Conference Centre has been arranged on Friday, 21
February 2020 at the following times:
13:15 to Stansted and Heathrow airports.
13:30 to Cambridge train station and city centre (Downing Street).
A sign-up sheet will be available at the conference registration desk from 15:30 on Wednesday, 19
February until Thursday, 20 February. Please note that places are limited and will be allocated on a
first come first served basis.
Please allow a 30-40 minute journey time to both Cambridge and Stansted Airport, and two and a
half hours to Heathrow.
Messages and Miscellaneous
Lockers are located outside the Conference Centre toilets and are free of charge.
All messages will be available for collection from the registration desk in the Conference Centre.
A variety of toiletry and stationery items are available for purchase at the Conference Centre
reception. Cards for our self-service laundry are also available.
Certificate of Attendance
A certificate of attendance can be provided. Please request one from the conference organiser
based at the registration desk.
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Contact numbers
Wellcome Genome Campus Conference Centre – 01223 495000 (or Ext. 5000)
Wellcome Genome Campus Conference Organiser (Jemma) – 07473 934631
If you have any queries or comments, please do not hesitate to contact a member of staff who will
be pleased to help you.
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Conference Summary
Wednesday, 19 February
11:30 – 12:50 Registration with buffet lunch
12:50 – 13:00 Welcome and introduction
13:00 – 14:30 Session1: Why the no-specific effects of vaccines are important
14:30 – 15:30 Keynote lecture: Mihai Netea, Radboud University, The Netherlands
15:30 – 16:00 Afternoon tea
16:00 – 17:30 Session 2: Potential non-specific effects of vaccines – evidence from clinical
trials
17:30 – 18:00 Lightning talks
18:00 – 19:00 Poster session 1 (odd numbers) and drinks reception
19:00 – 21:00 Dinner
Thursday, 20 February
09:00 – 10:45 Session 3: Effects of vaccines on immunity and the epigenome
10:45 – 11:15 Morning coffee
11:15 – 12:30 Session 4: Sex-differnces in immunity and response to vaccines
12:30 – 14:00 Lunch
14:00 – 15:30 Session 5: Potential off-target use of vaccines
15:30 – 16:00 Afternoon tea
16:00 – 17:30 Session 6: Conference Q&A
17:30 – 18:00 Lightning talks
18:00 – 19:00 Poster session 2 (even numbers) and drinks reception
19:00 – 21:00 Dinner
Friday, 21 February
09:00 – 10:00 Session 7: Vaccination of the elderly
10:00 – 10:30 Session 8: Non-specific effects of vaccines: A complex and controversial topic
10:30 – 10:45 Morning coffee
10:45 – 12:45 Session 9: Looking toward the future: New vaccines/testing products in the
pipeline
12:45 – 12:55 Closing remarks
12:55 – 13:15 Lunch
13:15 Coach departs to London Heathrow airport via London Stansted airport
12:45 Coach departs to Cambridge train station and city centre (Downing Street)
The Conference Centre hosts hundreds of one-day and residential meetings for biomedical sector clients each year, and offers preferential rates to organisers from this sector.
Facilities:
We would love to welcome you and your delegates to our venue at the heart of life-changing science.
• 300-seat auditorium with all the latest audiovisual capabilities• 8 distinctive meeting rooms with flexible set-up options for groups of 2-120 people• Large naturally-lit exhibition space with bar • 300-seat restaurant
• On-site accommodation: 134 modern and comfortable bedrooms• Outdoor space for team building activities and BBQs in summer• Complimentary parking for 180 cars and bike rack
Hold your own meeting at the Wellcome Genome Campus Conference Centre
To enquire or to book a show round please call the Sales team on 01223 495123 or email [email protected]
www.wellcomegenomecampus.org/conferencecentre
We chose the conference facility for the beautiful surrounds, the professionalism of the staff, the high quality of the venue itself and the amazing wow factor.
Health Enterprise East Innovation Showcase”“
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Optimmunize: Improving the beneficial effects of vaccines
Wellcome Genome Campus Conference Centre,
Hinxton, Cambridge
19 – 21 February 2020
Lectures to be held in the Francis Crick Auditorium
Lunch and dinner to be held in the Hall Restaurant
Poster sessions to be held in the Conference Centre
Spoken presentations - If you are an invited speaker, or your abstract has been selected for a
spoken presentation, please give an electronic version of your talk to the AV technician.
Poster presentations – If your abstract has been selected for a poster, please display this in the
Conference Centre on arrival.
Conference programme
Wednesday, 19 February
11:30-12:50 Registration with lunch
12:50-13:00 Welcome and Introductions
Programme Committee
13:00-14:30 Session 1: Why the non-specific effects of vaccines are important
Chair: Nigel Curtis
13:00 Opening note
Nigel Curtis
Melbourne University, Australia
13.10 Why the non-specific effects of vaccines are important
Peter Aaby
Bandim Health Project, Guinea-Bissau
13:30 Off target effects: the box is finally open but the contents are still
confusing
Adam Finn
University of Bristol, UK
13:50 Q&A & discussion
14:30-15:30 Keynote Lecture:
Trained immunity: a memory for innate host defense
Mihai Netea
Radboud University, The Netherlands
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15:30-16:00 Afternoon Tea
16:00-17:30 Session 2: Potential non-specific effects of vaccines – evidence from
clinical trials
Chair: Sabra Klein
16:00 The Melbourne Infant Study: BCG for Allergy and Infection Reduction
(MIS BAIR)
Nigel Curtis
Melbourne University, Australia
16:30 Repurposing of Vaccines: What is in a name?
Tobias Kollmann
Telethon Kids Institute, Australia
17:00 Immune system development varies according to age, location and
anemia in African children
Danika Hill
Babraham Institute, UK
17:15 Evidence for BCG-induced protection against heterologous infectious
disease in Ugandan neonates: an investigator-blind randomised
controlled trial.
Sarah Prentice
East and North Hertfordshire NHS Trust, UK
17:30-18:00 Lightning talks
18:00-19:00 Poster Session 1 (odd numbers) with drinks reception
19:00 Dinner
Thursday, 20 February
09:00-10:45 Session 3: Effects of vaccines on immunity and the epigenome
Chair: Mihai Netea
09:00 What have we learnt about BCG vaccination in the last 20 years?
(and can we improve its efficacy?)
Hazel Dockrell
LSHTM, UK
09.30 Non-specific effects of vaccines and nanoparticles: potential use in
cancer patients
Magda Plebanski
RMIT, Australia
10.00 BCG and DTPw vaccination induce altered programmes of “trained”
innate immunity in mice
David Lynn
South Australian Health and Medical Research Institute, Australia
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10.15 Exploring the role of RORa on trained immunity in human monocytes
Gizem Kilic
Radboud University Medical Center, The Netherlands
10.30 Systemic bacterial burden of sepsis-challenged neonatal mice
significantly associated with survival
Byron Brook
University of British Columbia, Canada
10:45-11:15 Morning Coffee
11:15-12:30 Session 4: Sex-differences in immunity and response to vaccines
Chair: Eleanor Fish
11:15 Age-associated sex differences in immunity to seasonal inactivated
influenza vaccines
Sabra Klein
Johns Hopkins University, USA
11:45 Vertically transferred immunity in neonates: Mothers, mechanisms and
mediators
Petra Arck
University Medical Center Hamburg-Eppendorf, Germany
12:15 Female-biased effects of aging on a chimeric hemagglutinin-based
universal influenza virus vaccine in mice
Santosh Dhakal
Johns Hopkins University, USA
12:30-14:00 Lunch
14:00-15:30 Session 5: Potential off-target use of vaccines
Chair: Christine Stabell Benn
14:00 BCG vaccines off target effects: so many good things with an emphasis
on type 1 diabetes
Denise Faustman
Massachusetts General Hospital, USA
14:30 Sex-differential effects of rabies vaccine on survival in young free-
roaming dogs, a novel animal model for the study of non-specific
effects of vaccines in high-mortality populations
Darryn Knobel
Ross University School of Veterinary Medicine, West Indies
15:00 BCG vaccination is associated with reduced malaria prevalence in
children under the age of five in sub-Saharan Africa
Mike Berendsen
Bandim Health Project, Guinea-Bissau
15:15 Discussion: How can we use off-target effects to optimize vaccination?
15:30-16:00 Afternoon Tea
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16:00-17:30 Session 6: Conference Q&A
Chair: Christine Stabell Benn
Young investigators(< 10 yrs post last degree (PhD, MD) will be asked to provide one
critical question related to the conference subject when registering. The organizers
will select the 2 best abstracts to be presented during this session. In addition, the
organizers will select the 5 most thought provoking questions, and they will be
discussed in a subsequent panel session that will include relevant speakers and the
young researchers who posed the critical questions.
17:30-18:00 Lightning talks
18:00-19:00 Poster Session 2 (even numbers) with drinks reception
19:00 Dinner
Friday, 21 February
09:00-10:00 Session 7: Vaccination of the elderly
Chair: Sarah Prentice
09:00 The impact of immunosenescence on immune responses after
influenza vaccination in older individuals
Inna Ovsyannikova,
Mayo Clinic, USA
09:20 Evidence for immunomodulatory effects of vaccination in aging
Australians
Katie Flanagan
Monash University, Australia
09:40 Panel discussion:
Can vaccines be used to combat immunosenescence?
10:00-10:30 Session 8: Non-specific effects of vaccines: a complex and
controversial topic
Chair: Eleanor Fish
10:00 Non-specific effects of vaccines: Complex and controversial….and a
challenge for current vaccine paradigms
Rebecca Chandler
Uppsala Monitoring Centre, Sweden
10:15 Discussion
10:30-10:45 Morning Coffee
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10:45-12:45 Session 9: Looking toward the future: New vaccines/testing products
in pipeline
Chair: Rebecca Chandler
10:45 Specific and off-target effects of novel live attenuated pertussis vaccine
Camille Locht
Institute Pasteur, France
11:15 Impact of adjuvants, sex, and the microbiome on SIV-vaccine-induced
immunity and protective efficacy in rhesus macaques
Marjorie Robert-Guroff
National Cancer Institute, USA
11:45 Precision adjuvants for next generation vaccines tailored to
vulnerable populations
Ofer Levy
Harvard University, USA
12:15 New live attenuated tuberculosis vaccine MTBVAC induces trained
immunity and confers protection against experimental lethal
pneumonia
Jorge Dominguez Andres
Radboud University Medical Center, The Netherlands
12:30 MV130 as a Trained Immunity-based Vaccine, clinical implications and
mechanism of action
Laura Conejero
Immunotek, Spain
12.45-12:55 Closing remarks
12:55 -13:15 Lunch
13:15 Coach depart to Heathrow Airport via Stansted Airport
13:30 Coach departs to Cambridge City Centre and Train Station
The following abstracts should not be cited in bibliographies. Materials contained herein should be treated as personal communication and should be cited as such
only with consent of the author.
2020 CONFERENCES
Evolutionary Systems Biology12-14 FebruaryOptimmunize: Improving the beneficialeffects of vaccines NEW19-21 FebruarySingle Cell Biology11-13 MarchGenomics of Brain Disorders 18-20 MarchGenomics of Rare Diseases25-27 MarchProteomics in Cell Biology and Disease Mechanisms30 March-1 AprilLongitudinal Studies20-22 AprilNursing, Genomics and Healthcare NEW27-29 AprilAntimicrobial Resistance - GenomeBig Data and Emerging Technologies4-6 MayCurating the Clinical Genome20-22 MayHealthy Ageing27-29 MayGenomic Epidemiology of Malaria 7-10 JuneVirus Genomics and Evolution15-17 JuneReproducibility, Replicability and Trustin Science NEW9-11 SeptemberGenome Informatics14-17 SeptemberCRISPR and beyond: perturbations at scale to understand genomes23-25 SeptemberGenomic Imprinting - from Biology to Disease NEW28-30 SeptemberExploring Human Host-Microbiome Interactions in Health and Disease21-23 October
COURSESLABORATORY COURSESGenomics and Clinical Microbiology19-24 JanuaryGenomics and Clinical Virology23–28 FebruaryGenetic Engineering of Mammalian Stem Cells15–27 MarchNext Generation Sequencing20–27 AprilLow Input Epigenomics NEW12-20 MayRNA Transcriptomics17-26 JuneSingle Cell Technologies and Analysis24-31 JulyMolecular Pathology and Diagnosis of Cancer22-27 NovemberDerivation and Culture of Human Induced Pluripotent Stem Cells (hiPSCs)14-18 December
COMPUTATIONAL COURSESMathematical Models for Infectious Disease Dynamics24 February-6 MarchFungal Pathogen Genomics11-16 MaySummer School in Bioinformatics22-26 JuneSystems Biology: From Large Datasets to Biological Insight6-10 JulyGenetic Analysis of Mendelian and Complex Disorders15-21 JulyProteomics Bioinformatics26-31 JulyGenetic Analysis of Population-based Association Studies21-25 SeptemberWorking with Protozoan Parasite Database Resources4-9 OctoberNext Generation Sequencing Bioinformatics18-24 OctoberComputational Systems Biology for Complex Human Disease NEW6-11 December
@ACSCeventswellcomegenomecampus.org/coursesandconferences
LECTURE/DISCUSSION COURSESClinical Genomics: Fundamentals ofVariant Interpretation in Clinical Practice29-31 JanuaryGenomic Practice for Genetic Counsellors3-5 FebruaryPractical Aspects of Small Molecule Drug Discovery21-26 JuneEvolutionary Biology and Ecology of Cancer29 June-3 JulyScience Policy: Improving the Uptake of Research into UK Policy19-21 AugustGenomics for Dermatology25-27 November
OVERSEAS COURSESNext Generation Sequencing Bioinformatics19-24 January (Chile) 9-14 February (Malaysia)Molecular Approaches to Clinical Microbiology in Africa 21-27 March (The Gambia)Genomics and Epidemiological Surveillance of Bacterial Pathogens19-24 April (Paraguay)Working with Pathogen Genomes10-15 May (Vietnam)Viral Genomics and Bioinformatics7-12 June (Uruguay)Antimicrobial Resistance of Bacterial Pathogens 27 September-3 October (Kenya)Malaria Experimental Genetics 8-13 November (The Gambia)Practical Aspects of Drug Discovery 29 November-4 December (Uruguay)
ONLINE COURSESBacterial Genomes - 4 coursesGenetic Counselling - 1 course
Please see our website for more details and scheduling of online courses
WGC_Courses_and_Conferences_2020-Abstract-Books(Blue-FullColour)december2019.indd 1WGC_Courses_and_Conferences_2020-Abstract-Books(Blue-FullColour)december2019.indd 1 03/12/2019 11:08:0403/12/2019 11:08:04
S1
Spoken Presentations
Why the non-specific effects of vaccines are important
Peter Aaby
Statens Serum Institut, Denmark
For public health, a vaccine serves to prevent a specific disease. Thus, the effect of a
vaccine on overall survival is assumed to be proportional to the number of specific infections
prevented. However, from measuring the overall effects of vaccines on morbidity and
mortality has come a growing number of contradictions of this assumption, and an increasing
realisation that vaccines also have important non-specific effects (NSEs). With this
knowledge, we can define new vaccination policies with more profound effects on survival.
While there is now amble evidence that vaccines not only have specific effects, we are still in
the process of understanding the NSEs, but some strong principles have emerged: First, so
far it has been shown that four live vaccines enhance resistance to unrelated infections
(beneficial NSEs) by reducing child mortality more than can be explained by prevention of
the vaccine-targeted infection. Second, in contrast, six live vaccines have deleterious NSEs,
increasing the risk of other infections, particularly for females. Third, combining live and non-
live vaccines have variable effects. Fourth, females and males react differently to vaccines.
Fifth, the sequence and combination of vaccines is important since the most recent vaccine
has the strongest NSEs. Sixth, vaccinating with live vaccines in the presence of existing
maternal immunity amplifies the beneficial NSEs. Seventh, boosting with live vaccines
amplifies the beneficial NSEs. Eight, as immune-stimulants vaccines may interact
beneficially or deleteriously with other interventions affecting the immune system. Systematic
searches for the effect of various vaccines and combinations will undoubtedly produce more
principles of NSEs in the future.
As illustrated by a few examples, public health will benefit if the NSEs are taken into
consideration. First, the live high-titre measles vaccine (HTMV) was effective in preventing
measles infection, but had to be withdrawn by WHO because it was associated with two-fold
increased female mortality. This negative effects was due to non-live vaccines being given
after the live measles vaccine. Second, campaigns with measles vaccine and live oral polio
vaccine (OPV) have played a major role in reducing child mortality in low-income countries in
the last decades. Hence, stopping live vaccines after eradication may increase mortality as
happened with smallpox vaccine and may soon happen with OPV. Third, several non-live
vaccines including the malaria vaccine (RTS,S) currently being tested in Africa have been
associated with increased female-to-male mortality. Co-administration of non-live vaccine
with a live vaccine may reduce the negative effect for girls.
S2
Notes
S3
Off target effects: the box is finally open but the contents are still confusing
Adam Finn
University of Bristol, UK
Vaccines are developed, tested, licensed and, usually, implemented based on evidence
showing their direct (on target) protective effects and safety in recipients. Evidence of their
indirect effects (impact on transmission of the target infection in the wider population) usually
follows universal implementation and often exceeds expectations. Recently models
predicting such effects have begun to be incorporated into cost-benefit models which drive
implementation and even targeting strategies (e.g. paediatric influenza and adolescent
meningococcal programmes). However the extent to which immunisation, especially in early
childhood, may have off target effects is much less clear. Epidemiological evidence of some
important downstream off-target effects (when prevention of the target infection in turn
prevents secondary infections that otherwise would have ensued e.g. varicella-group A
streptococcus; influenza-pneumococcal pneumonia; measles-multiple infections) are
beginning to emerge with supporting explanatory mechanisms in some cases. However the
picture with respect to pure off-target effects (where administration of the vaccine itself alters
the recipients’ susceptibility to unrelated infections) currently appears to be both complex
and hard-to-call. Confronted with the apparent paradox of modest efficacy of the candidate
sporozoite vaccine RTS,S against malaria alongside a numerically small but proportionally
(between groups) large safety signal with an excess of cases of meningitis, diverse in both
aetiology and timing, and even of cerebral malaria in the vaccine recipients, we developed
an alternative hypothesis that the non-live rabies vaccine, given to controls in the older study
group in whom the apparent central nervous system infection signal was observed, might
actually have been protective in some non-specific off target way. We found several studies
in the literature published over a 50 year period that support this theory as well as studies
suggesting that components of the rabies virus present in the inactivated vaccine may
activate multiple unrelated lymphocyte clones. We are currently investigating possible
mechanisms for such an effect in more detail. If proven to exist, any added protective value
of such non-specific effects of rabies vaccine might drive its introduction in communities in
which deaths from paediatric rabies cases occur but not in sufficient numbers to justify the
cost of universal prevention.
S4
Notes
S5
Trained immunity: a memory for innate host defense Mihai G. Netea, Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands The inability of innate immunity to build an immunological memory, considered one of the main characteristics differentiating it from adaptive immunity, has been recently challenged by studies in plants, invertebrates, and mammals. Long-term reprogramming of innate immunity, that induces adaptive traits and has been termed trained immunity characterizes prototypical innate immune cells such as natural killer cells and monocytes, and provides protection against reinfection in a T/B-cell-independent manner. In contrast, trained immunity has been shown to be able to induce protection against reinfection in a lymphocyte-independent manner. Non-specific protective effects dependent on trained immunity have also been shown to be induced after BCG vaccination in humans. Specific signaling mechanisms including the dectin-1/Raf1 and NOD2-mediated pathways induce trained immunity, through induction of histone modifications (methylation, acetylation) and epigenetic reprogramming of monocyte function. Complex immunological and metabolic circuits link cell stimulation to long-term epigenetic reprogramming of the function of myeloid cells and their bone marrow progenitors. The concept of trained immunity represents a paradigm change in immunity and its putative role in infection and inflammation may represent the next step in the design of future vaccines and immunotherapeutic approaches.
S6
Notes
S7
The Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) Nigel Curtis University of Melbourne, Australia
The Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) [misbair.org.au] is a randomised controlled trial of neonatal BCG vaccination in which over 1200 newborns in Melbourne have been recruited. The clinical outcomes, measured over the first five years of life, are respiratory infections, eczema, allergic sensitisation (measured by skin prick test) and asthma. Parent-completed online questionnaires have been used to collect extensive and detailed antenatal, perinatal and postnatal data. The trial includes an extensive biobank of blood and stool samples [lifecourse.melbournechildrens.com] for laboratory studies to investigate the immunological and molecular basis for the heterologous (non-specific) effects of BCG vaccine.
.
S8
Notes
S9
Repurposing of Vaccines: What is in a name?
Tobias R. Kollmann, Nelly Amenyogbe
Telethon Kids Institute; Perth Children's Hospital; University of Western Australia
Vaccination induces changes far beyond the intended immune memory response targeting a specific pathogen. These effects have variously been labelled non-specific, off-target or heterologous. All of these terms suggest a vague, unintended impact. While that may have been true during the original discovery of effects that go beyond those targeting a specific pathogen, there now is ample data to suggest that the host modulatory functions of vaccines can specifically be harnessed to provide targeted benefit from e.g. preventing newborn mortality to reducing several non-communicable diseases. To reflect this confidence in the science associated with this stream of vaccine evaluation, we suggest use of the term 'repurposing of vaccines' to capture the active, intentional harnessing of this vast and largely untapped field of science. In analogy to the field of repurposing drugs, this name would also help demystify current research efforts on this topic and emphasize the benefits to be gained, ranging from accelerating vaccine discovery and design to increased safety to reduced R&D expenditure, thus market value.
S10
Notes
S11
Immune system development varies according to age, location and anemia in African children
Danika L. Hill 1,2‡, Edward J. Carr1,3, Tobias Rutishauser4,5, Gemma Moncunill6, Joseph J. Campo6, Silvia Innocentin1, Maxmillian Mpina4,5,7, Augusto Nhabomba8, Anneth Tumbo4,5,7, Chenjerai Jairoce8, Henriëtte A. Moll9, Menno C. van Zelm2, Carlota Dobaño6,8*, Claudia Daubenberger4,5*‡, Michelle A. Linterman1*‡.
1. Lymphocyte Signalling & Development, Babraham Institute, Cambridge, UK. 2. Department of Immunology and Pathology, Central Clinical School, Monash University and Alfred Hospital, Melbourne, Victoria, Australia 3. Department of Medicine, University of Cambridge, Cambridge, UK 4. Swiss Tropical and Public Health Institute, Basel, Switzerland. 5. University of Basel, Switzerland. 6. ISGlobal, Barcelona Centre for International Health Research, Hospital Clínic–Universitat de Barcelona, Catalonia, Spain. 7. Ifakara Health Institute, Bagamoyo, Tanzania 8. Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique. 9. Department of Pediatrics, Sophia Children’s Hospital, Erasmus MC, University Medical Center, Rotterdam, the Netherlands *Joint senior authors ‡ Corresponding authors
The high incidence of infectious disease in children from low- and middle-income countries
creates a challenge for their immune systems in first few years of life. These children have
the greatest need of the protection afforded by vaccination, however vaccines often show
reduced efficacy in these populations. An improved understanding of how age, infection,
nutrition, and genetics influence immune ontogeny and function is key to informing vaccine
design for this at-risk population. We sought to identify factors that shape immune
development in children under five years of age from Tanzania and Mozambique by detailed
immunophenotyping of longitudinal blood samples collected during the RTS,S malaria
vaccine phase III trial. In this cohort, the composition of the immune system is dynamically
altered during the first years of life, and this was further influenced by geographical location,
with some immune cell types showing an altered rate of development in Tanzanian children
compared to Dutch children enrolled in the Generation R population-based cohort study.
High titer antibody responses to the RTS,S/AS01E vaccine were associated with an
activated immune profile at the time of vaccination, including an increased frequency of
antibody secreting plasmablasts and follicular helper T cells. Anemic children had lower
frequencies of recent thymic emigrant T cells, isotype-switched memory B cells and
plasmablasts, and modulating iron bioavailability in vitro could recapitulate the B cell defects
observed in anemic children. Our findings demonstrate that the composition of the immune
system in children varies according to age, geographical location and anemia status.
S12
Notes
S13
Evidence for BCG-induced protection against heterologous infectious disease in Ugandan neonates: an investigator-blind randomised controlled trial.
Prentice S (a,b), Webb EL (c) Akello F (b) Kiwudhu F (b) Akurut H (b) Elliott AM (a,b) Dockrell HM (d) Cose S (b,d) The Delayed BCG Study Team
a: Clinical Research Department, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT b: MRC/UVRI and LSHTM Uganda Research Unit, 51-59 Nakiwogo Road, Entebbe, P.O. Box 49 c: Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT d: Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT
Trials conducted in low birth-weight infants in West Africa suggest that BCG vaccination
produces heterologous protection against non-tuberculous infectious disease during the
neonatal period. Uncertainty exists as to the generalisability of these findings, and thus their
broader public health implications. We conducted an investigator-blind randomised
controlled trial in 560 healthy neonates in East Africa, comparing BCG vaccination on the
day of birth with BCG vaccination at 6-weeks of age. Illness incidence during the first 10-
weeks of life was measured by active participant follow-up, comprising free access to
physician review and investigations, regular routine physician reviews and weekly telephone
interviews.
Infants randomised to receive BCG at birth had a 29% reduction in physician-diagnosed
non-tuberculous infectious disease incidence compared to BCG unvaccinated infants, during
the 6-week period prior to BCG vaccination in the delayed group (Hazard Ratio (HR) 0.71,
95% CI (0.53 to 0.95)). In pre-specified sub-group analysis, this reduction was more
pronounced in low birth-weight infants ≤2500g (HR 0.10 (0.01 to 0.75)) compared to normal
birth-weight infants (HR 0.79 (0.59 to 1.07)) interaction p-value 0.04). After BCG vaccination
in the delayed group at 6-weeks of age, there was no significant difference in physician-
diagnosed, non-tuberculous infectious disease incidence between the groups.
We conclude that BCG vaccination produces heterologous protection against non-
tuberculous infectious disease during the neonatal period, in addition to having TB specific
effects. This corroborates findings from other groups and suggests that the beneficial non-
specific effects of BCG are applicable in disparate high-mortality settings. Prioritisation of
BCG vaccination on the first day of life may have significant public health benefits through
reductions in all-cause infectious morbidity and mortality.
S14
Notes
S15
What have we learnt about BCG vaccination in the last 20 years?
(and can we improve its efficacy?)
H.M. Dockrell and S.G. Smith
London School of Hygiene & Tropical Medicine
Recent trials of new TB vaccines have used BCG vaccination as a control arm or are carried
out in populations where BCG has been given previously. These and other cross-population
observational studies that aimed to better understand the variable efficacy of BCG
vaccination have shown that although we have immunological assays that read out the
immunogenicity of BCG vaccination, we still lack proven correlates of protection. Induction of
antigen-specific Th1 responses are part of the protective immune response but not sufficient.
Antibodies and innate lymphoid cells have also been implicated. BCG vaccination has also
been shown to induce beneficial non-specific effects. Epigenetic and metabolic changes in
innate cells give rise to trained innate immunity which could explain such effects. Genetically
modified BCG vaccines, or even repeat BCG vaccination may give enhanced protection.
Exploiting the effects of particular metabolites, which by themselves appear to induce trained
immunity, may give another means of improving BCG’s efficacy. What is clear is that this old
vaccine still has much to teach us, and what we learn can inform the design of improved
vaccines for TB as well as providing protection against other infections in young children as
well as immunotherapies for use in autoimmune disease.
S16
Notes
S17
Non-specific effects of vaccines and nanoparticles: potential use in cancer patients
Magdalena Plebanski
School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria, Australia
The immune systems reactions to particulate material has been selected over evolution
based on environmental challenges, including nano and micro-sized viruses, bacteria and
parasites. However, such reactions have to be balanced against the need to maintain
homeostasis in response to internal particulate materials such as exosomes, as well as non-
lethal external particles, such as non-toxic fine and ultra-fine particulates in the air. Even as
current vaccines elicit sophisticated non-specific effects, that re-frame immune system
process, with significant impact on overall morbidity and mortality in high burden
environments, new generation vaccines engaging synthetic nanotechnology, are also likely
to trigger non-specific effects, based substantially on the rules of interaction established over
evolution between particulates and immunity, particularly at the level of antigen presenting
cells. Over the years we have mapped some of these rules, and show that nanoparticles and
microparticles used as vaccine components can elicit large non-specific effects, capable of
accelerating the clearance of infections such as malaria and influenza, as well as preventing
the elicitation of allergic airways inflammation. These non-specific effects are in turn
modulated by particle size, shape and charge. For example, dendritic cells exquisitely
internalize nanoparticles 40-60 nm, whereas other phagocytes prefer to take up
nanoparticles 500-2000 nm. After being taken up, synthetic nanoparticles also signal inside
these cells, promoting epigenetic imprinting and altered antigen presenting cell reactivity.
These studies are supporting the development of new generation synthetic nanovaccines,
with a priori defined non-specific effects, to treat cancer. We will further finalize this
presentation with considerations on the nature of immune systems alterations in cancer
patients, specifically ovarian cancer patients, which can alter their response to vaccines,
including those based on new generation synthetic nanoparticles.
S18
Notes
S19
BCG and DTPw vaccination induce altered programmes of “trained” innate immunity in mice.
David J. Lynn, Marjolein van Wolfswinkel 1, Natalie Stevens 1, Georgina Eden 1, Miriam A. Lynn 1, Damon Tumes 2
1 Computational and Systems Biology Program, Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia. 2 Allergy and Cancer Immunology Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia. 3 College of Medicine and Public Health, Flinders University, Bedford Park, South Australia.
Vaccines prevent >2 million deaths annually by eliciting antigen-specific adaptive immunity,
however increasing evidence suggests that vaccines also elicit nonspecific effects on
morbidity and mortality unrelated to the targeted disease. Live vaccinations (e.g. BCG) are
generally associated with beneficial nonspecific effects, while some inactivated vaccines
(e.g. DTPw) have controversially been associated with increased all-cause mortality. We
hypothesised that BCG and DTPw induce altered programmes of 'trained innate immunity'
i.e. epigenetic reprogramming which alters innate responses to subsequent stimuli. To
investigate this, we immunized 4-week-old mice with BCG or DTPw alone, or with both
vaccines in two different schedules (BCG followed two weeks later by DTPw or DTPw
followed by BCG). At 12 weeks post-immunisation, we assessed cytokine responses in
monocytes and DCs by ICS, following stimulation with bacterial, fungal or viral antigens.
BCG immunisation led to significantly increased TNF production by monocytes following
stimulation with heat-killed Candida albicans (HKCA), as has been previously reported. In
contrast, DTPw immunisation induced significantly increased IL6 production by DCs
stimulated with either HKCA or LPS. Interestingly, immunisation with BCG prior to DTPw
supressed IL6 production compared to DTPw alone or mock vaccination.
Our findings indicate that immunisation of mice with BCG or DTPw induces altered
programmes of trained innate immunity altering cytokine responses to subsequent microbial
encounters. Furthermore, our data demonstrate that previously administered vaccines may
modify the programme of trained innate immunity induced by other subsequently
administered vaccines. Our ongoing studies are now investigating the transcriptomic and
epigenetic basis for the observed phenotypes.
S20
Notes
S21
Exploring the role of RORa on trained immunity in human monocytes
Gizem Kilic, Simone JCFM Moorlag, Rob ter Horst, Valerie ACM Koeken, L Charlotte J de Bree, Vera P Mourits, Leo AB Joosten, Jorge Domínguez-Andrés, Mihai G Netea
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
Bacille Calmette-Guérin (BCG) is a live attenuated vaccine that has been traditionally used
against tuberculosis. Besides the development of strong and fast memory B and T cell
responses upon encounter with Mycobacterium tuberculosis, recent studies have shown that
BCG vaccination is also able to improve protection against non-specific infections by
mediating epigenetic and metabolic reprogramming of innate immune cells such as
monocytes, neutrophils and NK cells, what has been termed "trained immunity". However,
the strength and degree of BCG-induced trained immunity highly varies among people and
depends on age, sex and genetic variants. Among them, the transcription factor RORα is
known for its role as a regulator in the inflammatory response in monocytes and cholesterol
metabolism. Preliminary analyses in two cohorts of healthy volunteers showed that several
SNPs related to RORα might alter inflammatory responses and immune cell training after
BCG vaccination. With this in mind, we investigated the potential role of RORα on BCG-
induced trained immunity.
To test the role of RORα on training, human monocytes isolated from buffy coat were
stimulated with BCG (5 µg/ml) in the presence and absence of RORα inhibitor SR3335 for
24 hours, then cells were washed, and fresh media were added. Following 5 days of resting
period, cells were re-stimulated with LPS for 24 hours, and cytokine levels were measured
by ELISA. To study if IL-1 signaling has role on training promoted by RORα inhibition, IL-1
signaling was blocked by interleukin 1 receptor antagonist (IL-1RA), and monocytes were
trained with BCG in presence of SR3335.
Data revealed that inhibition of RORα by SR3335 significantly increased TNFα and IL-6
cytokine production in BCG-trained monocytes, in a dose dependent manner, upon re-
challenge with LPS. Furthermore, even in the absence of training stimuli, pre-exposure of
monocytes to SR3335 elevated pro-inflammatory cytokine production following re-stimulation
of monocytes with LPS. Of note, RORα inhibition with or without TLR ligands and BCG
stimulation for 24 hours did not lead to further increase in pro-inflammatory cytokine
production, indicating that RORα inhibition does not cause acute inflammation. Lastly,
impaired IL-1 signaling did not abolish increased production in TNFα and IL-6 mediated by
RORα inhibition. Collectively, RORα was identified as a modulator of BCG-induced trained
immunity in monocytes. To understand its role and regulatory function in detail, future
studies will be focusing on whether RORα inhibition regulates monocyte metabolism and
epigenome, similar to what is observed after BCG-induced trained immunity.
S22
Notes
S23
Systemic bacterial burden of sepsis-challenged neonatal mice significantly associated with survival.
Byron Brook*, Danny Harbeson*, Nelly Amenyogbe, Rym Ben-Othman, Tobias R. Kollmann‡, Radhouane Aniba‡. *,‡ authors contributed equally
University of British Columbia, Department of Experimental Medicine.
Neonates suffer a disproportionately high rate of mortality due to infectious disease
compared to adults, and neonatal interventions have had modest success in reducing
mortality. This has largely been attributed to different neonatal specific immune responses,
but the mechanism of how neonatal systems differ from adults has not been fully explored.
Understanding what controls life and death can identify biologically important targets for
future preventative treatments like vaccines, or future therapies, and death from bacterial
sepsis can be driven by hyper-inflammation, or bacterial-induced organ damage. A neonatal
mouse model of bacterial sepsis was employed to determine what controls survival.
Observing neonatal mice was essential for age-dependent responses, but were limiting due
to mice being too small for serial sampling. To obtain systemic samples mice were
euthanized, but then final outcome could not be directly observed, therefore we required a
method of predicting outcome so that systemic responses could be correlated with survival.
Measures of health like righting reflex, degree of mobility, and weight were observed
throughout the course of disease, and final outcome noted to determine whether the health
features could be used to separate survivors from non-survivors. Each health feature was
not accurate enough on its own to predict mortality, but their combination through algorithm
and machine learning techniques led to the development of a predictor with repeated 85%
accuracy and 93% sensitivity. This predictor of mortality allowed for the euthanasia of mice,
collection of samples, and determination of whether systemic bacterial burden was
correlated with survival. Mice predicted to survive had 10 - 1000 times reduced bacterial
burden compared to non-survivors. This implicated bacterial clearance as an essential
functional mediator of outcome, and that a 1 - 3 log reduction in systemic bacterial burden
was physiologically relevant to survival. These results however do not rule out inflammation
induced damage, which is an area of study for future experiments. It is important to measure
the pathways that actually associate with life and death during the implementation of new
neonatal vaccines and therapies to increase the chance of success for the application of
new interventions to human cohorts in preventing death and saving lives. The ability to
predict mortality can be used to further explore how neonates respond to sepsis, but could
also be adapted and employed to other challenge or vaccination models.
S24
Notes
S25
Age-associated sex differences in immunity to seasonal inactivated influenza
vaccines
Sabra L. Klein,
Johns Hopkins Bloomberg School of Public Health
Influenza is an ongoing threat to human health, despite the recommended annual
vaccination. Among adults, females typically develop greater vaccine-induced immunity and
protection than males, which is caused by sex differential epigenetic modifications in X-
linked genes in B cells as well as sex steroid signaling. Furthermore, inactivated as well as
universal influenza vaccine-induced immunity declines with age, but to a greater degree in
females than males, which is associated with hormonal changes occurring during
reproductive senescence. Taken together, both sex steroids and X-linked genes affect
antibody production and results in sex-specific differences in the efficacy of vaccination
against influenza.
This work was supported by the NIH/NIAID Center of Excellence in Influenza Research and
Surveillance contract HHS N272201400007C and the NIH/ORWH/NIA Specialized Center of
Research Excellence in Sex Differences U54AG062333.
S26
Notes
S27
Vertically transferred immunity in neonates: Mothers, mechanisms and mediators
Petra Clara Arck1
1Laboratory for Experimental Feto- Maternal Medicine, Department of Gynecology and
Obstetrics, University Clinic of Hamburg- Eppendorf, Germany ([email protected])
Early life immunity is fragile and neonates are prone to infections, which creates a major
threat to offspring’s survival and future health. A sex-specific bias has often been reported,
with boys being more susceptible to early life infections. Besides congentinal infections,
vaccine-preventable infectious diseases pose a threat to neonatal immunity, as their immune
system is still immature. However, the vulnerability during infancy can be mitigated by the
transplacental transfer of pathogen-specific antibodies and possibly other mediators of
immunity from mother to the fetus during pregnancy, followed postnatally by breast milk-
mediated immunity. Since this largely antibody-mediated passive immunity can prevent the
newborn from infections, neonatal immunity depends strongly on the maternal immune
status, including the concentration of respective specific antibodies during pregnancy.
Moreover, emerging concepts propose that mothers may transfer immunity to the newborns
via vertical transfer of immune cells. Here, a preferential differentiation of hematopoietic
stem and progenitor cells towards myelopoiesis induced by maternal immune cells could be
detected in fetal mice, along with an improved resilience against cytomegalovirus infection in
neonates. In humans, low number of maternal immune cells in cord blood have been
associated with an increased number of infections in the first year of life, primarily in male
newborns. Hence, neonatal immunity is crucially determined by the mother and adjustments
of e.g. prenatal vaccination regimes may mitigate the risk for early life infections.
S28
Notes
S29
Female-biased effects of aging on a chimeric hemagglutinin-based universal influenza virus vaccine in mice
Santosh Dhakal (1), Sharvari DeshPande (1), Meagan McMahon (2), Florian Krammer (2), Sabra L. Klein (1)
(1) Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA, 21205. (2) Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA, 10029.
Adult females, both in humans and mice, develop greater antibody responses to inactivated
influenza vaccines (IIV) than males, which has implications for vaccine efficacy. The female-
biased immunity to IIV diminishes with advanced age. Inactivated influenza vaccines are 10-
60% effective and, therefore, efforts to develop more efficacious influenza vaccines are
underway. Targeting the conserved stalk region of the hemagglutinin (HA) protein of
influenza viruses has shown promise as a universal influenza vaccine candidate. Whether
biological sex and age affect immunity and protection provided by universal influenza
vaccines has not been evaluated and formed the basis of this study. We used chimeric HA
(cHA)-based universal influenza vaccine constructs expressing the same H1 stalk with an
irrelevant head from H9, H11, or H12 influenza A viruses. Adult (8-10 weeks) or aged (68-70
weeks) C57BL/6 mice were immunized with influenza B virus expressing cH9/1, followed by
cH11/1 and cH12/1 protein and subsequent challenge with mouse-adapted 2009 H1N1.
Following vaccination, adult mice immunized with the chimeric HA-based universal influenza
vaccine developed significantly greater serum IgG, and IgG2c but not IgG1 antibody titers
against different group 1 influenza A viruses than vaccinated aged mice. The age-specific
decline in vaccine-induced antibody titers was significantly more pronounced in female than
male mice. After virus challenge, vaccinated aged females experiences greater morbidity
than vaccinated adult females, with age-associated changes in protection being significantly
less pronounced among males. The extent to which age-associated changes in sex steroid
hormones, including estradiol, contribute to immunosenescence is currently under
investigation. These data suggest female-biased effects of aging on cHA-based universal
influenza vaccine-induced antibody responses and protection and highlight the importance of
inclusion of sex and age in the design and dosage of diverse influenza vaccine platforms.
S30
Notes
S31
BCG vaccines off target effects: so many good things with an emphasis on type 1
diabetes
Denise Faustman
Massachusetts General Hospital, USA
Abstract unavailable at time of printing
S32
Notes
S33
Sex-differential effects of rabies vaccine on survival in young free-roaming dogs, a
novel animal model for the study of non-specific effects of vaccines in high-mortality
populations
Darryn L. Knobel1,2 (presenter), Sintayehu M. Arega1, Anne Conan1
1 Center for Conservation Medicine and Ecosystem Health, Ross University School of
Veterinary Medicine, St. Kitts ([email protected])
2 Department of Veterinary Tropical Diseases, University of Pretoria, South Africa
The preponderance of epidemiological evidence in support of non-specific effects (NSEs) of
vaccines is derived from populations with high burdens of mortality due to infectious and
parasitic diseases. There are considerable methodological and ethical challenges to the
study of vaccine NSEs in these populations. We propose a novel animal model system for
the study of vaccine NSEs: populations of owned, free-roaming domestic dogs. Free-
roaming dogs are a useful model for the epidemiological study of NSEs, due to their
abundance, accessibility, high mortality rates due to infectious and parasitic diseases, and
low rates of routine vaccination. The ethical acceptability of (indeed, encouragement of)
surgical sterilization (gonadectomy) in these populations also provides avenues to
investigate the role of gonadal sex hormones in modification of vaccine NSEs by sex.
In a recent randomized controlled trial comparing the effect of animal rabies vaccine (ARV,
an inactivated, aluminum-adjuvanted vaccine) on all-cause mortality against a placebo
injection in such a population of young dogs, we found that ARV substantially increased the
hazard rate of death in female but not male dogs. We also observed that, in the placebo
group, male mortality was substantially greater than female mortality, an effect which we
presume is due to greater male susceptibility to prevalent infectious and parasitic diseases in
the population. We contend that these two findings–relatively low female compared to male
mortality in the placebo group and increased female but not male mortality in the vaccinated
group compared to the placebo group–are related and point to a plausible mechanistic
explanation. We hypothesize that the detrimental effect of ARV (and possibly other vaccines)
on female survival is mediated through an effect on the immune system that alters
susceptibility to concurrent or subsequent unrelated infections, to which females are
normally less susceptible than males due to the influence of sex-related factors (hormonal
and/or genetic). We present a causal structure of this hypothesis, and propose to test it in
populations of free-roaming dogs through factorial randomized controlled trials, stratified by
sex, that could feasibly investigate the joint effects of vaccination, treatment against
concurrent or subsequent unrelated infections, and gonadectomy on mortality rates.
Integrating measures of immunological changes following interventions will allow evaluation
of the mediating effects of the immune system. We propose that establishment of free-
roaming dogs in high-mortality populations as a novel animal model system will open up new
avenues for causal inference in the study of NSEs of vaccines.
S34
Notes
S35
BCG vaccination is associated with reduced malaria prevalence in children under the age of five in sub-Saharan Africa
Mike Berendsen MSc1,2,3,4, Sjors van Gijzel BSc1 Jeroen Smits PhD2 Quirijn de Mast MD1 Peter Aaby DMSc3,5 Christine Benn DMSc3,4 Mihai Netea MD1,6,7 Andre van der Ven MD1
1 Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands 2 Global Data Lab, Institute for Management Research, Radboud University, Nijmegen, The Netherlands 3 Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark. 4 Open, Odense Patient Data Explorative Network, University of Southern Denmark, Odense University Hospital, Odense, Denmark 5 Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau. 6 Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Germany 7 Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova, Romania
Introduction
Malaria continues to be a major cause of morbidity and mortality in sub-Saharan Africa
(SSA) without effective interventions. Bacillus Calmette-Guérin (BCG) vaccine possesses
protective non-specific effects (NSEs). This study explores whether BCG is associated with
protection against malaria in children under the age of five in SSA.
Methods
We used data from the Demographic Health Survey (DHS) program, including 34,206
children from 13 SSA countries. BCG status was taken from vaccination cards when
present; if not, mother's recall was used. Presence of malaria was defined as a positive rapid
diagnostic test (RDT). Maternally reported presence or absence of fever in the previous two
weeks defined symptomatic status. Multilevel logistic regression was used to account for the
two-stage cluster sampling method.
Results
Of the 34,206 children, 12,325 (36.0%) children were malaria positive and 29,766 (87.0%)
were BCG vaccinated. BCG vaccination was associated with a lower malaria prevalence
(adjusted Odds Ratio (aOR)=0.94, [0.90 to 0.98], especially among children of whom BCG
information was retrieved from a vaccination card (aORcard=0.88, [0.82 to 0.94]). Restricting
the analysis to children from regions with suboptimal BCG coverage increased the
association (aORcard=0.81, [0.73 to 0.89]). BCG associations were similar for asymptomatic
(aORcard=0.86, [0.81 to 0.92]) and symptomatic malaria (aORcard=0.89, [0.78 to 1.01]).
Conclusion
BCG vaccination is associated with protection against malaria. These results indicate a
possible role for timely BCG vaccination in the protection and elimination of malaria. If
confirmed in further research, our findings have substantial implications for global efforts to
reduce malaria burden.
S36
Notes
S37
The Impact of Immunosenescnece on Immune Responses after Influenza Vaccination in Older Individuals Inna G. Ovsyannikova, Richard B. Kennedy, Iana H. Haralambieva, Diane E. Grill, Gregory A. Poland
Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, Minnesota, USA Influenza is a major threat to human health worldwide and is responsible for up to 650,000 deaths globally each year. Age and immunosenescence, and their impact on immune responses after influenza vaccination, are of increasing importance for the development of better vaccines for the elderly. The aim of this study was to examine associations between age and immunosenescence markers and vaccine-induced immune responses and identify immunosenescence-associated differences in gene expression and gene regulation in an older study population receiving seasonal influenza A/H1N1 vaccination. A cohort of 159 healthy recipients who received seasonal TIV (Fluarix) was used for this study. Baseline median HAI/VNA antibody titers (1/80; IQR 1/40-1/320) demonstrated the presence of pre-existing antibodies. A positive correlation (r=0.49) was observed between the %CD4+CD28- and the %CD8+CD28- cells and a negative correlation (r=-0.33) was found between TREC and the %CD8+CD28- cells. Telomerase (TERT) activity was positively correlated with the observed increase in the influenza-specific memory B-cell Elispot response at Day 28 compared to baseline (p=0.025). T cell receptor excision circle (TREC) levels were positively correlated with the baseline and early (Day 3) influenza A/H1N1-specific memory B-cell Elispot response (p=0.04 and 0.035, respectively). We identified an interconnected set of gene expression pathways (antigen processing/presentation, MAPK, mTOR, TCR, BCR, calcium signaling, and other cellular activities) that were associated with immunosenescence markers. Using miRNA sequencing, several miRNAs (miR-320a, miR-320b, and miR-320d) associated with markers of immunosenescence, such as age, %CD4+CD28- cells and CD4+/CD8+ T cell ratio (p<0.003), were discovered. We found several CpG methylation sites (examples include KLF14 regulating TGFβ signaling and TSPAN33 having a role in cell differentiation) associated with age within the genes controlling immune function. In conclusion, our findings provide further evidence that immunosenescence is a complex phenomenon involving multiple aspects of immunity. These data suggest that influenza-specific immunity is significantly influenced by age, and that specific markers of immunosenescence are correlated with different humoral immune response outcomes observed after vaccination in older individuals.
S38
Notes
S39
Evidence for immunomodulatory effects of vaccination in aging Australians
Katie Flanagan
Monash University, Australia
Introduction: This talk will describe preliminary results from the VITAL Trial: Vaccine
Immunomodulation Throughout the Aging Lifespan. The trial is taking a systems vaccinology
approach to study how the diphtheria-tetanus-acellular pertussis (dTap) and seasonal
influenza vaccines interact in aging Australians. It is further exploring the processes of
immunosenescence and inflammaging that occur with advancing age, and how they impact
vaccine immunogenicity. The rationale is that the elderly respond poorly to these vaccines
and that non-targeted effects of vaccines have not been explored in the elderly.
Methods: 300 adults (20-50 years) and 300 elderly (>65 years) individuals are being
randomized into one of three vaccine groups. Group 1: dTap vaccination followed by
seasonal influenza vaccination 4 weeks later; Group 2: influenza vaccination alone; Group3:
dTap plus influenza vaccination. Blood is taken at multiple timepoints for transcriptome
analysis, epigenetics, multicolour flow cytometry, cytokine multiplex and vaccine antibodies,
FBC, CRP; and stool for microbiome sequencing at baseline. Reactogenicity / adverse event
data are collected at each study visit. The trial is registered at www.clinicaltrials.gov identifier
NCT02765126.
Results: To date 264 people have been recruited into the study. Herein, we report
reactogenicity, CRP, FBC and influenza antibody data. Preliminary flow cytometry,
microbiome and transcriptome data will also be presented. Prior or concomitant dTap
negatively affects influenza antibody levels in younger males and the elderly. CRP and FBC
parameters were altered by dTap vaccination and the dual vaccination group experienced
significantly greater reactogenicity.
Conclusion: Prior or concomitant dTap vaccination impacts responses to seasonal
influenza vaccination in this interim analysis of an ongoing trial.
Disclosure of Interest Statement:
KLF has recently served on the influenza vaccine advisory boards for Seqiris and Sanofi-
Pasteur but they played no role in the design or funding for this study. She is a member of
the Australian Technical Advisory Group on Immunisation but this abstract represents her
personal views and not necessarily those of ATAGI.
S40
Notes
S41
Specific and off-target effects of novel live attenuated pertussis vaccine
Camille Locht
Center for Infection and Immunity of Lille, Inserm U1019, CNRS UMR8204, Institut Pasteur
de Lille
Pertussis, mainly caused by Bordetella pertussis, is a severe respiratory disease affecting all
age groups, but is most severe in less than 6-old months infants. While the introduction of
vaccines in the mid-20th century has led to a substantial decrease in the incidence of the
disease, it has not been controlled in any country, despite a > 85% global vaccine coverage.
In recent years many countries have even experienced a dramatic resurgence of pertussis.
Although several factors may contribute to this resurgence, the most parsimonious
explanation appears to be asymptomatic transmission of B. pertussis. None of the currently
available vaccines prevent infection by and transmission of B. pertussis, while they provide
good protection against disease. Unlike current vaccines, infection by B. pertussis induces
sterilizing immunity. We have thus developed a live attenuated pertussis vaccine to be
delivered nasally. This vaccine, named BPZE1, was shown to be safe in pre-clinical models,
including severely immunocompromised mice, and to provide strong protection against nasal
infection in both mice and non-human primates. Clinical studies have shown that it is safe in
humans, up to a dose of 109 CFU, able to transiently colonize the human respiratory tract
and to induce B- and T-cell responses to B. pertussis antigens after a single nasal delivery.
This vaccine is currently undergoing a clinical phase 2 trial involving 300 volunteers. In pre-
clinical studies we found that BPZE1 protects also against other Bordetella species, such as
Bordetella parapertussis and Bordetella bronchiseptica. Interestingly, protection against B.
bronchiseptica was based on a dual mechanism: antigen-specific inhibition of colonization,
due to cross-reactive antigens, and non-specific inhibition of B. bronchiseptica-induced
inflammation. This latter off-target effect was further investigated in Bordetella-unrelated
infectious models. BPZE1 was found to abolish lung inflammation, cytokine storm and death
induced by influenza virus A, although no cross-reactive B- or T-cell epitope exist between
the influenza virus and BPZE1. Similarly, in a murine model of RSV infection, the vaccine
showed protection that lasted for at least 8 weeks and was found to depend on BPZE1-
induced IL-17. Furthermore, in a model of non-infectious inflammation, such as allergic
asthma, vaccination with BPZE1 prior to sensitization or between sensitization and challenge
with house-dust mite prevented lung inflammation and restored the respiratory capacity of
the mice. These observations are in line with important off-target effects of live attenuated
vaccines, but, in contrast to other vaccines, BPZE1 has potent anti-inflammatory properties,
without being immunosuppressive.
S42
Notes
S43
Impact of adjuvants, sex, and the microbiome on SIV-vaccine-induced immunity and protective efficacy in rhesus macaques
Thomas Musich1, Vishal Thovarai2, Slim Fourati3, David J. Venzon4, Venkatramanan Mohanram1, Iskra Tuero1, Leia K. Miller-Novak1, Sabrina Helmold Hait1, Mohammad Arif Rahman1, Ruth Hunegnaw1, Wuxing Yuan2, Colm O’hUigin2, Mark J. Cameron5, Luca Schifanella6, Monica Vaccari6, Yongjun Sui7, Celia Labranche8, David Montefiori8, Jay A. Berzofsky7, George N. Pavlakis9, Barbara K. Felber10, Genoveffa Franchini6, and Marjorie Robert-Guroff1
1Immune Biology of Retroviral Infection Section, 4Biostatistics and Data Management Section, 6Animal Models and Retroviral Vaccines Section, and 7Molecular Immunogenetics and Vaccine Research Section, Vaccine Branch, NCI, Bethesda, MD; 2Cancer and Inflammation Program, NCI, Bethesda, MD; 3Department of Pathology and 5Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH; 8Department of Surgery, Duke University Medical Center, Durham, NC; 9Human Retrovirus Section and 10Human Retrovirus Pathogenesis Section, Vaccine Branch, NCI, Frederick, MD.
We compared two vaccine strategies in the SIV rhesus macaque model that aimed to elicit mucosal as well as systemic immunity. Rhesus macaques were mucosally primed (first via intranasal and oral routes and next by the intratracheal route) with replicating Adenovirus SIV-recombinants encoding SIV Env and Gag. Subsequently they were boosted twice intramuscularly with ALVAC encoding SIV Gag, Pro, and Env plus Env protein in alum, or DNA encoding SIV Env, Gag, and rhesus IL-12 plus Env protein in alum. Both regimens induced strong viral-specific cellular and humoral immune responses in mucosal and systemic compartments. Following repeated low-dose intrarectal SIV challenges, significant delay of viral infection in vaccinated macaques compared to adjuvant controls that received empty Adenovirus vector plus alum only was not observed. However, delayed SIV acquisition in both the ALVAC/Env and DNA&Env vaccine arms and adjuvant controls was observed when compared to naïve controls. Transcriptomic analysis identified signatures associated with protective innate immunity. Vaccinated females that became infected, but not males, exhibited significantly lower acute viremia compared to same-sex controls, confirming our previously reported sex-difference in SIV vaccine outcomes. The rectal microbiome of females and males responded differently to the prime-boost regimen, especially following the recombinant adenovirus priming immunizations, and differentially associated with viremia control and systemic and mucosal humoral immunity. We conclude that the impact on protective efficacy of vaccine-induced microbiome alteration in males and females as well as trained innate immunity are factors of significant importance in vaccine outcome.
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Notes
S45
Precision adjuvants for next generation vaccines tailored to vulnerable populations
Ofer Levy MD, PhD
Director, Precision Vaccines Program, Boston Children’s Hospital
Professor, Harvard Medical School
Associate Member, Broad Institute of MIT & Harvard
Vaccines are the most important biomedical intervention over the past century, yet their path
to discovery and development has been ad hoc, slow and frequently unsuccessful.
Moreover, distinct immunity of the young and elderly renders these populations
simultaneously more susceptible to infection as well as more difficult to successfully protect
via immunization. Next generation approaches to de-risk and accelerate effective vaccine
development include targeted clinical studies coupled with systems vaccinology to generate
hypotheses re vaccine immunogenicity, population-specific human in vitro modeling for
discovery of novel adjuvants and to characterize mechanism of action and benchmark to
licensed vaccines, as well as select animal models that . While live vaccines have the
potential to induce trained immunity and heterologous benefit, this approach is limited by
divergence of vaccine strains propagated under diverse conditions, as is noted with Bacille
Calmette-Guérin (BCG), as well as by the risk of inadvertent administration of a live vaccine
to those with primary immunodeficiencies. In this context, identification of scalable small
molecule adjuvants that are effective towards a target population is an attractive solution to
enhance vaccine effectiveness in the most vulnerable. Supported by the U.S. National
Institutes of Health/National Institute of Allergy & Infectious Diseases, the Precision Vaccines
Program has undertaken several rounds of small molecule screening against human
leukocytes that have identified several lead families targeting diverse pattern recognition
receptors. Remarkably, there is a distinct ontogeny to innate immune responses to adjuvants
and their combinations with distinct activity towards leukocytes that can be synergistic,
additive or antagonistic depending on the age of a study participant. The horizon for
progress towards next generation vaccines includes adjuvanted vaccines tailored to
vulnerable populations that enhance both specific and heterologous (“non-specific”)
immunity.
S46
Notes
S47
New live attenuated tuberculosis vaccine MTBVAC induces trained immunity and confers protection against experimental lethal pneumonia
Jorge Domínguez-Andrés, Raquel Tarancón, Santiago Uranga, Anaísa V. Ferreira, Laszlo A. Groh, Mirian Domenech, Fernando González-Camacho, Niels P. Riksen, Nacho Aguilo, José Yuste, Carlos Martín, Mihai G. Netea
Department of Microbiology, Faculty of Medicine, University of Zaragoza, Spain CIBERES and Research Network on Respiratory Diseases, Spanish Ministry of Health and Instituto de Salud Carlos III, Madrid, Spain Department of Internal Medicine and Radboud Center for Infectious diseases (RCI), Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, 6500HB Nijmegen, the Netherlands. Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, 4050-313, Portugal. Centro Nacional de Microbiología. Instituto de Salud Carlos III, Madrid, Spain Servicio de Microbiología, Hospital Miguel Servet, ISS Aragón, Zaragoza, Spain Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova, Romania
Among the infectious diseases, tuberculosis is the leading cause of death worldwide, and represents a serious threat especially in developing countries. The protective effects of Bacillus Calmette-Guerin (BCG), the current vaccine against tuberculosis, have been related not only to specific induction of T-cell immunity, but also with the long-term epigenetic and metabolic reprogramming of the cells from the innate immune system through a process termed trained immunity. Here we show that MTBVAC, a live attenuated strain of Mycobacterium tuberculosis, that has been shown to be safe and immunogenic against tuberculosis antigens in adults and newborns, is also able to induce trained immunity through the induction of glycolysis and glutaminolysis, accumulation of histone methylation marks at the promoters of proinflammatory genes, facilitating an enhanced response after secondary challenge. Importantly, these findings in human primary myeloid cells are complemented by a strong MTBVAC-induced heterologous protection against a lethal challenge with Streptococcus pneumoniae in an experimental murine model of pneumonia. Collectively, our evidence underlines that MTBVAC is able to exert metabolic and epigenetic immunomodulatory effects through mechanisms similar to those of BCG. In line with this, vaccination with MTBVAC is likely to recapitulate the non-specific protective effects of BCG vaccination against heterologous infections, while at the same time improving the specific responses against Mtb infection. All together, these results underline the potential that MTBVAC has as an excellent candidate for mass vaccination, representing a possible improvement compared to the currently available BCG vaccine.
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Notes
S49
MV130 as a Trained Immunity-based Vaccine, clinical implications and mechanism of action
Antonio Nieto García 1, Paola Brandi 2, Laura Conejero 2,3, Ángel Mazón 1, María Nieto 1, Francisco J. Cueto 2, Sarai Martínez-Cano 2, Paula Saz-Leal 2,3, Michel Enamorado 2, Joaquín Amores-Iniesta 2, Miguel Casanovas 3, José Luis Subiza3, David Sancho2
1 Servicio de Alergia y Neumología Pediátrica. Hospital Universitario La Fe. Valencia, Spain 2 Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) Madrid, Spain. 3 Inmunotek S.L., Madrid, Spain
Background
Despite recurrent wheezing affects one third of children and is, therefore, a global health
problem with considerable expenditure and impact on quality of life, specific vaccines
licensed for its prevention are still lacking. Virtually all wheezing attacks (WA) in young
children are of viral etiology. In clinical practice, bacterial immunostimulants have offered a
strategy for the prevention of recurrent respiratory tract infections, including those of viral
origin. However, the underlying immune mechanisms are poorly understood.
Trained immunity-based vaccines (TIbV) have been recently described as those composed
of trained immunity inducers that are intended to be effective not only against the specific
pathogens targeted by the vaccine, but also against heterologous pathogens.
Aim
To evaluate the efficacy and safety of a sublingual bacterial preparation (MV130) based on
heat‐inactivated whole‐cell bacteria in preventing WA in children, and to investigate in vitro
and in experimental models, its underlying mechanism of protection.
Methods
A phase III randomized, double‐blind, placebo‐controlled, parallel‐group trial, including 120
children <3years old with ≥3 WA during the previous year was performed. They were
randomly allocated to receive active treatment (MV130) or placebo for six months; the
primary endpoint was the number of WA within one year after the first dose. The main
secondary endpoints were the duration of WA (days) and symptoms and medication scores.
Mechanisms of action of MV130 were addressed experimentally in mouse models of viral
and fungal infection and in vitro assays in human monocytes.
Results
A reduction of 40% in the number of WA in the active vs the placebo group (p<0.001) was
observed with an excellent safety profile. Secondary outcomes were also significantly
improved in the active group vs placebo. Both outcomes were significant not only during the
treatment (1st half year) but once it was discontinued (2nd half year).
MV130 induces trained immunity hallmarks in human monocytes (enhanced glycolytic
metabolism and cytokine production), and in vivo against C. albicans reinfection. In addition,
administration of MV130 in mice confers protection to intranasal viral infection mediated by
trained immunity.
Discussion
We provide evidence for the first time that a mucosal polybacterial preparation induces
trained immunity, confers protection against unrelated pathogens, and shows a quite long
lasting clinical efficacy against a virus‐related condition such as recurrent WA.
Although the TIbV concept is emerging, we believe that several current anti-infectious
vaccines and immunostimulants, including MV130, may already fall in this category.
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Notes
P1
Poster Presentations
Non-live rabies vaccine at six weeks of age increases all-cause mortality rate in
female but not male puppies: a randomized controlled trial
Sintayehu Arega, Anne Conan, Darryn Knobel
Center for Conservation Medicine and Ecosystem Health, Ross University School of Veterinary Medicine, St. Kitts.
Epidemiological evidence suggests that some non-live vaccines may have non-specific
detrimental effects in females but not males in high-mortality populations. We investigated
this proposition in a randomized controlled trial in a population of owned, free-roaming dogs.
The objectives of the trial were to evaluate whether injection of non-live rabies vaccine (RV)
in puppies at 6 six weeks of age affected survival (to all causes of mortality) through to 13
weeks of age, compared to injection of sterile water (SW), and to determine whether this
effect was modified by sex. The study design was a single-site, owner-blinded, randomized,
placebo-controlled trial in South Africa. At six weeks of age, puppies born to vaccinated
mothers (dams), were randomly assigned within litters in a 1:1 ratio to receive a
subcutaneous injection of either RV or SW. A total of 358 puppies were randomized (with
approximately equal male-to-female ratio in each group). The primary outcome was death to
all causes through seven weeks after injection. Effect size was estimated using a mixed-
effects Cox proportional hazards model stratified by body weight and adjusting for sex, with
a random effect for litter. Mortality rate was 2,664/1,000 dog-years in the RV group and
1,955/1,000 dog-years in the SW group (hazard ratio 1.35; 95% confidence intervals (CI)
0.83-2.18). The effect of RV on survival was modified by sex (p-value of likelihood ratio test
for interaction = 0.02): In the RV group relative to the SW group, female survival was
reduced (hazard ratio in females 3.09; 95% CI 1.24-7.69) while there was no evidence that
survival in males was affected (hazard ratio in males 0.79; 95% CI 0.41-1.53). We conclude
that non-live rabies vaccine at six weeks of age increased all-cause mortality in female
puppies, with no evidence of an effect in male puppies. Further randomized controlled trials
should be conducted in other high-mortality dog populations to confirm these findings. Free-
roaming dog populations provide opportunities to test additional hypotheses that may
otherwise be challenging in humans, including the effects of vaccination with live and non-
live vaccines.
P2
Non-specific effects of rabies vaccine on mortality in a Danish pig herd
Kristoffer Jarlov Jensen, Lola Kathe Tolstrup, Darryn Knobel, Charlotte Sonne Kristensen,
Gregers Jungersen, Christine Stabell Benn
The new malaria vaccine RTS,S was recently tested in phase-III randomized controlled trials
in malaria-endemic African sites. Despite a modest specific protection against malaria, girls
receiving the malaria vaccine had a worryingly 2-fold increased all-cause mortality compared
to the comparator vaccine recipients. The inactivated rabies vaccine was used as a
comparator vaccine in one of the study arms. The explanations for the adverse association
could be a female specific detrimental non-specific effect of the new non-live malaria
vaccine. Alternatively, it was hypothesised that the comparator rabies vaccine had beneficial
protective effects on mortality, corroborated by reduced meningitis incidences among the
rabies vaccine recipients. A few historical experimental murine studies and lately also an
observational study in free roaming dogs have indicated that rabies vaccine may non-
specifically reduce non-rabid mortality. Overall, whereas there is a growing body of evidence
of non-specific effects of human vaccines, there is a paucity of systematic investigations of
potential non-specific effects of veterinary routine vaccines. The present study was designed
to investigate if the veterinary inactivated rabies vaccine may have non-specific effects of
morbidity and mortality in young pigs.
In a Danish herd of commercial pigs free of wildtype rabies virus using a 2x2 factorial
randomized design, 575 pregnant sows (2-3 weeks before scheduled farrowing) and 5747 of
their subsequent offspring (median 6 days of age) were allocated (1:1) to rabies vaccine or
no rabies vaccine. Except for the rabies vaccine, all animals were treated as customary.
Death or antibiotics treatment were observed until departure from the observation stables
(approximately 12 weeks of age / 20 kgs).
Until 21 days of life, overall mortality was 1.6% (90 pigs died, rabies vaccine: n=50; control:
n=40), the mortality rate ratio being 1.27 (95% confidence interval: 0.85-1.90).
Prior sow rabies vaccination did not modify the effect of neonatal vaccination. Nonetheless,
for mortality as well as antibiotic treatments within 21 days of life, there was non-significant
indication of a beneficial effect of rabies vaccine in female piglets, but a negative effect in
male piglets from rabies-naïve sows, and a negative effect of rabies vaccine in female
piglets from rabies-vaccinated sows. These effects had waned at 12 weeks of age.
With a slightly higher mortality in the piglets receiving inactivated rabies vaccine, the study
did not lend support to the proposed beneficial effect of the rabies vaccine used in the
human malaria vaccine trial in African children. Although the low mortality impaired the
power of subgroup analyses, the study indicated an interacting effect modification by sex
and maternal vaccination.
P3
BCG vaccination induces innate immune training in adults over 50 years of age.
Mike Berendsen1,2,3, Pauli Bles1,2, Charlotte de Bree1, Kristoffer Jensen2,4, Clara Jensen5, Delfim Mendes6, Mihai Netea1,7,8, Christian Wejse9,10, Christine Benn3,5
1 Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. 2 Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau. 3 Open, Odense Patient data Explorative Network, University of Southern Denmark, Odense University Hospital, Odense, Denmark. 4 Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark, Kgs Lyngby, Denmark 5 Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark 6 Hospital Raoul Follereau, Bissau, Guinea-Bissau 7 Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Germany 8 Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova, Romania 9 Department of Public Health, Aarhus University, Aarhus, Denmark 10 Department of Infectious Diseases, Skejby University Hospital, Aarhus, Denmark
Introduction Bacillus Calmette-Guérin (BCG) was developed as a vaccine against tuberculosis, but many studies have shown its ability to induce potent protection against other infectious diseases. These non-specific effects (NSEs) could be explained by an increased production of innate cytokines after BCG vaccination, the so called 'innate immune training', which has been seen in children and adolescents. However, it is not known if BCG induces similar responses in elderly. Methods Randomized placebo-controlled trial (RCT) among 40 HIV-negative, TB-negative, Bissau-Guinean adults above 50 years of age, randomized 1:1 to BCG-Japan or solvent. Levels of interleukin (IL)-1β, IL-6, IL-10, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured from supernatants of peripheral blood mononuclear cells (PBMCs) stimulated with heat-killed M. Tuberculosis, Lipopolysaccharide (LPS)/Phytohaemagglutinin (PHA), S. Aureus, C. Albicans and S. Pneumoniae before immunization, 2 weeks and 2 months after immunization. Results Among the 40 participants, only 2 (5%) had visible signs of previous BCG vaccination, while 32 (80%) had a positive Quantiferon test indicating that a large part of our population had either latent or passed M. Tuberculosis infection. Two weeks after vaccination, cytokine responses in the BCG-vaccinated group were lower than the responses in the solvent group. This was, however, completely reversed at two months after vaccination, where cytokine responses were highest in the BCG-vaccinated group; an increase that was slightly higher when restricted to Quantiferon positive individuals. Conclusion This study indicates that BCG vaccination can induce innate immune training also in adults above 50 years and might be an interesting tool in counteracting immunosenescence in elderly. The fact that responses were higher in Quantiferon positive individuals suggests a boosting effect regarding the NSEs of BCG.
P4
Lifestyle Differences Between Western European and African Populations Contribute to Differential Immune Responses in the Elderly
Ozlem Bulut, Godfrey Temba, Valerie Koeken, Simone Moorlag, Charlotte de Bree, Vera Mourits, Martin Jaeger, Jorge Dominguez Andres, Andre van der Ven, Leo A.B. Joosten, Quirijn de Mast, Mihai Netea
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
Impairment of adaptive immune responses with old age leads to higher susceptibility to
infections and increased mortality. Adaptive immunity defects are also believed to be the
underlying reason of poor vaccination efficiency in the elderly. Trained immunity is the
adaptation of innate host defense which leads to non-specific immunological memory in
innate immune cells through epigenetic and metabolic reprogramming. It is the proposed
mechanism for non-specific protective effects of vaccines. Since innate immunity is mostly
intact in the elderly, induction of trained immunity could be utilized to improve vaccination.
The aim of this study is to identify the factors affecting the innate response in the elderly with
the hope of identifying new targets for improving vaccine efficacy.
To this end, metabolomic profiles were measured by high-throughput mass spectrometry
from the plasmas of a Western European cohort of 324 healthy individuals between the ages
of 18-71 and a Tanzanian cohort of 323 healthy individuals between the ages of 18-62.
Metabolome data was analyzed using MetaboAnalyst v4.0. Out of 1376 metabolites, 57
were significantly more abundant and 77 were diminished in the elderly (>50 years old) in
both cohorts compared to younger individuals. Pathway analyses revealed that metabolites
from histidine metabolism and primary bile acid biosynthesis pathways were significantly
downregulated in the elderly in both cohorts. When the elderly of the two cohorts were
compared, 403 metabolites were significantly more abundant in Europeans. These include
metabolites contributing to oxidative stress, whereas the 398 metabolites more abundant in
the Tanzanians include metabolites with anti-oxidant and anti-inflammatory properties.
Although age-related defects are observed in the production of T-cell derived cytokines such
as IFNγ in both cohorts, there is also a lower production of monocyte-derived cytokines IL-6
and TNFα in Tanzanians in contrast to Europeans. These differences of the innate immune
response could partially be explained with the different metabolic repertoire. Most of the
metabolites which are highly different between two cohorts are food-derived and have not
yet been linked to immunological functions.
These results indicate that differences in lifestyle, especially diet, reflected by the
metabolomic signature might influence the aging of the immune system. Both unique and
shared metabolites found in the European and African cohorts would provide valuable
insights to the mechanism of immune aging. The next step will be investigating the effect of
the most differentially regulated metabolites on trained immunity response in vitro and at a
later stage potentially in vivo.
P5
The influence of β-1,3-1,6-glucans on rabies vaccination titers in cats
Byrne J., Butaye P.
Ross University School of Veterinary Medicine
The aim of this study was to evaluate the immune stimulation capacity of a fully formulated
diet with β-1,3-1,6 glucans in cats by assessing the rabies antibody titer after vaccination.
Therefore, we recruited thirty-five healthy rabies antibody negative cats. The cats were
broken into two groups and fed standard diet of feed in accordance to body weight. One
group had the β-glucans incorporated; the other group served as control group. After two
weeks, of digestive adjustment and immunological stimulation, the rabies vaccine
(Imrab3TF) was administered on days 14 and 35. Blood samples were taken on days 14, 35,
and 56. Titers are determined with the Rapid Florescent Foci Inhibition Test (RFFIT). Titers
will be compared with the student t-test to determine significant differences between the
titers of the two groups.
P6
EXPLORATIVE STUDY TO THE EFFECT OF BCG BOOSTER METHODS ON THE
Priya A. Debisarun 1, Gizem Kiliç 1, Charlotte de Bree 1, Jorge Domínguez-Andrés 1, Mihai Netea 1,2,3
1. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands 2. Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany 3. Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova, Romania.
Rationale: the live attenuated vaccine Bacillus Calmette-Guérin is able to induce non-
specific beneficial effects and protect against non-related infectious diseases via epigenetic
and metabolic rewiring of innate
immune cells, which has been termed 'trained immunity' or innate immune memory.
However, the effect of BCG on innate immune responses wanes after three months, and the
response is highly variable between individuals. Therefore, development of methods to boost
the non-specific effects is of great importance. There are indications that the beneficial, non-
specific effects of BCG and other live vaccines may be
enhanced by means of revaccination. Albeit BCG revaccination is not a general WHO policy,
there are many countries where this is standard care. This study will investigate the effect of
BCG revaccination as well as
high-dose primary BCG vaccinations on the induction and course of trained immunity in
healthy volunteers. We hypothesize that this may increase the duration and strength of its
beneficial non-specific effects, and thereby contribute to the changing perspective on the
general immunological effects of vaccines and optimize the use of already existing vaccines.
Objective: determine the effect of BCG revaccination and high dose BCG vaccination on the
induction of innate immune memory.
Study design: a randomized controlled explorative pilot study.
Study population: 50 healthy adult volunteers.
Intervention: participants will be randomized 3:3:3:1 to four different intervention groups.
Group 1 will receive standard dose BCG vaccination followed by a subsequent standard
dose BCG vaccination three months later. Intervention group 2 will receive placebo
vaccination followed by a high dose BCG vaccination three months later. Intervention group
3 will receive placebo vaccination followed by standard dose BCG vaccination three months
later. Intervention group 4 will receive two times placebo
vaccination. Throughout the study blood will be drawn from healthy volunteers at timepoints
0, 3 months and 6 months, to analyze changes in immune responses.
Main study parameters/endpoints: comparison of cytokine responses after ex-vivo PBMC
and NK-cell re-stimulation, epigenetic and RNA transcriptome profiles.
P7
Timeliness of DTaP-IPV-Hib vaccination and development of atopic dermatitis before one year of age - A register-based cohort study of the Danish birth cohorts 1997-2012
Lise Gehrt 1, 2, Andreas Rieckmann1, 7, Nicholas Kiraly3, Aksel Karl Georg Jensen1, 4, Peter Aaby1, 5, Christine Stabell Benn1, 2, Signe Sørup1, 6
1 Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark 2 OPEN, Open Patient data Explorative Network, Odense University Hospital/Department of Clinical Research, University of Southern Denmark, J.B. Winsløws Vej 9 A, 3. Sal, DK-5000 Odense C, Denmark 3 Gastro and Food Allergy, Murdoch Children’s Research Institute, Royal Children's Hospital, 50 Flemington Rd Parkville, Victoria 3052 Australia 4 Section of Biostatistics, University of Copenhagen, Øster Farimagsgade 5, DK-1014 Copenhagen K, Denmark 5 Bandim Health Project, Indepth Network, Apartado 861, 1004 Bissau Codex, Guinea-Bissau 6 Department of Clinical Epidemiology, Aarhus University, Olof Palmes Allé 43-45, DK-8200 Aarhus N, Denmark 7 Section of Epidemiology, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
Abstract
Background Vaccines may have non-specific effects affecting the susceptibility towards
conditions not targeted by the vaccine. A study from Australia including 4433 children found
that delayed Diphtheria- Tetanus-acellular Pertussis (DTaP) containing vaccination was
associated with a reduced risk of developing atopic dermatitis (AD) and reduced use of
prescription medicines for AD before 1 year of age. We tested if delayed vaccination with
DTaP-containing vaccines reduced the risk of developing AD before 1 year of age in Danish
children. Methods We used nationwide registers to follow 883,160 children born in Denmark
from 1997 to 2012, and to identify disease specific prescriptions and hospital contacts for AD
to define onset of AD. Binary regression models adjusting for potential confounding factors
were applied to estimate adjusted relative risks (aRR) of developing AD comparing children
with delayed vaccination against diphtheria, tetanus, acellular pertussis, polio, and
Haemophilus Influenzae type b (DTaPIPV-Hib) and children without delayed DTaP-IPV-Hib
vaccination.
Results Among 143,429 children with a delayed first dose of DTaP-IPV-Hib, 4847 (3.4%)
developed AD before 1 year of age, compared with 27,628 (3.7%) among 739,731 children
not having delayed DTaP-IPV-Hib (aRR 0.94 (95% confidence interval (CI): 0.91-0.97)). The
aRR was 0.93 (95% CI: 0.90-0.98) for children with a delayed second dose, and aRR=0.91
(95% CI: 0.87-0.95) comparing children with delayed first and second dose with all timely
vaccinated children.
Conclusion The results support the hypothesis that delayed vaccination with DTaP-IPV-Hib
is associated with reduced risk of developing AD. The dose-dependent relationship further
strengthens the evidence of a causal relationship. Bias related to health care seeking
behavior may explain some of the observed effect and further evidence from other settings is
required.
P8
Innate immune priming by Influenza vaccines
Helen R. Wagstaffe1, Anna Rodrigues Galan1, Ciara Lusa1, Jason P. Mooney1,2, Asia-Sophia
Wolf1,4, Natalie Prevatt5, Ron H. Behrens5, Eleanor M. Riley1,2, Martin R. Goodier1
1 Department of Infection biology, London School of Hygiene and Tropical Medicine. 2 The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh. 3 Division of Infection and Immunity, University College London. 4 Department of Clinical Research, London School of Hygiene and Tropical Medicine. Seasonal influenza vaccines are potent inducers of myeloid cell derived cytokines with the
potential to promote the responses of innate and adaptive effectors cells. Natural killer cells
are innate lymphoid effector cells which are activated by cytokines, by immune complexes and
by signals transduced via activating ligands on other host cells. After vaccination adaptive
immune responses can enhance both cytokine-driven and antibody-dependent NK cell
responses.
Our recent studies provide mechanistic insights into how influenza vaccination also primes
human natural killer cells both directly, through cell-intrinsic mechanisms, and indirectly via
the priming of NK cell activating cytokine production by myeloid cells.
An initial study of 52 adult volunteers revealed that seasonal trivalent inactivated influenza
intramuscular and intradermal and live attenuated intranasal vaccines primes NK cells for
enhanced in-vitro responsiveness (CD25 expression and IFN- production) to activating
cytokines (IL-12 and IL-18) with effects being observed up to 3 months post vaccination.
Vaccine induced enhancement demonstrated several characteristics of cytokine-induced
memory-like NK cells (CIML-NK), involves enhancement of responses within less
differentiated subsets and is reflected in vaccine effects measured directly ex-vivo.
We subsequently demonstrate in a further 51 volunteers that seasonal influenza vaccination
promotes increased myeloid cell-derived cytokine production on in-vitro re-stimulation. IL-15
alone, in the absence of vaccine antigen reveals enhancement of GMCSF, IL-10, IL-1 , TNF-
and IFN- secretion from post vaccination compared to baseline samples. Parallel
enhancement of NK cell function involves the production of IL-12 from myeloid DC.
We conclude that influenza vaccination-induced training of accessory cells combines with the
generation of CIML NK cells to enhance the overall NK cell response post-vaccination.
These studies raise several important questions surrounding vaccine induced innate immune
priming, including the impact of vaccination route and the durability of these responses.
P9
Nasal challenge with a TLR7/8 agonist (R848) induces in vivo mucosal interferons and chemokines with increased responses observed in allergy and asthma
Akhilesh Jha, Ryan S Thwaites, Tanushree Tunstall, Onn Min Kon, Robin J Shattock, Trevor T Hansel, Peter J M Openshaw
National Heart and Lung Institute, Imperial College London, UK Department of Medicine, University of Cambridge, UK Department of Infectious Diseases, Imperial College London, UK
Background
Respiratory viral infections causes significant global morbidity and mortality, especially in
vulnerable populations such as those with respiratory disease. Host recognition of viruses is
mediated in particular by Toll-like receptors (TLRs) to elicit innate immune responses. The
development of respiratory mucosal vaccine adjuvants and methods to accurately assess
respiratory mucosal immune responses are lacking.
Objectives
A synthetic analogue of single-stranded RNA (ssRNA) and TLR7/8 agonist (R848) was
administered in vivo to assess nasal mucosal innate immune responses and to study the
effect of allergy and asthma.
Methods
Nasal spray with saline and R848 was administered to healthy non-allergic (n=12), allergic
rhinitis (n=12) and allergic asthma (n=11) participants. Serial non-invasive nasal mucosal
samples and blood was collected to assess immune mediators and mucosal gene
expression.
Results
R848 was well tolerated with no evidence of systemic immune activation. R848 significantly
induced nasal mucosal IFN-α2a, IFN-γ, pro-inflammatory cytokines (TNF-α, IL-2, IL-12p70)
and chemokines (CXCL10, CCL2, CCL3, CCL4 and CCL13) compared to saline.
Participants with allergic rhinitis and asthma had increased IFN-α2a, CCL3 and CCL13
relative to healthy participants, whilst those with asthma alone had increased gene
expression of interferon stimulated genes DDX58, MX1 and IFIT3.
Conclusions
These results confirm that nasal delivery of R848 is well tolerated and innate immune
function can be assessed non-invasively and with precision. It highlights it as a tool to study
innate immune responses in airway disease and other host disease states, and has potential
for use as a vaccine adjuvant.
Future work
In-vivo and ex-vivo experiments utilising R848 will be performed to assess the epigenetic
mechanisms of innate immune memory in airway epithelial and immune cells using a single-
cell transcriptomic approach.
P10
Sex differences in immune response to influenza vaccine in healthcare workers during the 2017-2018 influenza season
Helen Kuo, Rosemary Morgan, Kathryn Shaw-Saliba, Katherine Fenstermarcher, Santosh Dhakal, Richard Rothman, Andrew Pekosz, Sabra Klein
Johns Hopkins School of Public Health
Seasonal influenza epidemics affect five to fifteen percent of the world population with an
estimated 290,000 to 650,000 annual respiratory deaths due to influenza (1). The Center for
Disease Control recommends annual influenza vaccination for healthcare workers (HCWs)
because not only does their occupation increase their risk of contracting influenza, but
HCWs care for people at higher risk for developing influenza related complications (2).
Seroconversion, a 4-fold difference between pre and post vaccination, is often used as an
indirect measurement of seroprotection against influenza post vaccination. Studies have
shown immune responses, such as seroconversion, differ between male and female vaccine
recipients, but few have focused on HCWs and their influenza vaccine responses by sex. To
understand the sex differences in immune response to the influenza vaccine in the HCWs
population, 111 participants (38 male; 73 female) were recruited during the 2017-2018
influenza season as part of the Johns Hopkins Centers for Excellence in Influenza Research
and Surveillance (JH-CEIRS) annual serological surveys among Johns Hopkins Hospital
HCWs that take part in the annual hospital-wide vaccination campaigns. Participants were
recruited just prior to receiving their annual influenza vaccine, which protects against
influenza type A/Michigan H1N1, A/Hong Kong H3N2, and B/Brisbane viruses, and blood
was collected to measure baseline antibody titer. After 28 days, blood was collected to
assess post vaccination antibody titer levels. Neutralizing antibody assays were used to
measure pre and post antibody titers against A/Michigan H1N1 and A/Hong Kong H3N2.
Pre-vaccination antibody titers were higher among those who do not seroconvert compared
to those who did seroconvert for both A strain influenza viruses. Male participants were 2.86
times more likely to seroconvert for the H1N1 antibody and 1.15 times more likely to
seroconvert for the H3N2 antibody than female participants. However, female participants
had much higher pre-vaccination antibody titer compared to male participants, suggesting
female participants were maintaining their high antibody titers throughout the year. Factors,
such as sex, BMI, age and direct patient contact were explored in a regression model as
possible correlations for female participants maintaining their pre-vaccination antibody titers.
Sex was the only statistically significant (p<0.01) factor that appears to show correlation to
seroconversion. Additional studies are needed to understand sex differences in immune
response to the influenza vaccine.
P11
A Brief Review of Adversomics: Understanding Genetic Drivers for Adverse Events
after Vaccination
Inna G. Ovsyannikova, Richard B. Kennedy, Gregory A. Poland
Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, Minnesota, USA
Despite the huge population benefits of routine immunization, the rare occurrence of vaccine severe adverse events (SAEs) inhibits vaccine acceptance and infectious disease prevention. The molecular mechanisms underlying the immune response during SAEs after vaccination in humans are not well understood, but may be predictable rather than random. Introduced in 2009, the term “adversomics” refers to the application of immunogenetics, immunogenomics, and systems biology approaches to identifying genetic and molecular signatures for vaccine SAEs at the individual and population level. The current state of the adversomics field includes limited studies exploring genetic and proteomic signatures/biomarkers of AEs following smallpox, 17D-derived yellow fever (YF), measles-mumps-rubella (MMR), influenza and hepatitis B (HBV) vaccines. As described in published literature, genetic polymorphisms in the IL1, IL4, and IL18 genes/haplotypes and inflammatory cytokine response pathways (ICAM-1, IL-10, and CSF-3) have been associated with systemic AEs after smallpox vaccination. YF vaccine-associated disease was characterized by viremia, robust T/B cell responses, and polymorphisms in the cytokine receptor CCR5 (delta32) and its ligand RANTES (403 G/A) genes. With respect to both MMR vaccine-related febrile seizures and measles neutralizing antibody responses, GWAS associations of CD46 (rs1318653) and IFI44L (rs273259) genetic variants with febrile seizures and decreased antibodies have been recently published. Furthermore, an increased incidence of narcolepsy after adjuvanted influenza pH1N1 vaccine has been associated with HLA-DQB1*06:02/DQA1*01:02 alleles, suggesting that antigen presentation by these alleles is crucial. HBV-associated major AEs have been linked to class II HLA-DRB1* (*01:01/*03:01/*04:01/*13:01/*15:01) alleles/haplotypes and class I HLA-A2 gene interactions. Understanding and preventing vaccine SAEs is critical in order to improve public trust in
vaccine safety and to develop new safe and effective vaccines that minimize or avoid SAEs.
In this presentation I will review the current knowledge about the field of adversomics, as
well as the known associations and mechanisms of vaccine SAEs.
P12
Unconventional protection to Mycobacterium tuberculosis infection conferred by molds
Marta ROMANO, Pauline PERCIER; Giresse TIMA; Fabienne JURION and Olivier DENIS
Service Immune Response, Directorate Infectious Diseases in Humans; SCIENSANO, Brussels, Belgium
Introduction:
Molds are ubiquitous filamentous fungi and more than one hundred different indoor and
outdoor mold species have been recognized as major sources of aeroallergens that can
cause respiratory forms of allergy, ranging from allergic rhinitis to asthma.
Conflicting results have been reported on the association between allergy and infection with
M. tuberculosis and/or active Tuberculosis disease.
In this study, we wanted to address if a previous allergic sensitization with the outdoor mold
Alternaria alternata could have an effect on the susceptibility to infection with M.
tuberculosis.
Material & Methods:
For that purpose, well defined murine models of sensitization with different compounds
isolated from A. alternata or heat-killed spores were used. Intranasal instillations with these
induce lung inflammation with different profiles (differences in type of cells recruited to the
airway and in the local cytokine and chemokine expression profiles induced). Mice were
treated with the mold antigens before or after pulmonary M. tuberculosis infection.
Results:
Interestingly, our results indicate that previous sensitization with an A. alternata fraction
inducing a genuine eosinophilic / pro-Th2 response has no effect on susceptibility to
infection with M. tuberculosis, while treatment with fractions of A. alternata inducing a mixed
pro-Th2/pro-Th17 response results in an improved control of M. tuberculosis infection.
This control of pulmonary growth of M. tuberculosis is observed as early as 6 days after
infection, it is maintained for several weeks without need of continuous instillation of A.
alternata and M. tuberculosis specific adaptive immune response is not influenced by the
previous treatment with A. alternata.
In addition, treatment of M. tuberculosis infected mice with heat-killed A. alternata spores
results in a control of the bacterial burden.
Discussion-Conclusion:
Even if our results warrant further mechanistic analysis, our data collectively indicate and
confirm that the pulmonary environment can significantly shape outcome of infection with M.
tuberculosis infection.
P13
Immunological mechanisms of MV140, a polybacterial vaccine to prevent urinary tract infections
Paula Saz-Leal 1, 2, Caihong Wang 2, Marianne M. Ligon 2, Carmen M. Díez-Rivero 1, Laura Conejero 1 and Indira U. Mysorekar 2,3
1 Inmunotek, SL. Alcalá de Henares, Madrid, Spain. 2 Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA. 3 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Background
Urinary tract infections (UTIs) are the most reported bacterial infections in women. High
rates of recurrence lead to 5-10% of total women suffering from recurrent UTIs (rUTI).
Because of the lack of effective alternatives, antibiotic prophylaxis is still the gold standard
treatment for rUTI, contributing to the massive rise of antimicrobial resistance.
MV140 is a sublingual vaccine based on a mixture of whole-cell heat-inactivated bacteria
indicated for rUTI prophylaxis. Clinical studies in more than 1,000 subjects have
demonstrated that MV140 significantly reduces UTI episodes compared to antibiotic
prophylaxis, preventing recurrence in 80-90% of individuals during the year following
vaccination. Moreover, MV140 is effective against the specific pathogens targeted by the
vaccine, but also against heterologous infections.
Mechanistically, sublingual immunization with MV140 showed to induce a systemic CD4+ T
cell response in experimental models, but the underlying mechanisms in the context of
infection were still unknown.
Aim
To evaluate the protection conferred by the polybacterial preparation MV140 in an
experimental model of uropathogenic Escherichia coli (UPEC)-mediated UTI and to
investigate its mechanism of action. Additionally, to compare MV140 effect to that provided
by a monobacterial vaccine consisting of the specific UPEC infectious challenge.
Methods
Mice were vaccinated intranasally either with MV140 (E. coli, K. pneumoniae, E. faecalis, P.
vulgaris) or a specific UPEC strain (UTI89)-based vaccine, both heat-inactivated, and
subsequently subjected to a UTI89-induced acute UTI. Bacterial load, as well as the immune
response in urine and bladder, were measured following infection. Otherwise, the systemic
immune response to both MV140 and UPEC was evaluated in the spleens of vaccinated
versus control uninfected mice.
Results
Both MV140 and the UPEC-based vaccine conferred significant protection to infection with
an early reduction in bacterial load compared to controls. These results were accompanied
with increased numbers of myeloid immune cells in the urine, and a heightened CD4+ T cell
response in the bladder.
Both types of vaccination induced similar systemic T helper (Th) 1, Th17 and IL-10-mediated
responses against the MV140 and UTI89.
Discussion
We demonstrate for the first time that MV140 confers protection in an acute UTI
experimental model. This is accompanied by the induction of local myeloid and adaptative T
cell responses, the latter correlating with that observed systemically.
The protection conferred by MV140 against a UTI89 challenge is comparable to that
provided by its specific vaccine, and may further support a quite broad-spectrum anti-
infectious profile of this polybacterial preparation.
P14
BCG skin reactions by 2 months of age are associated with better survival in infancy: A prospective observational study
Frederik Schaltz-Buchholzer1,2,3, Mike Berendsen1,2,3,4, Adam Roth5,6, Kristoffer Jarlov Jensen1,7, Morten Bjerregaard-Andersen2,3, Marcus Kjær Sørensen2,3, Ivan Monteiro2, Peter Aaby2, Christine Stabell Benn1,2,3,8
1 Bandim Health Project, Institute of Clinical Research, Uni. Southern Denmark and Odense University Hospital, Odense, Denmark: FSB (MD), MB (MSc), CSB (Professor, DMSc). 2 Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau: FSB, MB, KJJ (PhD), MBA (MD, PhD), MKS (medical student), IM (trial supervisor), PA (Professor, DMSc), CSB. 3 Research Centre for Vitamins and Vaccines, Copenhagen, Denmark: FSB, MB, MBA, MKS, CSB. 4 Department of Internal Medicine, Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands: MB. 5 Public Health Agency of Sweden, Nobels väg 18, 171 82 Solna, Sweden: AR (MD, PhD). 6 Institution for Translational Medicine, Lund University, J Waldenströms g 35, CRC, hus 92, plan 11, Malmö, Sweden: AR. 7 Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark, Kgs Lyngby, Denmark: KJJ. 8 Danish Institute of Advanced Science, Uni. Southern Denmark, Odense, Denmark: CSB.
Objectives: Receiving Bacillus Calmette-Guérin (BCG)-Denmark vaccine at birth has been
associated with a ~40% reduction in all-cause neonatal mortality and among BCG-
vaccinated infants, developing a BCG scar during infancy has been associated with a similar
reduction in subsequent mortality. We evaluated determinants of early BCG reactions and
the reaction size by 2 months of age and tested whether having developed a BCG reaction
by 2 months and the reaction size were associated with subsequent all-cause mortality.
Design: Prospective observational study within five trials providing BCG-at-birth. The BCG
reaction status and reaction size was evaluated at home-visits by 2 months of age; mortality
up to 12 months was assessed at subsequent home-visits.
Setting: Bissau, Guinea-Bissau.
Participants: 6,012 infants BCG-vaccinated within 1 week of birth.
Main outcome measures: BCG reaction determinants were evaluated by binomial regression
providing Risk Ratios (RRs). Cox-models providing adjusted Mortality Rate Ratios (aMRRs)
were used to assess the association between 1) having a 2-month reaction (yes/no) and 2)
the reaction size tertiles and the subsequent 2-12-month mortality risk. A subgroup of infants
had their BCG reaction evaluated and were bled at age 4 weeks; samples underwent in vitro
analysis for specific and non-specific cytokine responses.
Results: 5,804 infants (97%) had developed a BCG reaction by 2 months of age; 208 (3%)
had no reaction. The BCG strain was the main determinant for both developing a 2-month
BCG reaction and the reaction size: the RR for large-reaction comparing BCG-Russia vs.
BCG-Denmark was 0.38 (0.30-0.47) and 0.61 (0.51-0.72) for BCG-Russia vs. BCG-Japan.
The 2-12-month mortality risk was 4.8% (10/208) for non-reactors, 2.9% (64/2,213) for small
reactors, 1.8% (30/1,710) for medium reactors and 0.8% (15/1,881) for large reactors. The
reactor/non-reactor aMRR was 0.49 (0.26-0.95) and there was a linear trend of decreasing
mortality with increasing reaction size (p for trend<0.001). BCG reactors had higher 4-week
specific and non-specific cytokine responses, responses that were highest among those with
large reactions.
Conclusion: Among BCG-vaccinated infants, having a BCG skin reaction by 2 months of age
was associated with markedly better survival, as was the reaction size. Our findings support
that BCG has substantial non-specific effects on all-cause mortality and indicate that
emphasising at-birth vaccination with immunogenic BCG strains and revaccinating non-
reactors could have major public health benefits.
P15
Re-vaccination with measles-mumps-rubella vaccine and hospitalization for infections lasting 2 days or longer in Denmark and Sweden – an interrupted time-series analysis
Signe Sørup, Hélène Englund, Ida Laake, Heta Nieminen, Adam Roth, Christine Benn
Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark (Signe Sørup and Christine Benn); Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark (Signe Sørup); Public Health Agency of Sweden, Nobels väg 18, 171 82 Solna, Sweden (Hélène Englund and Adam Roth); Department of Infectious Disease Epidemiology and Modelling, The Norwegian Institute of Public Health, Oslo, Norway (Ida Laake); Department of Public Health Solutions, Finnish Institute for Health and Welfare, Tampere, Finland (Heta Nieminen); Department of Translational Medicine, Lund University, Malmö, Sweden (Adam Roth); OPEN, Open Patient data Explorative Network, Odense University Hospital/Department of Clinical Research, University of Southern Denmark, Odense, Denmark (Christine Benn)
Background: In low-income countries, re-vaccination with live vaccines has been associated
with reduced morbidity and mortality not related to the targeted diseases. In a previous
cohort study of 4-year-old Danish children, re-vaccination with the live measles-mumps-
rubella (MMR) vaccine was associated with a 16% reduction in the rate of hospitalizations
for infections lasting 2 days or longer.
Aim: To examine if the introduction of a second MMR-dose (MMR-2) at 4 years of age in
Denmark (spring 2008) and at 6-9 years of age in Sweden (Autumn 2009) was associated
with a reduction in the rate of hospitalizations for infections lasting 2 days or longer on a
population level.
Methods: We performed an interrupted time series analysis using Poisson regression to
estimate the change in the level of the rate of hospitalizations for infections lasting 2 days or
longer following the introduction of MMR-2 adjusting for seasonality (dummy variables for
season: spring, summer, autumn, and winter). We included the 4-year olds in Denmark and
the 9-year olds in Sweden. We defined the pre-intervention, phase-in (excluded from the
model), and post-intervention periods to be March 2005 to February 2008, March 2008 to
February 2009, and March 2009 to February 2012 in Denmark and September 2005 to
August 2009, September 2009 to August 2012 and September 2012 to August 2015 in
Sweden. We estimated the observed rate of hospitalizations for infection lasting 2 days or
longer for each season and year based on the number of hospitalizations from nationwide
registers (infections identified by ICD-10 codes) and person-years at risk approximated from
population statistics.
Results: The crude rate of hospitalizations for infections lasting 2 days or longer among 4
year-olds in Denmark was 8.3 per 1000 person-years before and 7.9 per 1000 person-years
after the introduction of MMR-2. The corresponding rates among 9 year-olds in Sweden
were 2.7 and 2.5 per 1000 person-years, respectively. Although the rate decreased over the
entire study period, the Poisson regression predicted that the rate was 0.5 per 1000 person-
years higher after the phase-in of MMR-2 in Denmark (p value for level change=0.48) and
0.2 per 1000 person-years higher in Sweden (p value for level change=0.56) than what
would have occurred without the introduction of MMR-2.
Conclusion: On a population level, the introduction of MMR-2 was not associated with a
reduction in the rate of hospitalizations for infection lasting 2 days or longer in Denmark nor
in Sweden.
P16
Investigation of Mother to Child Transmission of HLA Antibodies
DM Savulescu1, M Groome2, SCK Malfeld1, S Madhi2, A Koen2, S Jones2 and M Suchard1,3
1. Centre for Vaccines and Immunology (CVI), National Institute for Communicable Diseases
(NICD), a division of the National Health Laboratory Service, South Africa
2. Respiratory and Meningeal Pathogens Research Unit (RMPRU), University of the
Witwatersrand, South Africa
3. Chemical Pathology, Faculty of Health Sciences, University of the Witwatersrand, South
Africa
Vaccination during pregnancy is a growing field of interest, however many aspects of
humoral immunity during pregnancy remain poorly understood. Human leukocyte antigens
(HLA) are proteins responsible for presentation of peptide fragments to T lymphocytes. HLA-
encoding genes are extremely polymorphic, and the foetus has a different HLA antigen
repertoire from the mother. Late in pregnancy, women produce and transfer high amounts of
antibodies, including antibodies agains HLA (HLA antibodies), to the fetus, where
presumably the antibodies may act as autoantibodies. Little is known about specificity or
transfer rate of HLA antibodies to the foetus.
We describe the prevalence of HLA antibodies in serum of thirty mother-infant pairs six
weeks post-partum. We used Luminex single angtigen technology that allows for highly
sensitive antibody detection. We found that 72% of babies and 80% of mothers expressed
HLA antibodies. In babies, 77% of HLA-I antibodies and 50% of HLA-II antibodies matched
those of their mothers, suggesting that the remaining antibodies were self-made. In contrast,
the proportion of maternal antibodies that matched those of their babies was only 16% for
HLA-I and 24% for HLA-II, suggesting that not all HLA antibodies produced during
pregnancy cross to the fetus.
Production of self-made antibodies by six weeks of age indicates early capacity of the
neonatal immune system to generate HLA antibodies; either natural antibodies or preceded
by exposure to specific HLA antigens. Our findings further indicate that there is selective
antibody transfer of particular antibody specificities from mother to infant. Because HLA
antibodies may act against paternal antigens present in the neonate, the mechanism of
selective antibody transfer or depletion may give insights into mechanisms of infant immune
tolerance.
P17
Sex-specific effects of early life influenza vaccination on protection against diverse influenza viruses in mice
Rebecca L Ursin, Yishak Woldetstadik, Georgia Stavrakis, Kristyn E. Sylvia, Harrison R. Powell, Hsuan Liu, Andrew Pekosz, and Sabra L. Klein
Johns Hopkins University Bloomberg School of Public Health, Departments of Biochemistry and Molecular Biology, and the W. Harry Feinstone Department of Molecular Microbiology and Immunology, Baltimore, MD 21205
Influenza viruses kills tens of thousands of people annually worldwide, with seasonal
influenza vaccines serving as the best mode for protection. Vaccine efficacy depends on a
myriad of factors, including intrinsic characteristics of the virus, such as mutations that
enable viruses to escape host immunity, as well as host factors, including sex, age, and
immune history. To test the hypothesis that early life exposure to influenza vaccines may
differentially affect responses to vaccination and infection later in life, we immunized and
boosted male and female C57BL/6 mice beginning at postnatal day (PND) 11-14 with a 2009
H1N1 inactivated influenza vaccine (IIV) followed by re-vaccination in adulthood (PND 63-
75) and subsequent infection with a 2009 H1N1 drift variant virus. Prior to puberty, both
males and females mounted low neutralizing antibody (nAb) titers, with no sex differences in
vaccine-induced immune responses. Upon vaccination in adulthood, robust, sex-
differentiated responses were observed in which females had greater nAb titers than males
and were better protected following challenge with the drift variant virus. To determine the
range of cross-neutralization and protection against mutating influenza viruses, we
developed a panel of 2009 H1N1 viruses that contain the following mutations in the
immunodominant hemagglutinin (HA) protein: a single amino acid mutant virus with a
mutation at position K166Q; a double mutant at positions K166Q and G157E; a triple mutant
with K166Q, G157E, and N211D; and a virus with the K166Q mutation plus an entire
antigenic region substituted with a non-human HA. Using these viruses, we determined that
regardless of the mutations in HA, unvaccinated adult females experience greater morbidity
and mortality and have a lower lethal dose 50 (LD50) than their male counterparts. Whether
immunization with IIV prior to puberty and/or in adulthood differentially affects cross-
neutralization and protection against the panel of 2009 H1N1 viruses that contain HA
mutations is currently under investigation. These studies are critical for understanding how
pre-existing immunity affects protection against viral infection and will help to develop better
influenza vaccines, including universal influenza vaccines, that provide equal protection
against circulating strains of influenza viruses in both males and females.
P18
Towards a Vaccine Based on Enterococcal Membrane Vesicles
Theresa Wagner (1), Mona Johannessen (1), Kristin Hegstad (1,2)
(1) Research group for Host-Microbe Interactions, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø – The Arctic University of Norway (2) Norwegian National Advisory Unit on Detection of Antimicrobial Resistance, Department of Microbiology and Infection Control, University Hospital of North-Norway, Tromsø, Norway
Enterococcus faecium is a leading cause of nosocomial infections, especially in
immunocompromised patients. Multi-resistant E. faecium, including Vancomycin Resistant
Enterococci (VRE) impair therapy and limit treatment options. Thus, novel therapeutic
approaches and alternatives for infection control are desperately needed to combat VRE.
Vaccines are promising alternatives in times of increasing antimicrobial resistance, since the
risk of resistance development is low and vaccines can be used prophylactically. For
enterococci, there are no available vaccines yet, even though research has been ongoing to
identify vaccine candidates.
In a previous study, we isolated and characterized membrane vesicles (MVs) produced by E.
faecium. We described their proteomic content in four clinically relevant strains, including
VRE. The E. faecium MV contained known virulence factors, among them adhesins,
collagen binding proteins, fibronectin binding protein, as well as biofilm promoting factors.
Also, antimicrobial resistance related proteins were found to be MV-associated, including all
proteins of the vanA-cluster of a VRE. Furthermore, we found six described vaccine
candidates to be associated with enterococcal MVs.
MVs would be auspicious vaccine candidates since they are highly stable, non-infectious
and non-replicative. They contain major immunogenic proteins, and would be able to elicit
protective immune responses and act as adjuvant.
Since high amounts of pure MVs will be needed for vaccination studies, we optimized the
production of MV, by investigating the influence of antibiotic exposure, as well as different
isolation methods, on the outcome. The cytotoxicity of MVs was tested in various cell lines.
At present we are immunizing rabbits with E. faecium MV and are planning to characterize
their serum.
In the future, we would like to explore the potential use of MVs to elicit protective immunity
against E. faecium, including VRE, infection.
P19
Notes
P20
Notes
Delegate List
Peter Aaby
Statens Serum Institut
Asimenia Angelidou
Boston Children's Hospital
du
Petra Arck
University Medical Center Hamburg
Sintayehu Arega
Ross University School of Veterinary
Medicine
Christine Stabell Benn
University of Southern Denmark
Mike Berendsen
Bandim Health Project
Byron Brook
University of British Columbia
Ozlem Bulut
Radboud University Medical Center
Egle Butkeviciute
LSHTM
Jake Byrne
Ross University School of Veterinary
Medicine
Rebecca Chandler
Uppsala Monitoring Centre
LAURA CONEJERO
INMUNOTEK
Maria Giulia Conti
Sapienza University of Rome
Nigel Curtis
University of Melbourne
Mia Damhus
Center for Nutrition and Therapy
Joseph de Vrieze
Oost Indische Inkt
Priya Debisarun
RadboudUMC
Santosh Dhakal
Johns Hopkins University
Hazel Dockrell
London School of Hygiene & Tropical
Medicine
Jorge Dominguez Andres
Radboudumc
David Elliman
PHE/GOSH
Jorge Esparza Gordillo
GlaxoSmithKline
Denise Faustman
Harvard Medical School
Zoltan Fehervari
Nature Research
Adam Finn
University of Bristol
Eleanor Fish
University of Toronto
Katie Flanagan
UTAS/RMIT/Monash University
Anna Fletcher
Micropathology LTD.
PILAR GARCA CORBEIRA
GlaxoSmithKline
Lise Gehrt
University of Southern Denmark
MARTIN R GOODIER
LSHTM
Danika Hill
Babraham Institute
Akhilesh Jha
University of Cambridge
Kamilla Josefsdottir
Directorate of Health
Konstantinos Karampatsas
St George's University of London
Christine Karanja Chege
Kenyatta University
Gizem Kilic
Radboudumc
Sabra Klein
Johns Hopkins University
Henrik Kloverpris
Africa Health Research Institute
Darryn Knobel
RUSVM
Tobias Kollmann
Telethon Kids Institute
Helen Kuo
Johns Hopkins School of Public Health
Ofer Levy
Boston Children's Hospital
Camille Locht
Inserm
David Lynn
SAHMRI
Anne Marie Rosendahl Madsen
University of Southern Denmark
Siddhartha Mahanty
University of Melbourne
Hafza Zahira Manzoor
University of Veterinary and Animal
Sciences
Francois Mayer
Nature Microbiology
Victoria McLelland
ION Osteopaths
Kirsty Minton
Nature Reviews Immunology
Jessica Mwinyi
Swedish Medical Products Agency
Mihai Netea
Radboud UMC Nijmegen
Inna Ovsyannikova
Mayo Clinic
Magdalena Plebanski
RMIT University
Katrina Pollock
Imperial College London
Sarah Prentice
East and North Hertfordshire NHS Trust
Marjorie Robert Guroff
National Institutes of Health
Marta Romano
ISP-WIV Belgium
Christine Rueckert
CureVac AG
PAULA SAZ
INMUNOTEK
Frederik Schaltz-Buchholzer
Bandim Health Project
Klaus Schwamborn
Valneva
Frank Shann
University of Melbourne
Sven Arne Silfverdal
Umea University
Signe Soerup
Statens Serum Institut AND Aarhus
UNiversity
Adrian Spillmann
Valneva
Melinda Suchard
National Institute for Communicable
Diseases
Rebecca Ursin
Johns Hopkins University
Theresa Wagner
University of Tromsø
Hilton Whittle
LSHTM
Index
Aaby, P S1 Robert-Guroff, M S43
Arck, P S27 Romano, M P12
Arega, S P1
Saz, P P13
Benn, C. S P2 Schaltz-Buchholzer, F P14
Berendsen, M S35, P3 Soerup, S P15
Brook, B S23 Suchard, M P16
Bulut, O P4
Byrne, J P5 Ursin, R P17
Conejero, L S49 Wagner, T P18
Curtis, N S7
Debisarun, P P6
Dhakal, S S29
Dockrell, H S15
Dominguez Andres, J S47
Faustman, D S31
Finn, A S3
Flanagan, K S39
Gehrt, L P7
Goddier, M P8
Hill, D S11
Jha, A P9
Kilic, G S21
Klein, S S25
Knobel, D S33
Kollmann, T S9
Kuo, H P10
Levy, O S45
Locht, C S41
Lynn, D S19
Netea, M S5
Ovsyannikova, I S37, P11
Plebanski, M S17
Prentice, S S13
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