Global Dengue Vaccine Recommendations

and Considerations for Vaccine Decision-Making

Asia Dengue Summit, Bangkok

13-14 January 2016

Joachim Hombach

Initiative for Vaccine Research (IVR)

Department of Immunization, Vaccines and Biologicals (IVB)

2 |

Clinical Dengue Vaccine

Development Pipeline

DEN-80E Merck

DPIV

GlaxoSmithKline, Biomanguinhos,

WRAIR

TVDV Naval Medical

Research Center

DENVax2 Takeda

TV003/TV005

US National Institutes of Health,1

Butantan

Phase II Phase III Phase IIb Phase I

CYD-TDV

Sanofi Pasteur

1Licensing agreements also with Merck, Panacea, SII, Vabiotech

Phase 3 study approved for Butantan

Live attenuated

(recombinant)

Inactivated

Subunit

DNA

Registration

TLAV-TPIV WRAIR

Heterologous

Prime-Boost

TV003/TV005

US National Institutes of Health,1

Butantan

3 |

Examples of WHO activities to support global

vaccine guidance and introduction

Pre-product registration

Guidance and standards for manufacturing, clinical trial design, safety assays, data needs

Consultation with experts regarding pivotal clinical trial results

Identification of areas important for pre-introduction country consideration (e.g. registration, post-licensure safety assessments)

Technical support to NRAs

Post-product registration

Guidance and recommendations

for vaccine introduction and use

Support for country decision-

making

Introduction / training materials

Guidance for monitoring vaccine

effectiveness and safety post-

licensure

WHO Prequalification

Guidance for evaluation of

second-generation vaccines

Vac

cin

e R

eg

iste

red

4 |

WHO guidance on new vaccine introduction and use

WHO Vaccine Position Papers

– Global recommendations for use of a specific vaccine

– Issued after a vaccine is licensed by functional NRA

– Endorsed by Strategic Advisory Group of Experts (SAGE) on immunization

– Published in WER

– Includes review of evidence for key policy questions

– Review of the quality of evidence using GRADE

– Updated regularly

5 |

Examples: 2015 WHO Vaccine

Recommendations

http://www.who.int/immunization/documents/positionpapers/en/

WHO recommends that countries completing mass

vaccination campaigns introduce meningococcal A

conjugate vaccine into the routine childhood immunization

programme.

JE vaccination should be integrated into national

immunization schedules in all areas where JE is

recognized as a public health priority.

In the absence of sufficient information at this time, WHO

does not make a recommendation on the introduction of

the vaccine for routine use in national programmes in

populations where epidemic and sporadic hepatitis E

disease is common.

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Pathways for WHO Recommendations on

Vaccine Use

SAGE

Relevant existing

technical advisory

committee

Background

Paper Global Advisory

Committee on

Vaccine Safety

Expert committee

on Biological

Standardization

Regional TAGS

Regional

consultations

WHO

Position

Paper

WHO DG

Secretariat

SAGE

working group

Input

Request for review of

evidence

Country

Decision

making

Recommendations

Other relevant non immunization

related WHO policy

recommendation making body

Immunization and

Vaccines related

Implementation

Research Advisory

Committee

Industry and

other partners

Product Development

for Vaccines Advisory

Committee

Immunization

Practices

Advisory

Committee

Broad

stakeholder

consultation

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MEMBERSHIP

Terry Nolan (Co-Chair), Australia

Jeremy Farrar (Co-Chair), UK

Ananda Amarasinghe, Sri Lanka

Alan Barrett, USA

Anna Durbin, USA (until 31.12.2015)

Elizabeth Ferdinand, Barbados

Maria Guzman, Cuba

Maria Novaes, Brazil

Lee Ching Ng, Singapore

Amadou Sall, Senegal

Peter Smith, UK

Wellington Sun, USA

Piyanit Tharmaphornphilas, Thailand

Stephen Thomas, USA

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Dengue vaccine: Key considerations

for policy Vaccine safety

– Reactogenicity and serious adverse events, AESI

– Long-term safety and risk of hospitalized/severe dengue

Vaccine efficacy – Overall, by age, by serostatus, by serotype

– Efficacy against lab confirmed dengue, severe disease

– Duration of protection

Programmatic aspects – Dose scheduling

– Co-administration

– Vaccine introduction strategies including outbreak response

– Vaccine impact and cost-effectiveness

– Criteria for country decision-making

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Comparative modelling of dengue vaccine

public health impact (CMDVI)

1. Provide information for SAGE recommendations in 2016

on the use of dengue vaccine.

2. Understand the key features of dengue vaccine models

that influence results, in order to improve the standard of

modelling and help country-level decision makers interpret

the results of modelling evidence they are confronted with.

3. Identify circumstances for potential long term safety

concerns of CYD.

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Previous WHO comparative modelling

exercises Antigen 2008 2009 2010 2011 2012 2013 2014

PCV1

Rotavirus2

HPV3,4

Malaria5

1Chaiyakunapruk et al. BMC Medicine 2011; 9:53; 2Postma et al. BMC Medicine 2011: 9:84; 3Jit et al. BMC Medicine 2011; 9:54; 4Jit et al. BMC Medicine 2013; 11:23; 5Penny et al., Lancet 2015

Format: Face-to-face meeting between modellers to present key model

features and discuss issues Preparation of a commonly agreed on case study Running case study on each model Discussion of key lessons learnt Preparation of manuscript in open access journal

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Comparative modelling of dengue vaccine public health

impact: key questions

Economic evaluation:

• Traditional cost-effectiveness analysis (costs per clinical case and costs per

DALY averted)

• Delivery costs to be adapted from HPV vaccine delivery experience

• Literature appraisal of broader economic impact (no modelling)

Disease impact evaluation:

• Routine introduction at 9 years of age

• Catch-up vaccination (10-17 years)

• Asian and Latin-American reference country scenarios and different

transmission intensities

• Vaccine impact on infection, clinical cases, severe cases, death

• Overall and by age group, 10 year and 30 year time horizon

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Expert groups* contributing to CMDVI

Impact modelling

Laurent Coudeville (Sanofi Pasteur)

Derek Cummings (JHSPH/UFL)

Neil Ferguson (Imperial College)

Katia Koelle (Duke)

Ira Longini (U Florida)

George Milne (U of Western Australia)

Alex Perkins (U of Notre Dame)

Mario Recker (Oxford)

Project coordination

Mark Jit (LSHTM)

Stefan Flasche (LSHTM)

Kirsten Vannice (WHO)

(*group leaders)

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Public health impact modelling: example from malaria (Penny et al., Lancet 2015)

Cumulative impact 15 years. Model prediction of clinical cases and deaths averted per 100,000 children fully vaccinated with 3 or 4 dose schedule across various transmission intensities (in the presence of existing malaria control interventions)

Suggests higher impact in moderate-high transmission settings

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Tentative timelines for

WHO global policy on dengue vaccine

Today, WHO has no position on dengue vaccines

April 2016: Anticipated SAGE session on dengue

vaccines

– SAGE issues recommendations to WHO

– Available publically the week following SAGE meeting

Mid-2016: First WHO Vaccine Position Paper on Dengue

Vaccines

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Developing Vaccine Policy

SAGE WHO

Headquarters

Regional TAG WHO

Regional Offices

NITAG Government

Agency

“Careful review and consideration of the scientific evidence is an

essential step in recommendations and guidelines development.”

WHO Guidance for the development of evidence-based

vaccine-related recommendations

Level

Global

Regional

National

Decision-Makers Advisory Bodies

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Considerations for Vaccine Introduction

WHO (2014) Principles and considerations for adding a vaccine into a national

immunization programme.

Vaccine performance

• Good traditional

safety/reactogenicity

• Longer-term FU

• VE by serotype,

serostatus, etc.

• Indication (age, schedule)

• Duration of protection?

• Herd immunity?

• High morbidity, low

mortality

• Outbreaks, burden

on health system

• School/work

absenteeism

• Alternatives (vector

control)

• Vaccine availability

• Vaccine price

• Programme costs

• Economic impact

• National budget and vaccine

affordability

• Funding gaps and

sustainability

17 |

Programmatic Considerations HPV vaccine CYD dengue vaccine

Target age (gender) 9-13 years (girls) 9+ (boy and girls)

Number of doses 2 or 3 3

Dosage regimen 2 dose: 0, 6-12 months

3 dose: 0, 1-2, 6 months

3 dose: 0, 6, 12 months

Target populations Females

(includes males or MSMs in

some countries)

Geographical focus?

Lag time to expected

public health benefits

10 to 30 years In months/few years

Sensitivities Sexuality, fertility Not likely

Delivery platform School/school health ??

Vaccine cost as a

barrier?

++ ?

Ancillary control

strategies

Cervical cancer screening,

tertiary prevention

Vector control, clinical case

management (supportive care)

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Sustained Coverage in Dengue-Interest

Countries*

HPV1 HPV2 HPV3

National Year

introduced

Earlier coverage (%)

(2006–2012)

Latest available coverage (%)

(2013–2014)

HPV2 HPV3 HPV2 HPV3

Argentina 2011 50 50

Brazil 2014 60

Chile 2014 >90

Colombia 2012 89 76

Mexico 2012 67 90

Panama 2008 67 83

United States 2006 32 38

Bhutan 2010 73 >90

Cook Islands 2011 94

Fiji 2013 86

Japan 2011 74 0.6

Malaysia 2010 98 98

*Information from the WHO/UNICEF JRF (July 2015), published data, presentations or

personal communications; completeness and quality of data may vary and may be incomplete

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Programmatic Considerations:

School Readiness Overall Readiness

– National policy, census data, vaccination strategy, school and student characteristics, etc.

School Readiness – Compulsory education policy, enrolment

data, school health services, clean water/location for immunization, access to health facility, etc.

Implementation Readiness – Vaccine supply, waste disposal plan,

communication and education for schools/communities/parents, plan for administering to absent/out-of-school children, etc.

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Programmatic Considerations:

Tracking vaccination

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Opportunities for integration with

vector control

Vaccination will not be replacement for

vector control

– Could be synergistic effects to reduce

transmission

Points of contact can be used to

reinforce messages about dengue

prevention

– COMBI – advocate for vaccination

– Vaccine visits – advocate for source

reduction

22 |

Summary

WHO official recommendations related to dengue vaccination are forthcoming following vaccine registration

There are multiple considerations at the global, regional, and national level for vaccine decision-making – Vaccine characteristics/profile

– Disease burden

– Health systems and programmatic considerations

– The complexity of the vaccine performance and heterogeneity of dengue epidemiology will call for careful decision-making

Mathematical modeling increasingly informs policy choices

Programmatically, lessons can be learned from other vaccination efforts in this age group

An opportunity to strengthen immunization infrastructure, such as registries

Further information:

http://www.who.int/immunization/research/development/dengue_vaccines/en/

http://www.who.int/immunization/policy/sage/sage_wg_dengue_mar2015/en/

Acknowledgement: Kirsten Vannice