Global Dengue Vaccine Recommendations and Considerations for Vaccine Decision-Making. Asia Dengue Summit, Bangkok January 2016

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1 Global Dengue Vaccine Recommendations and Considerations for Vaccine Decision-Making Asia Dengue Summit, Bangkok January 2016 Joachim Hombach Initiative for Vaccine Research (IVR) Department of Immunization, Vaccines and Biologicals (IVB)

2 Clinical Dengue Vaccine Development Pipeline Phase I Phase II Phase IIb Phase III Registration DPIV GlaxoSmithKline, Biomanguinhos, WRAIR TV003/TV005 US National Institutes of Health, 1 Butantan TV003/TV005 US National Institutes of Health, 1 Butantan CYD-TDV Sanofi Pasteur DEN-80E Merck DENVax2 Takeda TVDV Naval Medical Research Center Live attenuated (recombinant) DNA TLAV-TPIV WRAIR Heterologous Prime-Boost Inactivated Subunit 1 Licensing agreements also with Merck, Panacea, SII, Vabiotech 2 Phase 3 study approved for Butantan

3 Examples of WHO activities to support global vaccine guidance and introduction Vaccine Registered 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 decisionmaking Introduction / training materials Guidance for monitoring vaccine effectiveness and safety postlicensure WHO Prequalification Guidance for evaluation of second-generation vaccines 3

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 4

5 Examples: 2015 WHO Vaccine Recommendations 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. 5

6 Pathways for WHO Recommendations on Vaccine Use Industry and other partners Global Advisory Committee on Vaccine Safety Expert committee on Biological Standardization Product Development for Vaccines Advisory Committee Background Paper Secretariat Relevant existing technical advisory committee SAGE SAGE working group Recommendations Other relevant non immunization related WHO policy recommendation making body WHO DG Broad stakeholder consultation WHO Position Paper Country Decision making Immunization and Vaccines related Implementation Research Advisory Committee Input Request for review of evidence Immunization Practices Advisory Committee Regional TAGS Regional consultations 6

7 MEMBERSHIP Terry Nolan (Co-Chair), Australia Jeremy Farrar (Co-Chair), UK Ananda Amarasinghe, Sri Lanka Alan Barrett, USA Anna Durbin, USA (until ) 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 7

8 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 8

9 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. 9

10 Previous WHO comparative modelling exercises Antigen PCV 1 Rotavirus 2 HPV 3,4 Malaria 5 1 Chaiyakunapruk et al. BMC Medicine 2011; 9:53; 2 Postma et al. BMC Medicine 2011: 9:84; 3 Jit et al. BMC Medicine 2011; 9:54; 4 Jit et al. BMC Medicine 2013; 11:23; 5 Penny 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 10

11 Comparative modelling of dengue vaccine public health impact: key questions 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 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) 11

12 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) Project coordination Mark Jit (LSHTM) Stefan Flasche (LSHTM) Kirsten Vannice (WHO) George Milne (U of Western Australia) Alex Perkins (U of Notre Dame) Mario Recker (Oxford) 12 (*group leaders)

13 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 13

14 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 14

15 Developing Vaccine Policy Level Global Advisory Bodies SAGE Decision-Makers WHO Headquarters Regional Regional TAG WHO Regional Offices National NITAG Government Agency Careful review and consideration of the scientific evidence is an essential step in recommendations and guidelines development. 15 WHO Guidance for the development of evidence-based vaccine-related recommendations

16 Considerations for Vaccine Introduction High morbidity, low mortality Outbreaks, burden on health system School/work absenteeism Alternatives (vector control) Vaccine performance availability Vaccine Good traditional price safety/reactogenicity Programme costs Longer-term FU Economic impact VE by serotype, National budget and vaccine serostatus, etc. affordability Indication (age, schedule) Funding gaps and sustainability Duration of protection? Herd immunity? 16 WHO (2014) Principles and considerations for adding a vaccine into a national immunization programme.

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 Target populations Lag time to expected public health benefits 2 dose: 0, 6-12 months 3 dose: 0, 1-2, 6 months Females (includes males or MSMs in some countries) 3 dose: 0, 6, 12 months Geographical focus? 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) 17

18 National Sustained Coverage in Dengue-Interest Year introduced Countries* Earlier coverage (%) ( ) Latest available coverage (%) ( ) HPV2 HPV3 HPV2 HPV3 Argentina Brazil Chile 2014 >90 Colombia Mexico HPV1 HPV2 HPV3 Panama United States Bhutan >90 Cook Islands Fiji Japan Malaysia *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

19 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. 19

20 Programmatic Considerations: Tracking vaccination 20

21 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 21

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 22

23 Further information: Acknowledgement: Kirsten Vannice