Edwin J. Asturias Associate Director

Transcription

1 Edwin J. Asturias Associate Director Center for Global Health Associate Professor of Pediatrics and Epidemiology Effectiveness Dengue Vaccine Washington DC, June 2014 UNIVERSITY OF COLORADO COLORADO STATE UNIVERSITY UNIVERSITY OF NORTHERN COLORADO

2 Address definitions and what is being measured for vaccine effectiveness Outcomes and public health correlates External validity of data across settings Importance for guiding public health practice

3 Efficacy Reduction in probability of individual to become infected or reducing infectiousness if breakthrough or vaccine is a modifier

4 Population Vaccine A Time ARVdz Control ARUdz

5 VE = ARU ARV x 100 ARU or VE = (1-RR) x 100 ARU = attack rate in unvaccinated population ARV = attack rate in vaccinated population

6 Reduction of infection or infectiousness or disease in the unimmunized as a result of immunization of a proportion

7 Vaccinated Indirect protection

8 Unvaccinated and not protected Vaccinated and protected Unvaccinated but Indirect protection

9 Efficacy Reduction in probability of individual to become infected or reducing infectiousness if breakthrough or vaccine is a modifier Effectiveness Reduction in transmission rate of an average individual in a population with a vaccination program compared to no program

10 Direct protection affects vaccinated individual outcome measures Indirect protection affects unvaccinated individual outcomes At certain program coverage, the sum of directly and indirectly prevented outcomes equals effectiveness But

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12 Case-control analysis VEs = (1-OR) x 100 Indirect cohort analysis ( quasi cohort) Case-coverage or case-cohort method Ecological or observational cohort Vaccine probe studies Vaccine preventable disease incidence Household secondary attack method

13 Diarrhea and rotavirus related admissions among children aged less than 5 years at seven hospitals in El Salvador, January to June de Palma O et al. BMJ 2010;340

14 VEs = 1- (% cases vaccinated X % pop vaccinated) Orenstein 1- PCV PPV

15 Average coverage equal coverage Infectiousness and transmission is related to Ro and community size/density Risk of infection differs in vector borne diseases by ecology and cyclic patters Outcome expression may be different or confounded in different populations

16 Measles Cases Measles Cases United States, Vaccine Licensed 1 st Dose Recommendation nd Dose Recommendation 2000 Elimination Declared 1-dose preschool coverage Resurgence 2-dose adolescent coverage % Measles Vax Coverage Year

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18 Incidence of Deaths Impact: Deaths Averted

19 Lower immunogenicity? Case definition? Increased number of co-infections RV Ag(+) yet caused by other bacteria or virus Malnutrition? Programmatic? (cold-chain, dose, interference)

20 20 Patel et.al. JID 2009

21 Tate JE et al. EID 2013

22 Frequency of most commonly detected nondengue infections in febrile participants in Asia. Capeding MR PLoS Negl Trop Dis 7(7): e2331

23 Asymptomatic dengue AFI AFI SD Dengue vaccinated SD Control (unvaccinated)

24 Asymptomatic dengue AFI AFI SD Dengue vaccinated SD Control (unvaccinated)

25 Will those vaccinated be protected against the target disease as expected? How efficacy changes with time since vaccination? Benefit to those unvaccinated? Will the vaccine modify age of presentation of disease or severity?

26 Concerned with the extent to which a study s results can be extended (generalized) to other populations, settings, outcomes, and treatment variations. Types of external validity: Population validity Ecological validity Outcome validity Treatment variation validity

27 Outcome validity Can the results of a study be generalized to different but related dependent variables. E.g., hospitalized AFI, dengue-like HD Treatment variation validity. Can the results be generalized across variations in the independent variables? E.g., Dengue vaccine in Asia vs. Latin America

28 Factors that affect external validity should be addressed early for dengue vaccines VE estimates during high and low epidemic periods Vector density Effects of malnutrition, ethnicity and co-infections Improved surveillance and diagnostics Rapid-cycle sero-incidence methods Effect of vaccine introduction in unvaccinated age-groups

29 Number of serological confirmed dengue cases in Thailand from January to December in Sabchareon A,. PLoS Negl Trop Dis 6(7): e1732

30 Estimated relative prevalence of the 4 serotypes in Thailand Chao DL, PLoS Negl Trop Dis 6(10): e1876.

31 Maximizing information in efficacy studies will be key to inform issues with vaccine effectiveness Consensus on best methods to assess vaccine effectiveness and impact for dengue needed Post-licensure safety systems will be required and best to add effectiveness measures as for dengue, SAE will be an efficacy and safety outcome Ecological and modelling studies may signal vaccine effectiveness issues for dengue