ASSESSING THE VALUE OF VACCINE BEYOND EFFICACY AND SAFETY Bradford D. Gessner, MD Agence de Médecine Preventive First Regional Dengue Symposium Rio de Janeiro, Brasil November 3-4, 2015
BURDEN CONCEPTS
Vaccine Launches 2013 3
Disease burden has been consistently mentioned by policymakers in countries to be the number one factor in setting priorities for vaccines to be introduced into immunization programs; the higher the burden, the more attractive a potential addition to the immunization regime of the country would be. 4
Burden measure limitations Poor diagnostics: non-bacteremic Hib/Sp, typhoid Causal etiology gone at time of presentation: flu/viral ARI pathogens precipitating bacterial ARI Pathogen present but not causal: flu Lack of testing, poor specimen transport systems: all etiologies Limited health care access: all etiologies 5
Definition of measures Vaccine effectiveness/efficacy (VE) = 1 (Incidence[vaccinated] Incidence[unvaccinated]) Vaccine preventable disease incidence (VPDI) = Incidence[unvaccinated] Incidence[vaccinated] = Incidence[unvaccinated] X VE Feikin, Scott, Gessner. Use of vaccines as probes to define disease burden. Lancet 2015;383:1762-70 6
Impact of vaccine against pneumonia categories of pneumonia (Lancet 2014;383:1762-70) Category of pneumonia Unvaccinated Vaccinated Etiology conf. X-ray lobar consolidation Severe, not X-ray confirmed Mild Target etiology Target etiology Other etiologies Other etiologies
VACCINE EFFICACY AND PREVENTABLE DISEASE INCIDENCE EXAMPLES
Examples of vaccine preventable disease incidence (VPDI) use; VPDI per 100,000 CYO Syndrome Etiology confirmed Clinical outcome Gambia, PCV Indonesia, Hib Kenya, rotavirus Radiological pneumonia VE VPDI VE VPDI 70% 140 37% 1300 Hospitalized meningitis 86% 16 22% 160 AGE* (conf in hosp vs. all cause in comm) 84% 3300 34% 19,000 * AGE = acute gastroenteritis Lancet 2005;365:1139-46; Lancet 2005;365:43-52; Vaccine 2012;30 (suppl 1):A52-60 9
Vaccine preventable disease incidence (VPDI) is useful outside of developing country settings Study Vaccine efficacy VPDI (per 1000 CYO) Reference Finland Vaccine 2012;31:176-82 Confirmed inpatient AGE* 80% 3.9 All cause inpatient AGE* 54% 10.7 Kenya Vaccine 2012;30 Supp 1:A52-60 Confirmed severe 84% 33 Community severe AGE* 34% 190 * AGE = acute gastroenteritis 10
Public health impact can be greater in settings where vaccine efficacy is lower Study VE VPDI (per 100,000 CYO) Severe rotavirus AGE* NEJM 2010;362:289-98 South Africa 77% 4200 Malawi 49% 6700 Severe rotavirus AGE* Lancet 2010;376:615-23 Vietnam 64% 2200 Bangladesh 43% 3500 Ref * AGE = acute gastroenteritis 11
VPDI per 1000 vaccinees RTS,S VPDI against malaria-specific and 120 all-cause hospitalization 100 80 60 40 20 0-20 -40 Malaria All-cause Malaria All-cause Malaria All-cause Malaria All-cause No booster Booster No booster Booster 5 to 17 month old 6 to 12 weeks 12
DENGUE
Vaccine efficacy 100% Vaccine efficacy against confirmed dengue in children 9-16 years of age in Latin America 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% All serotypes Serotype 1 Serotype 2 Serotype 3 Serotype 4 All serotypes Confirmed dengue Hospitalized dengue 14
VDPI (per 100,000 per year) 1400 Vaccine preventable disease incidence (VPDI) for confirmed dengue in children age 9-16 years in Latin America 1200 1000 800 600 400 200 0 All serotypes Serotype 1 Serotype 2 Serotype 3 Serotype 4 All serotypes Confirmed dengue Hospitalized dengue 15
Vaccine efficacy 120% Vaccine efficacy for dengue compared to other vaccines studied and used in Latin America 100% 80% 60% 40% 20% 0% Confirmed rotavirus hospitalization Gastroenteritis hospitalization from any cause Vaccine serotype invasive pneumococcal disease Consolidated CAP Radiologically Suspected CAP confirmed CAP Invasive Hib disease Radiologically confirmed pneumonia Confirmed hospitalized dengue All confirmed dengue Rotavirus Latin America. NEJM 2006;354:11-22 Pneumococcus Latin America. PLoS Med 2014;11:e10011657 Hib Chile. Ped Infect Dis J 1999;18:1060-4 Dengue. NEJM 2015 16
VPDI (per 100,000 per year) 2000 Vaccine preventable disease incidence (VPDI) for dengue compared to other vaccines studied and used in Latin America 1800 1600 1400 1200 Dengue vaccine against syndromic disease? 1000 800 600 400 200 0 Confirmed rotavirus hospitalization Gastroenteritis hospitalization from any cause Vaccine serotype invasive pneumococcal disease Consolidated CAP Radiologically confirmed CAP Suspected CAP Invasive Hib disease Radiologically confirmed pneumonia Confirmed hospitalized dengue All confirmed dengue Rotavirus Latin America. NEJM 2006;354:11-22 Pneumococcus Latin America. PLoS Med 2014;11:e10011657 Hib Chile. Ped Infect Dis J 1999;18:1060-4 Dengue. NEJM 2015 17
BEYOND BURDEN
Age distribution Sp Hib Rotavirus Malaria DENGUE <5 year disease ++++ ++++ ++++ ++++ ++/+++ <5 year severity/sequelae ++++ -- -- ++++ + 5+ year disease ++/+++ + -- ++++ ++++ 5+ year severity/sequelae +++ + -- + + 19
Sequelae/mortality Cognitive (MR, dev delay, learning disability, language) Sensory (hearing, vision) Sp/Hib meningitis Sp/Hib pneumonia Rotavirus Malaria DENGUE ++++ -- -- +++ -- ++++ -- -- -- -- Physical (CP, seizures) ++++ -- -- +++ + Stunting?? + +++ -- Case fatality ratio ++++ +++ + ++ + E.g., in US, big cost driver for Hib was long-term care and institutionalization for meningitis sequelae 20
Indirect/replacement/rebound effects Sp Hib Rotavirus Malaria DENGUE Indirect +++ ++++ ++ --? Replacement +++ + (so far) -- --? Rebound -/+ (without booster) + (without booster in some settings) -- +++ (depends on transmission) Work in different directions: Indirect effects can greatly increase immunization efficiency and public health value Replacement can completely negate immunization efficiency 21Rebound shifts disease to older age; generally beneficial?
Immunization program issues Fits with current childhood schedule Duration of immunity (with booster) Variable geographic distribution within affected countries Sp Hib Rotavirus Malaria DENGUE +++ +++ +++ -- + +++ +++ Less relevant -/+?? -- -- -- ++ +++ 22
Health system impact Sp Hib Rotavirus Malaria DENGUE Outbreak potential + -- -- + +++ May overwhelm clinical resources Requires other intensive + expensive interventions Increasing incidence in absence of vaccine + -- ++ ++ +++ + + ++ +++ +++ -- -- -- -- +++ Political dimension + + + ++ +++ 23
SUMMARY Safety and efficacy just the start of assessing public health value of vaccine Burden is the foundation of decision making Incidence VPDI Sequelae Mortality Other key issues Vaccine characteristics Programmatic concerns Health system impact All of these features contribute to models estimating public health value of vaccine 24
QUESTIONS How can VPDI inform decision-making on dengue vaccine? What data exist on vaccine impact against clinical outcomes (e.g., fever hospitalization) and how will this alter public health value estimate of vaccine? What are the appropriate public health outcomes for dengue vaccine? Severe confirmed disease Clinical confirmed disease Fever hospitalization or clinic visit Outbreak control How important is health system impact compared to sequelae/mortality? How important are programmatic concerns? What additional studies are needed to Decide on vaccine use Determine scope of vaccine use (age groups/geography) Refine schedule Assess impact post introduction 25