Value of post-licensure data to assess public health value Example of rotavirus vaccines

Value of post-licensure data to assess public health value Example of rotavirus vaccines TM Umesh D. Parashar Lead, Viral Gastroenteritis Team CDC, Atlanta, USA uparashar@cdc.gov 1

Two New Rotavirus Vaccines Licensed in 2006 Large trials (60-70,000 infants) in US, Europe, and Latin America No increased risk of intussusception Vesikari et al and Ruiz-Palacios et al, NEJM 2006 2

High Efficacy of Both Vaccines in Trials in High/Middle Income Countries Vaccine Region Efficacy (95%CI) Rotarix Europe 96% (90%-99%) Rotarix Latin America 85% (72%-92%) RotaTeq Europe/US 98% (88%-100%) Vesikari et al and Ruiz-Palacios et al, NEJM 2006 Vesikari et al, Lancet, 2007. 3

National RV introductions, 81 countries* Not Gavi-eligible [43] Gavi-eligible [38] *As of May 1, 2016

How well will vaccines perform in routine use? 5

Rotavirus Vaccines in USA Feb 2006 RotaTeq recommended June 2008 Rotarix recommended 6

High effectiveness of RotaTeq against severe Rotavirus Disease in US infants Study 1 Study 2 Study 3 Study 4 Study 5 Boom et al, 2010 Staat et al, 2011 Cortese et al, 2011 Payne et al, 2013 Cortese et al, 2013 3 doses 89% (70, 96) 87% (71, 94) 90% (84, 94) 84% (78, 98) 92% (75, 97) 2 doses 82% (15, 96) 88% (66, 96) 90% (75, 96) 78% (65, 86) 84% (1, 99) 1 dose 65% (-11, 89) 74% (37, 90) 66% (16, 86) 70% (50, 82) NA 7

Sustained RotaTeq effectiveness over 4 years of life 100% 90% 80% 89% 70% 60% 50% 40% 30% 20% 10% 85% 83% 79% 0% 1 2 3 4 Age (years) Payne DC, et al. Clin Infect Dis 2013

Hospitalizations Impact of vaccination on all cause acute gastroenteritis and rotavirus AGE hospitalizations in US children 250 211 All-cause AGE Rotavirus 200 194 168 150 147 100 107 101 101 104 79 115 50 0 44 27 23 9 4 1 2006 2007 2008 2009 2010 2011 2012 2013 Payne DC, et al. Clin Infect Dis 2011

Decline in rotavirus hospitalization rate in 2008 and vaccine coverage by age Age Decline in rotavirus hospitalization rate (2008 vs. 2006) Rotavirus vaccine coverage in 2008 (>=1 dose) < 1 year 66% 56% 1 -< 2 years 95% 44% 2 -< 3 years 85% <1% This age cohort was ineligible to receive rotavirus vaccine Herd Protection? 10

Reduction in gastroenteritis hospitalizations in older children and young adults in the US Estimated Rotavirus Hospitalizations 2008 vs. 2000 2006 (median and range) Age 0-4 years: ~56,000 hospitalizations averted ($162 million) Age 5-24 years: ~10,000 hospitalizations averted ($42 million) Lopman et al. JID 2011 Gastanaduy Lopman et et al JAMA al. J Infect 2013Dis 2011:204:980

Number of gastroenteritis hospitalizations averted by age group in UK 25000 20000 15000 10000 Vaccinated 5000 0 <1 y 1 y 2 y 3 y 4 y 5 14 y 15 44 y 45 64 y 65 y 12 Christina J. Atchison et al. J Infect Dis. 2016;213:243-249

Will vaccination save lives? 13

Number of diarrhea deaths 250 200 150 100 50 Age 11 months Age 12-23 months Age 24-59 months Vaccine Introduced (May 2007) 2008 2009 0 Richardson et al, NEJM 2010 Month-Year 14

How well will live oral rotavirus vaccines work in the developing world? 15

Hurdles to Immunization for a Live Oral Rotavirus Vaccine Factors that lower viral titer Breast milk Stomach acid Maternal antibodies OPV Factors that impair immune response Malnutrition - Zn, Vit A Interfering microbes- viruses and bacteria Other infections- HIV, malaria, TBC 16

Moderate Efficacy of Rotavirus Vaccines in Africa and Asia Vaccine Region Countries Efficacy (95%CI) RotaTeq Africa Ghana, Kenya, Mali 64% (40%-79%) RotaTeq Asia Bangladesh, Vietnam 51% (13%-73%) Rotarix Africa South Africa, Malawi 62% (44%-73%) Armah et al. Lancet 2010 Zaman et al. Lancet 2010 Madhi et al NEJM 2010 17

Cases prevented per 100 child-years Rotavirus vaccines prevent more disease, despite lower vaccine efficacy, in higher burden settings Placebo Vaccine 14 12 10 13,1 6.7 episodes prevented 8 6 4 6,5 5,4 4.2 episodes prevented 2 1,2 0 Malawi South Africa 50% vaccine efficacy 77% vaccine efficacy Madhi, NEJM 2010

GAVI-supported RV introductions, 35 countries * Gavi-supported RV introductions by geographic region: 35 countries * Americas Bolivia (2008) Guyana (2010) Haiti (2013) Honduras (2009) Nicaragua (2006) Europe Armenia (2012) Georgia (2013) Moldova (2012) Africa Angola (2014) Madagascar (2014) Burkina Faso (2013) Malawi (2012) Burundi (2013) Mali (2014) Cameroon (2014) Mauritania (2014) Central African Rep. Mozambique Congo Rep. (2014) Niger (2014) Djibouti (2014) Rwanda (2012) Eritrea (2014) Senegal (2014) Ethiopia (2013) Sierra Leone (2014) The Gambia (2013) Sudan (2011) Ghana (2012) Tanzania (2012) Guinea-Bissau Togo (2014) Kenya (2014) Zambia (2013) Liberia Zimbabwe (2014) Middle East Tajikistan (2015) Uzbekistan (2014) Yemen (2012) Introduced (Year) [35] Approved [4]

janv.-09 avr.-09 juil.-09 oct.-09 janv.-10 avr.-10 juil.-10 oct.-10 janv.-11 avr.-11 juil.-11 oct.-11 janv.-12 avr.-12 juil.-12 oct.-12 janv.-13 avr.-13 juil.-13 oct.-13 janv.-14 avr.-14 juil.-14 oct.-14 Number of Hospitalizations Decline in childhood diarrhea hospitalizations at 27 district hospitals in Rwanda after rotavirus vaccine introduction 900 800 VACCINE 700 600 500 400 300 200 100 0 Ngabo et al. Lancet Global Health 2015

Decline in proportion of childhood hospitalizations caused by diarrhea in Rwanda Number of Admissions % of Total Hospital Admissions from AGE 12000 Total Hospital Admissions AGE Admissions % of Admissions Due to AGE VACCINE 25 10000 19% 20% 19% 19% 20 8000 15 6000 12% 13% 10 4000 2000 5 0 2009 2010 2011 2012 2013 2014 0 Ngabo et al. Lancet Global Health 2015

Reduction in all-cause gastroenteritis-related deaths among infants at 4 hospitals in Botswana after rotavirus vaccine implementation Leslie A. Enane et al. Clin Infect Dis. 2016;62:S168-S174

What is the economic impact of vaccination? 23

Cost-effectiveness of rotavirus vaccination in Malawi Prospective cohort N=530 Household & Societal perspective Itemised household expenditures Post-discharge home visit Detailed socioeconomic data Government perspective Detailed costing of individual healthcare actually received avert 54,000 cases of RVGE and $27 $143 281 per deaths DALY US$19 per DALY averted averted CID 2016

How well will vaccines protect against range of strains? 25

RotaTeq is Pentavalent & Rotarix is Monovalent RotaTeq Rotarix G1 G3 G2 P[8] G4 G1P[8] Five bovine-human rotavirus strains Single human rotavirus strain 26

Vaccine efficacy (%) Rotarix (G1P8): Serotype Specific Efficacy in Latin America 100 90 80 85 [71.7; 92.4] 85 [71.1; 92.7] 92 [74.1; 98.4] 91 [70.5; 98.2] 91 91 88 86 [61.7; 98.9] [61.7; 98.9] [8.3; 99.7] [9.3; 99.7] Clinical Vesikari scale 70 60 50 41 [-79.2; 82.4] 45 [-81.5; 85.6] 40 30 20 10 0 All wild-types G1 P8* G9P8 G3P8 G2P4 * Homotypic strain Ruiz-Palacios GM et al. New Engl J Med 2006; 354: 11 22 27

High Rotarix (G1P8) Effectiveness against Non-Vaccine Strains in Several Countries Country Post-vaccine strains Vaccine Effectiveness (95% CI) Brazil G2P[4] 85% (54, 95) Mexico G9P[4] 94% (16, 100) Bolivia G9P[8] 84% (64, 92) G2P[4] 71% (19, 90) G3P[8] 92% (60, 98) G9P[6] 87% (-10, 98) 28

High Rotarix (G1P8) Effectiveness against Non-Vaccine Strains in Several Countries Country Post-vaccine strains Vaccine Effectiveness (95% CI) Brazil G2P[4] 85% (54, 95) Mexico G9P[4] 94% (16, 100) Bolivia G9P[8] 84% (64, 92) G2P[4] 71% (19, 90) G3P[8] 92% (60, 98) G9P[6] 87% (-10, 98) 29

High Rotarix (G1P8) Effectiveness against Non-Vaccine Strains in Several Countries Country Post-vaccine strains Vaccine Effectiveness (95% CI) Brazil G2P[4] 85% (54, 95) Mexico G9P[4] 94% (16, 100) Bolivia G9P[8] 84% (64, 92) G2P[4] 71% (19, 90) G3P[8] 92% (60, 98) G9P[6] 87% (-10, 98) 30

Do rotavirus vaccines cause intussusception? 31

Post-Licensure Intussusception Data Mexico, Brazil, US, and Australia have reported a low risk of intussusception ~1-6 cases per 100,000 vaccinated With both vaccines Key Question How does the risk compare with benefits of vaccination? 32

Benefits vs. Risks of Vaccination Diarrhea Hospitalizations (Deaths) Prevented Intussusception Cases (Deaths) Caused Mexico 11,600 (663) 41 (2) Brazil 69,600 (640) 55 (3) Australia 7,000 (0) 6 (0) US 53,000 (16) 48 (0) * 33

Are there other, unmeasured benefits of vaccination? 34

The triple burden of enteric infections, stunted growth and development and chronic diseases / Microbiota DeBoer, Stein, Martorell, et al. Ann Epi 2013 / Health Guerrant, DeBoer, Moore, Scharf, Lima. Nature Rev Gastro Hep. 10: 220-9, 2013.

Post-licensure data has provided key evidence Indirect benefits to unvaccinated groups Reduction of diarrhea mortality High impact despite lower efficacy in low income settings Broad protection against range of strains Benefits outweigh risks of vaccination 36