Dr Michelle Groome MBBCh (Wits) DCH(SA) MScMed (Epi & Biostats) Department of Science and Technology/National Research Foundation: Vaccine

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1 Dr Michelle Groome MBBCh (Wits) DCH(SA) MScMed (Epi & Biostats) Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases; Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, University of the Witwatersrand, Johannesburg, South Africa World Immunization Week 2015

2 A leading cause of death in South African children < 5 years of age Global causes of childhood deaths in Li Liu, et al The Lancet, Volume 379, 2012

3 Rotavirus is the leading cause of severe gastroenteritis in young children. Estimated global deaths in ~25% detection among children hospitalised for diarrhoea in South Africa Tate JE et al. Lancet Infect Dis Seheri et al. J Infect Dis. 2010

4 Rotavirus infection not prevented by improvements in water and sanitation. Vaccination best public health intervention. Two licenced vaccines: Monovalent human rotavirus vaccine (Rotarix ) Pentavalent bovine-human reassortant rotavirus vaccine (RotaTeq )

5 Middle/high income countries Europe and Latin America Low-middle countries High efficacy (85-98%) against severe rotavirus gastroenteritis Ruiz-Palacios et al. 2006; Vesikari T et al South Africa, Malawi Madhi SA et al. NEJM 2010, Madhi SA et al. NEJM 2010 Ghana, Kenya, Mali Armah GE et al. The Lancet 2010 South Africa Vaccine efficacy against severe rotavirus-diarrhoea: 77% (56% 88%) during the first year of life. 59% (1% 83%) over two consecutive rotavirus seasons. Vaccine efficacy against all-cause severe gastroenteritis: 44% (20-61%).

6 National RV introductions by geographic region: 77 countries* Americas Argentina Bolivia Brazil Cayman Islands Colombia Dominican Republic Ecuador El Salvador Guatemala Guyana Haiti Honduras Mexico Nicaragua Panama Paraguay Peru United States Venezuela *As of April 1, 2015 RV = rotavirus vaccine Europe Armenia Austria Belgium Estonia Finland Georgia Germany Latvia Luxembourg Moldova Norway United Kingdom Africa Angola Eritrea Malawi Senegal Botswana Ethiopia Mali Sierra Leone Burkina South The Gambia Mauritania Faso Africa Burundi Ghana Morocco Sudan Cameroon Kenya Namibia Tanzania Congo, Rep. Libya Niger Togo Djibouti Madagascar Rwanda Zambia Middle East Bahrain Iraq Israel Jordan Qatar Saudi Arabia Tajikistan UAE Uzbekistan Yemen Not Gavi-eligible [42] Gavi-eligible [35] Asia Philippine s Western Pacific Australia Fiji Marshall Islands Micronesia New Zealand Palau

7 Introduced into national vaccination programme 1 Aug Rotarix recommended at 6 and 14 weeks of age. Estimates of coverage rates for the second dose of rotavirus vaccine increased from 67% in 2010 to 96% in Important to measure effectiveness and impact of vaccine introduction in the setting of routine use which may differ from ideal clinical trial settings. Effectiveness: case control study. Impact: time series analysis.

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9 Case-control study to estimate the effectiveness of the monovalent oral live-attenuated human rotavirus vaccine against hospitalisation for rotavirus gastroenteritis in children under two years of age in South Africa. April 2010 to October hospitals

10 Children hospitalised overnight with acute diarrhoea. Age-eligible to have received at least one dose of rotavirus vaccine (i.e. born after 14 June 2009). Assessed for eligibility, invited to participate and consent obtained. Stool specimen collected within 48 hours of admission. Demographic indicators, clinical history: parent interview. Vaccination status (exposure): Road-to-Health card. Medical record review. HIV infection status. Cases: positive for rotavirus. Controls: Rotavirus negative controls. Respiratory controls (subset of hospitals).

11 Number vaccinated First HRV dose Second HRV dose Age in weeks

12 Number of HRV doses a All hospitals No (%) of rotavirus-positive cases (n=540) Rotavirus-negative controls (n=1434) No (%) 0 (Reference) 136 (25) 244 (17) - ave % (95% CI) (23) 334 (23) 40 (16 57) (52) 856 (60) 57 (40 68)

13 Children who were fully vaccinated against rotavirus were 57% less likely to be hospitalized for rotavirus diarrhea compared to unvaccinated children. Additionally, children who received just one dose of rotavirus vaccine were 40% less likely to be hospitalized for rotavirus diarrhea.

14 Against hospitalisation for acute rotavirus diarrhoea. 1 dose (ave %) 2 doses (ave %) Total 40 (16 57) 57 (40 68) 18 weeks to 11 months 39 (9 59) 54 (32 68) 12 to 23 months 40 (-7 66) 61 (35 77) Age HIV-uninfected only 37 (10 56) 57 (39 70) HIV-exposed-uninfected (HEU) HIV-unexposed-uninfected (HUU) 61 (22 81) 64 (34 80) 24 (-17 51) 54 (31 69) HIV exposure

15 Introduction of these vaccines into national immunisation programmes in other countries has led to a substantial decrease in diarrhoea-related hospitalisations and diarrhoeal deaths. We aimed to investigate the impact of rotavirus vaccine introduction on all-cause diarrhoea hospitalisations from among HIV-infected and HIV-uninfected children under five years of age in Soweto, South Africa, stratified by age group.

16 Children under 5 years: hospitalised overnight 1 January 2006 to 31 December Collected discharge summaries completed on each patient in general paediatric wards. Admission registries short stay ward. Demographics, admission date, ICD 10 codes, HIV status. Calculated monthly case counts of gastroenteritis admissions. Plotted case counts against time (months). Developed models for case counts using data from baseline period. Potential outcome framework was used to estimate the counterfactual that would have occurred had we not introduced rotavirus vaccine.

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20 UNDER 1 YEAR Expected case count (95% IE) 1618 ( ) 1377 ( ) 1547 ( ) 1482 ( ) Observed case count Reduction in case count 687 ( ) 617 ( ) 866 ( ) 849 ( ) (95% IE) Percent reduction (95% IE) 42% (33 49) 45% (39 50) 56% (51 60) 57% (52 61) 1 YEAR Expected case count 419 ( ) 462 ( ) 449 ( ) 481 ( ) (95% IE) Observed case count Reduction in case count 5 (-68 71) 155 ( ) 187 ( ) 232 ( ) (95% IE) Percent reduction (95% IE) 1% (-15 20) 34% (27 40) 42% (35 47) 48% (43 53) 2 TO 4 YEARS Expected case count (95% IE) 208 ( ) 256 ( ) 228 ( ) 249 ( ) Observed case count Reduction in case count -37 (-87 85) 18 ( ) 27 ( ) 67 (16 187) (95% IE) Percent reduction (95% IE) -17% (-55 26) 7% (-13 36) 12% (-11 43) 27% (8 51)

21 Two approaches for assessing the benefit of introduction of rotavirus vaccine in South Africa: success story! Effectiveness of rotavirus vaccine against hospitalisation for rotavirus diarrhoea: case control study. Children under two years old who were fully vaccinated against rotavirus were 57% less likely to be hospitalized for rotavirus diarrhea compared to unvaccinated children. Protection sustained through two years of life. Similar protection in HIV-exposed and HIV-unexposed children. Trends in all-cause diarrhoeal hospitalisations over time. Significant reductions in all-cause diarrhoeal hospitalisations post rotavirus vaccine introduction. Reductions in the first year post introduction in <1 year. By second year, reductions in 1 year olds. By 2013, reduction in 2-4 year olds. Contribution of herd immunity.

22 Chris Hani Baragwanath Academic Hospital Dept of Paediatrics Shabir Madhi Susan Nzenze, Tselane Makgobo, study nurses Red Cross Children s Hospital Heather Zar, Ralph Diedericks, Christine Mulligan Earl Dietrich Ngwelezane Hospital Constant Kapongo, Dianette Conradie Rotavirus surveillance group Centre for Enteric Diseases, NICD Nicola Page, Jocelyn Moyes, Cheryl Cohen Division of Viral Diseases, CDC Umesh Parashar, Margaret Cortese PATH Jessica Fleming Bill and Melinda Gates Foundation Duncan Steele Support for this project was provided by PATH through funding from the GAVI Alliance. The views expressed by the authors do not necessarily reflect the views of GAVI, PATH, or the Centers for Disease Control and Prevention.

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