Rotavirus vaccine impact in Africa: greater than the sum of its parts?
Authors: James A Platts-Mills, A Duncan Steele
Journal: The Lancet Global Health (2018)

Before the availability of rotavirus vaccine (RV), rotavirus was identified as the single most important cause of fatal paediatric diarrhoea worldwide, responsible for approximately 40% of all mortality due to diarrhoea in children younger than 5 years.1Tate JE Burton AH Boschi-Pinto C et al.Global, regional, and national estimates of rotavirus mortality in children <5 years of age, 2000–2013.Clin Infect Dis. 2016; 62: S96-105Crossref PubMed Scopus (720) Google Scholar, 2Troeger C Forouzanfar M Rao PC et al.Estimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the Global Burden of Disease Study 2015.Lancet Infect Dis. 2015; 17: 909-948Summary Full Text Full Text PDF Scopus (664) Google Scholar To date, RV has been introduced into national immunisation programmes in 95 countries worldwide, details of which can be found on View-Hub. Evidence from several countries in the Americas, where RV was introduced more than one decade ago, clearly indicates a reduction in diarrhoea mortality after RV introduction.3Paternina-Caicedo A Parashar UD Alvis-Guzman N et al.Effect of rotavirus vaccine on childhood diarrhea mortality in five Latin American countries.Vaccine. 2015; 33: 3923-3928Crossref PubMed Scopus (39) Google Scholar These data were generated using national vital registration systems and thus are generally not available from low-income countries where the potential impact of RV introduction should be greatest. RV has now been introduced in 34 of 47 countries in the African Region of WHO, and additional introductions are planned. The potential impact is massive: the highest rates of rotavirus-associated mortality in children younger than 5 years are in sub-Saharan Africa,1Tate JE Burton AH Boschi-Pinto C et al.Global, regional, and national estimates of rotavirus mortality in children <5 years of age, 2000–2013.Clin Infect Dis. 2016; 62: S96-105Crossref PubMed Scopus (720) Google Scholar and rotavirus has been estimated to be responsible for about half of all acute watery diarrhoea that requires admission to hospital in children younger than 5 years before RV introduction.4Operario DJ Platts-Mills JA Nadan S et al.Etiology of severe acute watery diarrhea in children in the global rotavirus surveillance network using quantitative polymerase chain reaction.J Infect Dis. 2017; 216: 220-227Crossref PubMed Scopus (74) Google Scholar Although a reduction in in-hospital mortality from diarrhoea has been observed,5Enane LA Gastanaduy PA Goldfarb DM et al.Impact of rotavirus vaccination on hospitalizations and deaths from childhood gastroenteritis in Botswana.Clin Infect Dis. 2016; 62: S168-S174Crossref PubMed Scopus (45) Google Scholar no population-based estimates are available on the impact of RV introduction on diarrhoeal deaths in Africa. Such estimates are crucially needed, in particular given the low efficacy of RV against severe rotavirus gastroenteritis in clinical trials done in Africa6Isanaka S Guindo O Langendorf C et al.Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger.N Engl J Med. 2017; 376: 1121-1130Crossref PubMed Scopus (115) Google Scholar, 7Madhi SA Cunliffe NA Steele D et al.Effect of human rotavirus vaccine on severe diarrhea in African infants.N Engl J Med. 2010; 362: 289-298Crossref PubMed Scopus (18) Google Scholar and even lower efficacy against all-cause severe diarrhoea. Moreover, rotavirus appears to remain an important cause of diarrhoea that requires admission to hospital in Africa after RV introduction even when deploying molecular diagnostics, which have improved attribution of diarrhoea to a broad range of enteropathogens.4Operario DJ Platts-Mills JA Nadan S et al.Etiology of severe acute watery diarrhea in children in the global rotavirus surveillance network using quantitative polymerase chain reaction.J Infect Dis. 2017; 216: 220-227Crossref PubMed Scopus (74) Google Scholar, 8Platts-Mills JA Amour C Gratz J et al.Impact of rotavirus vaccine introduction and post-introduction etiology of diarrhea requiring hospital admission in Haydom, Tanzania, a rural African setting.Clin Infect Dis. 2017; 65: 1144-1151Crossref PubMed Scopus (28) Google Scholar Conversely, monitoring after introduction has suggested a greater impact, with reductions in rotavirus diarrhoea, all-cause severe diarrhoea, and admissions to hospital due to diarrhoea that have been clear and consistent.8Platts-Mills JA Amour C Gratz J et al.Impact of rotavirus vaccine introduction and post-introduction etiology of diarrhea requiring hospital admission in Haydom, Tanzania, a rural African setting.Clin Infect Dis. 2017; 65: 1144-1151Crossref PubMed Scopus (28) Google Scholar, 9Groome MJ Zell ER Solomon F et al.Temporal association of rotavirus vaccine introduction and reduction in all-cause childhood diarrheal hospitalizations in South Africa.Clin Infect Dis. 2016; 62: S188-S195Crossref PubMed Scopus (42) Google Scholar, 10Ngabo F Tate JE Gatera M et al.Effect of pentavalent rotavirus vaccine introduction on hospital admissions for diarrhoea and rotavirus in children in Rwanda: a time-series analysis.Lancet Glob Health. 2016; 4: e129-e136Summary Full Text Full Text PDF PubMed Scopus (50) Google Scholar However, demonstration of a reduction in diarrhoea mortality would clearly lend the strongest possible support to broad programmatic introduction. In this issue of The Lancet Global Health, Naor Bar-Zeev and colleagues11Bar-Zeev N King C Phiri T et al.Impact of monovalent rotavirus vaccine on diarrhoea-associated post-neonatal infant mortality in rural communities in Malawi: a population-based birth cohort study.Lancet Glob Health. 2018; 6: e1036-e1044Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar present estimates of the impact of RV introduction on all-cause diarrhoea mortality in both a prospective population-based cohort and a demographic surveillance system. In the prospective cohort, 48 672 live births were enrolled to identify 152 diarrhoea-associated deaths by verbal autopsy. RV coverage was greater than 90%, although it varied across districts. Adjusting for sociodemographic confounders, Bar-Zeev and colleagues estimated a 31% (95% CI 1–52) reduction in diarrhoea mortality after introduction of RV. A greater impact was seen during the rotavirus season, and greater RV coverage locally was associated with lower diarrhoea mortality. In a geographically unique demographic surveillance system, the authors observed a reduction in diarrhoea mortality of 46% (95% CI 26–60), though they acknowledge that water and sanitation interventions were implemented coincident with vaccine introduction in this population.11Bar-Zeev N King C Phiri T et al.Impact of monovalent rotavirus vaccine on diarrhoea-associated post-neonatal infant mortality in rural communities in Malawi: a population-based birth cohort study.Lancet Glob Health. 2018; 6: e1036-e1044Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar Several important limitations of their study should be noted. Similar to other studies using historical controls, the results are subject to confounding by other time-varying factors that might impact diarrhoea mortality. The authors appropriately adjust for sociodemographic predictors in the population-based cohort and for a preintroduction trend of decreasing diarrhoea mortality in the surveillance system. Additionally, verbal autopsy reports are susceptible to recall bias. Finally, these estimates are imprecise, despite the large sample sizes, because they study a rare outcome. However, they are consistent with expectations. For example, a modelling study12Shah MP Tate JE Mwenda JM Steele AD Parashar UD Estimated reductions in hospitalizations and deaths from childhood diarrhea following implementation of rotavirus vaccination in Africa.Expert Rev Vaccines. 2017; 16: 987-995Crossref PubMed Scopus (43) Google Scholar predicted a 39% reduction in deaths from diarrhoea with continent-wide introduction of RV in Africa. Put together, these data suggest that the impact of RV introduction on diarrhoea mortality might be greater than initially predicted based on reduced vaccine efficacy in these settings. Several explanations are possible for this observation. First, the use of severe gastroenteritis as an outcome might conceal a higher efficacy against the most severe diarrhoea. In a phase 3 trial6Isanaka S Guindo O Langendorf C et al.Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger.N Engl J Med. 2017; 376: 1121-1130Crossref PubMed Scopus (115) Google Scholar of a live, oral bovine rotavirus pentavalent vaccine in Niger, vaccine efficacy against severe gastroenteritis of any cause was only 10% compared with 68% against the subset of very severe gastroenteritis. Second, these efficacy trials were not designed to estimate indirect protection from vaccination. Finally, efficacy estimates might be biased toward the null by acquisition of natural immunity in unvaccinated children,13Rogawski ET Platts-Mills JA Colgate ER et al.Quantifying the impact of natural immunity on rotavirus vaccine efficacy estimates: a clinical trial in Dhaka, Bangladesh (PROVIDE) and a simulation study.J Infect Dis. 2018; 217: 861-868Crossref PubMed Scopus (24) Google Scholar particularly in settings with a high force of infection,7Madhi SA Cunliffe NA Steele D et al.Effect of human rotavirus vaccine on severe diarrhea in African infants.N Engl J Med. 2010; 362: 289-298Crossref PubMed Scopus (18) Google Scholar by misattribution of diarrhoea to rotavirus in the the setting of co-infections,14Mokomane M Tate JE Steenhoff AP et al.Evaluation of the influence of gastrointestinal coinfections on rotavirus vaccine effectiveness in Botswana.Pediatr Infect Dis J. 2018; 37: e562-e580Crossref Scopus (15) Google Scholar and by inclusion of population subsets that lack susceptibility to disease.15Lee B Dickson DM deCamp AC et al.Histo-Blood group antigen phenotype determines susceptibility to genotype-specific rotavirus infections and impacts measures of rotavirus vaccine efficacy.J Infect Dis. 2018; 217: 1399-1407Crossref PubMed Scopus (51) Google Scholar In the absence of nationwide vital registration data, a study of this size11Bar-Zeev N King C Phiri T et al.Impact of monovalent rotavirus vaccine on diarrhoea-associated post-neonatal infant mortality in rural communities in Malawi: a population-based birth cohort study.Lancet Glob Health. 2018; 6: e1036-e1044Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar is unlikely to be repeated, and the impact is striking and consistent with known reductions in severe diarrhoea in these settings after RV introduction. Taken together with data that show no evidence of increased intussusception with rotavirus vaccination in Africa,16Tate JE Mwenda JM Armah G et al.Evaluation of intussusception after monovalent rotavirus vaccination in Africa.N Engl J Med. 2018; 378: 1521-1528Crossref PubMed Scopus (61) Google Scholar these findings add considerable weight to the body of evidence that strongly supports RV introduction and maintenance in national immunisation programmes in low-income settings. We declare no competing interests. Impact of monovalent rotavirus vaccine on diarrhoea-associated post-neonatal infant mortality in rural communities in Malawi: a population-based birth cohort studyRV1 was associated with substantial reduction in diarrhoea-associated deaths among infants in this rural sub-Saharan African setting. These data add considerable weight to evidence showing the impact of rotavirus vaccine programmes. Full-Text PDF Open Access