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Rotavirus is the leading cause of gastroenteritis in children worldwide. In this report, the efficacy of the rotavirus vaccine among 4417 children in Malawi and South Africa was studied in a randomized trial. Severe rotavirus gastroenteritis occurred in 4.9% of the infants in the placebo group as compared with 1.9% of the infants in the pooled vaccine group; the vaccine efficacy was 61.2%. In this trial of rotavirus vaccine in Malawi and South Africa, severe rotavirus gastroenteritis occurred in 4.9% of the infants in the placebo group as compared with 1.9% of the infants in the pooled vaccine group; the vaccine efficacy was 61.2%. Rotavirus is the most important cause of severe gastroenteritis among children worldwide. The World Health Organization (WHO) estimates that globally 527,000 deaths occur each year among children as a result of rotavirus infection 1 ; more than 230,000 of the deaths occur in sub-Saharan Africa. Six of the seven countries with the highest mortality due to rotavirus diarrhea are located in Africa. 2 Similarly, data generated from global rotavirus surveillance networks highlight the burden of hospitalizations for rotavirus 3 ; among young children hospitalized for acute diarrhea, the median detection rate for rotavirus was 40% globally and 41% in Africa. Therefore, measures to . . .

► Human rotavirus vaccine reduced severe diarrhoea by half in a trial in Malawi. ► There was a substantial reduction of vaccine efficacy in the second year of life. ► Three vaccine doses may give more sustained protection compared with two doses. ► Routine rotavirus vaccination in Malawi will give significant public health benefit. ► The optimum rotavirus vaccine dosing schedule requires further investigation. Rotavirus gastroenteritis is a major cause of morbidity and mortality among African infants and young children. A phase III, placebo-controlled, multi-centre clinical trial of a live, oral G1P[8] human rotavirus vaccine (RIX4414) undertaken in Malawi and South Africa significantly reduced the incidence of severe rotavirus gastroenteritis in the first year of life. We now report on vaccine efficacy in the Malawi cohort of children who were followed into the second year of life. A total of 1773 healthy infants were enrolled in Blantyre, Malawi into three groups. Two groups received three doses of RIX4414 or placebo at age 6, 10, and 14 weeks and the third group received placebo at 6 weeks and RIX4414 at age 10 and 14 weeks. Subjects were followed by weekly home visits for episodes of gastroenteritis until 1 year of age, and were then re-consented for further follow-up to 18–24 months of age. Severity of gastroenteritis episodes was graded according to the Vesikari scoring system. Seroconversion for anti-rotavirus IgA was determined on a subset of children by using ELISA on pre- and post-vaccine blood samples. Rotavirus VP7 (G) and VP4 (P) genotypes were determined by RT-PCR. A total of 70/1030 (6.8%, 95% CI 5.3–8.5) subjects in the pooled (2 dose plus 3 dose) RIX4414 group compared with 53/483 (11.0%, 8.3–14.1) subjects in the placebo group developed severe rotavirus gastroenteritis in the entire follow-up period (vaccine efficacy 38.1% (9.8–57.3)). The point estimate of efficacy in the second year of life (17.6%; −59.2 to 56.0) was lower than in the first year of life (49.4%; 19.2–68.3). There were non-significant trends towards a higher efficacy in the second year of life among children who received the three-dose schedule compared with the two-dose schedule, and a higher anti-rotavirus IgA seroresponse rate in the three-dose RIX4414 group. Rotavirus strains detected included genotype G12 (31%); G9 (23%); and G8 (18%); only 18% of strains belonged to the G1P[8] genotype. While the optimal dosing schedule of RIX4414 in African infants requires further investigation, vaccination with RIX4414 significantly reduced the incidence of severe gastroenteritis caused by diverse rotavirus strains in an impoverished African population with high rotavirus disease burden in the first two years of life.

We aimed to assess the efficacy of the oral live attenuated human rotavirus vaccine Rotarix (RIX4414) for prevention of rotavirus gastroenteritis in European infants during their first 2 years of life. 3994 study participants were enrolled from six countries and were randomly assigned two oral doses of either RIX4414 (n=2646) or placebo (n=1348), which were coadministered with the first two doses of specific childhood vaccinations. Follow-up for gastroenteritis episodes was undertaken from 2 weeks post-dose two through the two consecutive rotavirus seasons following vaccinations (combined efficacy follow-up period; mean duration 17 months [SD 1·6]). Our primary endpoint was vaccine efficacy against rotavirus gastroenteritis of any severity during the first efficacy follow-up period (2 weeks post-dose two to the end of the first rotavirus season). Stool specimens obtained during gastroenteritis episodes were tested for rotavirus by ELISA and typed by RT-PCR. Episodes scoring 11 or greater on the 20-point Vesikari scale were classified as severe. Analysis was according to protocol. This study is registered with ClinicalTrials.gov, number NCT00140686 (eTrack102247). 120 infants were excluded from the according-to-protocol analysis. During the first efficacy follow-up period (mean duration 5·7 months [SD 1·2]), 24 of 2572 infants allocated RIX4414 versus 94 of 1302 given placebo had rotavirus gastroenteritis episodes of any severity, resulting in a vaccine efficacy of 87·1% (95% CI 79·6–92·1; p<0·0001). For the combined efficacy follow-up period, vaccine efficacy against severe rotavirus gastroenteritis was 90·4% (85·1–94·1; p<0·0001), for admission owing to rotavirus gastroenteritis 96·0% (83·8–99·5; p<0·0001), and for rotavirus-related medical attention 83·8% (76·8–88·9; p<0.0001), and significant protection against severe rotavirus gastroenteritis by circulating G1, G2, G3, G4, and G9 rotavirus types was shown. In a European setting, two doses of RIX4414 coadministered with childhood vaccines provided high protection against any and severe rotavirus gastroenteritis, with an overall reduction of admissions for gastroenteritis over two consecutive rotavirus epidemic seasons.

The low efficacy of rotavirus vaccines in clinical trials performed in low-resource settings may be partially explained by acquired immunity from natural exposure, especially in settings with high disease incidence. In a clinical trial of monovalent rotavirus vaccine in Bangladesh, we compared the original per-protocol efficacy estimate to efficacy derived from a recurrent events survival model in which children were considered naturally exposed and potentially immune after their first rotavirus diarrhea (RVD) episode. We then simulated trial cohorts to estimate the expected impact of prior exposure on efficacy estimates for varying rotavirus incidence rates and vaccine efficacies. Accounting for natural immunity increased the per-protocol vaccine efficacy estimate against severe RVD from 63.1% (95% confidence interval [CI], 33.0%-79.7%) to 70.2% (95% CI, 44.5%-84.0%) in the postvaccination period, and original year 2 efficacy was underestimated by 14%. The simulations demonstrated that this expected impact increases linearly with RVD incidence, will be greatest for vaccine efficacies near 50%, and can reach 20% in settings with high incidence and low efficacy. High rotavirus incidence leads to predictably lower vaccine efficacy estimates due to the acquisition of natural immunity in unvaccinated children, and this phenomenon should be considered when comparing efficacy estimates across settings. NCT01375647.

► Rotarix associated with 59% reductions in severe gastroenteritis over 2 consecutive rotavirus seasons in South Africa. ► 3-dose Rotarix schedule was associated with the trend of being more immunogenic than a 2-doses. ► 3-dose Rotarix schedule was associated with higher efficacy estimate over two seasons than a 2-doses. ► The optimal dosing schedule of Rotarix in providing long-term protection in African children needs to be explored. Human rotavirus vaccine (HRV; i.e., Rotarix) reduced the incidence of severe rotavirus gastroenteritis (RVGE) by 77% (95% Confidence interval: 56–88%) during the first year of life in South Africa. Persistence of HRV-derived protection against RVGE during subsequent rotavirus seasons, although evident in industrialized settings, remains to be established in African settings. This study reports on the efficacy of HRV against severe RVGE over two consecutive rotavirus seasons in South African children. A prospective, double-blind, placebo controlled multi-centered trial in South Africa and Malawi randomly assigned infants in a 1:1:1 ratio to receive either two (10 and 14weeks; HRV_2D) or three (6, 10 and 14weeks; HRV_3D) doses of HRV or placebo. The primary analysis involved pooling of HRV_2D and HRV_3D arms. Episodes of gastroenteritis caused by wild-type rotavirus were identified through active follow-up surveillance and graded by the Vesikari scale. 1339 infants (447 in the HRV_2D group, 447 in the HRV_3D group and 445 in the placebo group) were enrolled in Year 2 of the study, including 1035 (77.3%) who were followed up over two consecutive rotavirus seasons (i.e., Cohort 2 subjects). Rotarix was associated with ongoing protection against severe RVGE, preventing 2.5 episodes per 100 vaccinated children over two consecutive rotavirus seasons; vaccine efficacy: 59% (95% Confidence interval: 1–83%). An exploratory analysis indicated better immunogenicity (among Cohort 1 subjects) and a higher point-efficacy estimate over two seasons in the HRV_3D compared to HRV_2D arms of the study in Cohort 2 subjects. Rotarix is associated with significant reductions in severe gastroenteritis episodes through 2years of life among South African children. Further research is needed to determine the optimal dosing schedule of Rotarix in providing long-term protection against rotavirus illness in African children.

•Rotavirus vaccines (RVs) have been recently introduced in low-income settings.•Accurate post-introduction monitoring of RV effectiveness is important.•The test-negative design (TND) is used to measure RV effectiveness.•The TND was evaluated using randomized trials of RV in sub-Saharan Africa and Asia.•The TND is an appropriate method to measure RV effectiveness in low-income settings. The test-negative design (TND), an epidemiologic method currently used to measure rotavirus vaccine (RV) effectiveness, compares the vaccination status of rotavirus-positive cases and rotavirus-negative controls meeting a pre-defined case definition for acute gastroenteritis. Despite the use of this study design in low-income settings, the TND has not been evaluated to measure rotavirus vaccine effectiveness. This study builds upon prior methods to evaluate the use of the TND for influenza vaccine using a randomized controlled clinical trial database. Test-negative vaccine effectiveness (VE-TND) estimates were derived from three large randomized placebo-controlled trials (RCTs) of monovalent (RV1) and pentavalent (RV5) rotavirus vaccines in sub-Saharan Africa and Asia. Derived VE-TND estimates were compared to the original RCT vaccine efficacy estimates (VE-RCTs). The core assumption of the TND (i.e., rotavirus vaccine has no effect on rotavirus-negative diarrhea) was also assessed. TND vaccine effectiveness estimates were nearly equivalent to original RCT vaccine efficacy estimates. Neither RV had a substantial effect on rotavirus-negative diarrhea. This study supports the TND as an appropriate epidemiologic study design to measure rotavirus vaccine effectiveness in low-income settings.

Background Rotaviruses are the most important cause of severe acute gastroenteritis worldwide in children <5 years of age. The human, G1P[8] rotavirus vaccine Rotarix ™ significantly reduced severe rotavirus gastroenteritis episodes in a Phase III clinical trial conducted in infants in South Africa and Malawi. This paper examines rotavirus vaccine efficacy in preventing severe rotavirus gastroenteritis, during infancy, caused by the various G and P rotavirus types encountered during the first rotavirus-season. Methods Healthy infants aged 5–10 weeks were enrolled and randomized into three groups to receive either two (10 and 14 weeks) or three doses of Rotarix ™ (together forming the pooled Rotarix™ group) or three doses of placebo at a 6,10,14-week schedule. Weekly home visits were conducted to identify gastroenteritis episodes. Rotaviruses were detected by ELISA and genotyped by RT-PCR and nucleotide sequencing. The percentage of infants with severe rotavirus gastroenteritis caused by the circulating G and P types from 2 weeks post-last dose until one year of age and the corresponding vaccine efficacy was calculated with 95% CI. Results Overall, 4939 infants were vaccinated and 4417 (pooled Rotarix™  = 2974; placebo = 1443) were included in the per protocol efficacy cohort. G1 wild-type was detected in 23 (1.6%) severe rotavirus gastroenteritis episodes from the placebo group. This was followed in order of detection by G12 (15 [1%] in placebo) and G8 types (15 [1%] in placebo). Vaccine efficacy against G1 wild-type, G12 and G8 types were 64.1% (95% CI: 29.9%; 82%), 51.5% (95% CI:-6.5%; 77.9%) and 64.4% (95% CI: 17.1%; 85.2%), respectively. Genotype P[8] was the predominant circulating P type and was detected in 38 (2.6%) severe rotavirus gastroenteritis cases in placebo group. The remaining circulating P types comprised of P[4] (20 [1.4%] in placebo) and P[6] (13 [0.9%] in placebo). Vaccine efficacy against P[8] was 59.1% (95% CI: 32.8%; 75.3%), P[4] was 70.9% (95% CI: 37.5%; 87.0%) and P[6] was 55.2% (95% CI: -6.5%; 81.3%) Conclusions Rotarix ™ vaccine demonstrated efficacy against severe gastroenteritis caused by diverse circulating rotavirus types. These data add to a growing body of evidence supporting heterotypic protection provided by Rotarix™ . Trial registration number NCT00241644

► We combined data from two multicenter randomized double-blind, placebo controlled trials using identical methods in Asia and Africa. ► Combined vaccine efficacy against severe rotavirus gastroenteritis during the first year of life was 58.9% (95% confidence interval=40.0–72.3%). ► Combined vaccine efficacy against all cause severe gastroenteritis was 23% (95% CI=5.4–37.3%). ► The vaccine protected heterotypically, against G serotypes not included within the vaccine formulation. ► Vaccinated children had a reduction in their rate of rotavirus gastroenteritis of any severity when compared to unimmunized children of 3.7 episodes per 100 person-years and for severe rotavirus gastroenteritis of 2.3 episodes per 100 person-years. Efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq®, against severe rotavirus gastroenteritis (RVGE) was evaluated in two double-blind, placebo-controlled, multicenter Phase III clinical trials conducted in GAVI-eligible countries in Africa (Ghana, Kenya, and Mali) and in Asia (Bangladesh and Vietnam) from March 2007 through March 2009. The findings from each continent have been analyzed and presented separately, according to a single identical protocol. Ad hoc analyses combining data from the five sites were performed to further assess the impact of PRV. 6674 infants (4705 infants from Africa and 1969 infants from Asia), randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6-, 10-, and 14-weeks of age according to each country's EPI schedule, were included in the per protocol efficacy analysis. Breastfeeding and concomitant administration of EPI vaccines, including OPV, were allowed. Episodes of gastroenteritis (GE) in infants who presented to study facilities were captured and scored using the 20-point Vesikari scale. Stool samples were analyzed by rotavirus-specific EIA to detect presence of rotavirus antigen and RT-PCR to determine the G/P genotypes. We assessed efficacy to prevent all-cause GE and RVGE at a variety of cut-off points (score≥11, severe; score≥15, very severe). Vaccine efficacy (VE) against RVGE, regardless of serotype, through the entire follow-up period for any severity, severe (score≥11), and very severe (score≥15) was 33.9%, 95% CI (22.7, 43.5), 42.5%, 95% CI (27.4, 54.6), and 51.2%, 95% CI (26.3, 68.2), respectively. Through the first year of life, VE against severe RVGE was 58.9%, 95% CI (40.0, 72.3) and against all-cause severe GE was 23.0%, 95% CI (5.4, 37.3). VE against severe RVGE caused by non-vaccine G serotypes, G8 and G9, through the entire follow-up period was 87.5%, 95% CI (6.8, 99.7) and 48.0%, 95% CI (−5.5, 75.6), respectively. All G8 strains were associated with P2A[6] (a P-type not contained in PRV), while the majority of the G9 strains were associated with P1A[8] (a P-type contained in PRV). Combining data from the 5 sites strengthens the precision of VE estimates and reveals rising VE with increased RVGE severity. Extrapolating data from VE against severe GE and RVGE suggest that 39% of severe GE episodes during the first year of life were due to rotavirus, highlighting substantial, potentially preventable, public health burden of RVGE. PRV provides protection against non-vaccine serotypes (G8P2A[6]).

•Equine-like G3P[8] the major cause of gastroenteritis during RV3-BB efficacy trial.•The Indonesian equine-like G3P[8] strain was genetically similar to Hungarian and Spanish strains.•Equine-like G3P[8] strain is an emerging cause of gastroenteritis in Indonesia. The RV3-BB human neonatal rotavirus vaccine aims to provide protection from severe rotavirus disease from birth. The aim of the current study was to characterise the rotavirus strains causing gastroenteritis during the Indonesian Phase IIb efficacy trial. A randomized, double-blind placebo-controlled trial involving 1649 participants was conducted from January 2013 to July 2016 in Central Java and Yogyakarta, Indonesia. Participants received three doses of oral RV3-BB vaccine with the first dose given at 0–5 days after birth (neonatal schedule), or the first dose given at ∼8 weeks after birth (infant schedule), or placebo (placebo schedule). Stool samples from episodes of gastroenteritis were tested for rotavirus using EIA testing, positive samples were genotyped by RT-PCR. Full genome sequencing was performed on two representative rotavirus strains. There were 1110 episodes of acute gastroenteritis of any severity, 105 episodes were confirmed as rotavirus gastroenteritis by EIA testing. The most common genotype identified was G3P[8] (90/105), the majority (52/56) of severe (Vesikari score ≥11) rotavirus gastroenteritis episodes were due to the G3P[8] strain. Full genome analysis of two representative G3P[8] samples demonstrated the strain was an inter-genogroup reassortant, containing an equine-like G3 VP7, P[8] VP4 and a genogroup 2 backbone I2-R2-C2-M2-A2-N2-T2-E2-H2. The complete genome of the Indonesian equine-like G3P[8] strain demonstrated highest genetic identity to G3P[8] strains circulating in Hungary and Spain. The dominant circulating strain during the Indonesian Phase IIb efficacy trial of the RV3-BB vaccine was an equine-like G3P[8] strain. The equine-like G3P[8] strain is an emerging cause of severe gastroenteritis in Indonesia and in other regions.

Rotavirus (RV) is a major agent of gastroenteritis and an important cause of child death worldwide. Immunization (RVI) has been available since 2006, and the Federation of International Societies of Gastroenterology Hepatology and Nutrition (FISPGHAN) identified RVI as a top priority for the control of diarrheal illness. A FISPGHAN working group on acute diarrhea aimed at estimating the current RVI coverage worldwide and identifying barriers to implementation at local level. A survey was distributed to national experts in infectious diseases and health-care authorities (March 2015–April 2016), collecting information on local recommendations, costs and perception of barriers for implementation. Forty-nine of the 79 contacted countries (62% response rate) provided a complete analyzable data. RVI was recommended in 27/49 countries (55%). Although five countries have recommended RVI since 2006, a large number (16, 33%) included RVI in a National Immunization Schedule between 2012 and 2014. The costs of vaccination are covered by the government (39%), by the GAVI Alliance (10%) or public and private insurance (8%) in some countries. However, in most cases, immunization is paid by families (43%). Elevated cost of vaccine (49%) is the main barrier for implementation of RVI. High costs of vaccination (rs=−0.39, p=0.02) and coverage of expenses by families (rs=0.5, p=0.002) significantly correlate with a lower immunization rate. Limited perception of RV illness severity by the families (47%), public-health authorities (37%) or physicians (24%) and the timing of administration (16%) are further major barriers to large- scale RVI programs. After 10years since its introduction, the implementation of RVI is still unacceptably low and should remain a major target for global public health. Barriers to implementation vary according to setting. Nevertheless, public health authorities should promote education for caregivers and health-care providers and interact with local health authorities in order to implement RVI.