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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 . . .

Despite the success of rotavirus vaccines, suboptimal vaccine efficacy in regions with a high burden of disease continues to present a challenge to worldwide implementation. A birth dose strategy with a vaccine developed from an asymptomatic neonatal rotavirus strain has the potential to address this challenge and provide protection from severe rotavirus disease from birth. This phase 2a randomised, double-blind, three-arm, placebo-controlled safety and immunogenicity trial was undertaken at a single centre in New Zealand between Jan 13, 2012, and April 17, 2014. Healthy, full-term (≥36 weeks gestation) babies, who weighed at least 2500 g, and were 0–5 days old at the time of randomisation were randomly assigned (1:1:1; computer-generated; telephone central allocation) according to a concealed block randomisation schedule to oral RV3-BB vaccine with the first dose given at 0–5 days after birth (neonatal schedule), to vaccine with the first dose given at about 8 weeks after birth (infant schedule), or to placebo. The primary endpoint was cumulative vaccine take (serum immune response or stool shedding of vaccine virus after any dose) after three doses. The immunogenicity analysis included all randomised participants with available outcome data. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611001212943. 95 eligible participants were randomised, of whom 89 were included in the primary analysis. A cumulative vaccine take was detected in 27 (90%) of 30 participants in the neonatal schedule group after three doses of RV3-BB vaccine compared with four (13%) of 32 participants in the placebo group (difference in proportions 0·78, 95% CI 0·55–0·88; p<0·0001). 25 (93%) of 27 participants in the infant schedule group had a cumulative vaccine take after three doses compared with eight (25%) of 32 participants in the placebo group (difference in proportions 0·68, 0·44–0·81; p<0·0001). A serum IgA response was detected in 19 (63%) of 30 participants and 20 (74%) of 27 participants, and stool shedding of RV3-BB was detected in 21 (70%) of 30 participants and 21 (78%) of 27 participants in the neonatal and infant schedule groups, respectively. The frequency of solicited and unsolicited adverse events was similar across the treatment groups. RV3-BB vaccine was not associated with an increased frequency of fever or gastrointestinal symptoms compared with placebo. RV3-BB vaccine was immunogenic and well tolerated when given as a three-dose neonatal or infant schedule. A birth dose strategy of RV3-BB vaccine has the potential to improve the effectiveness and implementation of rotavirus vaccines. Australian National Health and Medical Research Council, the New Zealand Health Research Council, and the Murdoch Childrens Research Institute.

► 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.

Rotavirus vaccines are less effective in high mortality regions. A rotavirus vaccine administered at birth may overcome challenges to vaccine uptake posed by a complex gut microbiome. We investigated the association between the microbiome and vaccine responses following RV3-BB vaccine (G3P[6]) administered in a neonatal schedule (dose 1: 0-5 days), or infant schedule (dose 1: 6-8 weeks) in Indonesia (Phase 2b efficacy study) ( n  = 478 samples/193 infants) (ACTRN12612001282875) and in Malawi (Immunigenicity study) (n = 355 samples/186 infants) (NCT03483116). Vaccine responses assessed using anti-rotavirus IgA seroconversion (IgA), stool shedding of vaccine virus and vaccine take (IgA seroconversion and/or shedding). Here we report, high alpha diversity, beta diversity differences and high abundance of Bacteroides is associated with positive vaccine take and shedding following RV3-BB administered in the neonatal schedule, but not with IgA seroconversion, or in the infant schedule. Higher alpha diversity was associated with shedding after three doses of RV3-BB in the neonatal schedule compared to non-shedders, or the placebo group. High abundance of Streptococcus and Staphylococcus is associated with no shedding in the neonatal schedule group. RV3-BB vaccine administered in a neonatal schedule modulates the early microbiome environment and presents a window of opportunity to optimise protection from rotavirus disease. Here, the authors show that high alpha diversity, differences in beta diversity, and a high abundance of Bacteroides in the gut microbiome are associated with positive vaccine take and stool shedding following administration of RV3-BB vaccine in the neonatal schedule, but not in the infant schedule or placebo groups, suggesting that the early-life gut microbiome provides a gut environment that optimizes the potential for a positive vaccine response.

► 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.

In this double-blind trial, two oral doses of a live attenuated G1P[8] rotavirus vaccine were highly efficacious in protecting infants against severe diarrheal disease. During the active surveillance of 63,225 infants, the risk of intussusception was no greater after vaccination than it was with placebo (six cases vs. seven cases). In this double-blind trial, two oral doses of a live attenuated G1P[8] rotavirus vaccine were highly efficacious in protecting infants against severe diarrheal disease. Rotavirus is the leading recognized cause of diarrhea-related illness and death among infants and young children. 1 – 5 Every year, rotavirus is associated with 25 million clinic visits, 2 million hospitalizations, and more than 600,000 deaths worldwide among children younger than five years of age. 6 , 7 Development of a safe and effective rotavirus vaccine is therefore a high priority, particularly but not exclusively in developing countries, where the burden of disease is highest. 8 , 9 Since the withdrawal from the market of the tetravalent rhesus–human reassortant vaccine (RotaShield, Wyeth Laboratories) because of an association with intussusception, 10 , 11 ruling out such a risk . . .

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.

•Pentavalent reassortant rotavirus vaccine was tested for efficacy in infants.•The vaccine (BRV-PV) showed excellent tolerability and a good safety profile.•Primary analysis efficacy was 36% against SRVGE and up to 60.5% against VSRVGE.•The efficacy through 2years of age was 39.5% (SRVGE) and 54.7% (VSRVGE).•The intent to treat analyses confirmed all the per protocol analyses. Rotavirus is the most common cause of moderate-to-severe infant diarrhoea in developing countries, resulting in enormous morbidity, mortality, and economic burden. A bovine-human reassortant pentavalent rotavirus vaccine (BRV-PV) targeting the globally most common strains was developed in India and tested in a randomized, double-blind, placebo-controlled end-point driven Phase III efficacy clinical trial implemented at six sites across India. Infants 6 to 8weeks of age were randomized (1:1) to receive three oral doses of BRV-PV or placebo at 6, 10, and 14weeks of age along with routine vaccines. Home visit surveillance was conducted to detect severe rotavirus gastroenteritis (SRVGE) and safety outcomes until the children reached two years of age. A total of 3749 infants received BRV-PV while 3751 received placebo. At the time of the primary end-point (when the minimum number of cases needed for analysis were accrued) the vaccine efficacy against SRVGE was 36% (95% CI 11.7, 53.6, p=0.0067) in the per protocol (PP) analysis, and 41.9% (95% CI 21.1, 57.3, p=0.0005) in the intent to treat (ITT) analysis. Vaccine efficacy over the entire follow-up period (until children reached two years of age) was 39.5% (95% CI 26.7, 50, p<0.0001) in the PP analysis and 38.8% (95% CI, 26.4, 49, p<0.0001) in the ITT analysis. Vaccine efficacy against the very severe rotavirus cases (VSRVGE, Vesikari score≥16) was 60.5% (95% CI 17.7, 81, p=0.0131) at the time of the primary analysis and 54.7% (95% CI 29.7, 70.8, p=0.0004) for the complete follow-period in the PP population. The incidence of solicited, unsolicited, and serious adverse events were similar in both the vaccine and placebo groups. Likewise, the number of intussusceptions and deaths were similar between both groups. Thus, BRV-PV is an effective, well tolerated and safe vaccine in Indian infants. (Trial registration: Clinical Trials.Gov [NCT 02133690] and Clinical Trial Registry of India [CTRI/2013/05/003667]).

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.

Rotavirus gastroenteritis causes many deaths in infants in sub-Saharan Africa. Because rotavirus vaccines have proven effective in developed countries but had not been tested in developing countries, we assessed efficacy of a pentavalent rotavirus vaccine against severe disease in Ghana, Kenya, and Mali between April, 2007, and March, 2009. In our multicentre, double-blind, placebo-controlled trial, undertaken in rural areas of Ghana and Kenya and an urban area of Mali, we randomly assigned infants aged 4–12 weeks without symptoms of gastrointestinal disorders in a 1:1 ratio to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age. Infants with HIV infection were not excluded. Randomisation was done by computer-generated randomisation sequence in blocks of six. We obtained data for gastrointestinal symptoms from parents on presentation to health-care facilities and clinical data were obtained prospectively by clinicians. The primary endpoint was severe rotavirus gastroenteritis (Vesikari score ≥11), detected by enzyme immunoassay, arising 14 days or more after the third dose of placebo or vaccine to end of study (March 31, 2009; around 21 months of age). Analysis was per protocol; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00362648. 5468 infants were randomly assigned to receive pentavalent rotavirus vaccine (n=2733) or placebo (n=2735). 2357 infants assigned to vaccine and 2348 assigned to placebo were included in the per-protocol analysis. 79 cases of severe rotavirus gastroenteritis were reported in 2610·6 person-years in the vaccine group, compared with 129 cases in 2585·9 person-years in the placebo group, resulting in a vaccine efficacy against severe rotavirus gastroenteritis of 39·3% (95% CI 19·1–54·7, p=0·0003 for efficacy >0%). Median follow-up in both groups was 527 days starting 14 days after the third dose of vaccine or placebo was given. 42 (1·5%) of 2723 infants assigned to receive vaccine and 45 (1·7%) of 2724 infants assigned to receive placebo had a serious adverse event within 14 days of any dose. The most frequent serious adverse event was gastroenteritis (vaccine 17 [0·6%]; placebo 17 [0·6%]). Pentavalent rotavirus vaccine is effective against severe rotavirus gastroenteritis in the first 2 years of life in African countries with high mortality in infants younger than 5 years. We support WHO's recommendation for adoption of rotavirus vaccine into national expanded programmes on immunisation in Africa. PATH (GAVI Alliance grant) and Merck.