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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 . . .

•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]).

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.

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.

We conducted a phase I, randomized, double-blind, placebo-controlled trial including healthy adults in Sui County, Henan Province, China. Ninety-six adults were randomly assigned to one of three groups (high-dose, medium-dose, and low-dose) at a 3:1 ratio to receive one vaccine dose or placebo. Adverse events up to 28 days after each dose and serious adverse events up to 6 months after all doses were reported. Geometric mean titers and seroconversion rates were measured for anti-rotavirus neutralizing antibodies using microneutralization tests. The rates of total adverse events in the placebo group, low-dose group, medium-dose group, and high-dose group were 29.17 % (12.62 %–51.09 %), 12.50 % (2.66 %–32.36 %), 50.00 % (29.12 %–70.88 %), and 41.67 % (22.11 %–63.36 %), respectively, with no significant difference in the experimental groups compared with the placebo group. The results of the neutralizing antibody assay showed that in the adult group, the neutralizing antibody geometric mean titer at 28 days after full immunization in the low-dose group was 583.01 (95 % confidence interval [CI]: 447.12–760.20), that in the medium-dose group was 899.34 (95 % CI: 601.73–1344.14), and that in the high-dose group was 1055.24 (95 % CI: 876.28–1270.75). The GMT of serum-specific IgG at 28 days after full immunization in the low-dose group was 3444.26 (95 % CI: 2292.35–5175.02), that in the medium-dose group was 6888.55 (95 % CI: 4426.67–10719.6), and that in the high-dose group was 7511.99 (95 % CI: 3988.27–14149.0). The GMT of serum-specific IgA at 28 days after full immunization in the low-dose group was 2332.14 (95 % CI: 1538.82–3534.45), that in the medium-dose group was 4800.98 (95 % CI: 2986.64–7717.50), and that in the high-dose group was 3204.30 (95 % CI: 2175.66–4719.27). In terms of safety, adverse events were mainly Grades 1 and 2, indicating that the safety of the vaccine is within the acceptable range in the healthy adult population. Considering the GMT and positive transfer rate of neutralizing antibodies for the main immunogenicity endpoints in the experimental groups, it was initially observed that the high-dose group had higher levels of neutralizing antibodies than the medium- and low-dose groups in adults aged 18–49 years. This novel inactivated rotavirus vaccine was generally well-tolerated in adults, and the vaccine was immunogenic in adults (ClinicalTrials.gov number, NCT04626856).

In this randomized trial, the clinical efficacy of an oral, live pentavalent human–bovine reassortant vaccine was estimated to be 98.0 percent against severe gastroenteritis due to rotavirus. In the safety study, which included 68,038 infants, the rates of intussusception were similar in the vaccine and placebo groups (relative risk, 0.8; 95 percent confidence interval, 0.3 to 1.8). In this randomized trial, the clinical efficacy of an oral, live pentavalent human–bovine reassortant vaccine was estimated to be 98.0 percent against severe gastroenteritis due to rotavirus. Rotavirus is the leading cause of hospitalization and death from acute gastroenteritis among infants and young children worldwide. More than 2 million hospitalizations and nearly half a million deaths are attributed to this infection annually. 1 , 2 The strategy of preventing rotavirus through vaccination derives from studies demonstrating that wild-type rotavirus infection induces immunity against subsequent rotavirus gastroenteritis. 3 – 6 Primary rotavirus infection provides substantial protection against gastroenteritis caused by the same serotype and against severe disease regardless of serotype. The four most prevalent serotypes, which account for more than 80 percent of cases of human rotavirus disease worldwide, are G1P[8], G2P[4], . . .

•A randomized, double-blind, placebo-controlled trial was conducted in healthy Chinese infants.•Efficacy and safety of a pentavalent rotavirus vaccine (RV5) were assessed.•Efficacy against rotavirus gastroenteritis of any-severity caused by any serotype was 69.3%.•Efficacy against severe rotavirus gastroenteritis caused by any serotype was 78.9%.•RV5 was efficacious and generally well-tolerated in Chinese infants. A randomized, double-blind, placebo-controlled multicenter trial was conducted in healthy Chinese infants to assess the efficacy and safety of a pentavalent live human-bovine reassortant rotavirus vaccine (RotaTeq™, RV5) against rotavirus gastroenteritis (RVGE). 4040 participants aged 6–12weeks were enrolled and randomly assigned to either 3 oral doses of RV5 (n=2020) or placebo (n=2020), administered ∼4weeks apart. The participants also received OPV and DTaP in a concomitant or staggered fashion. The primary objective was to evaluate vaccine efficacy (VE) against naturally-occurring RVGE at least 14days following the third dose. Key secondary objectives included: VE against naturally-occurring severe RVGE and VE against severe and any-severity RVGE caused by rotavirus serotypes contained in the vaccine, occurring at least 14days after the third dose. All adverse events (AEs) were collected for 30days following each dose. Serious AEs (SAEs) and intussusception cases were collected during the entire study. (ClinicalTrials.gov registry: NCT02062385). VE against RVGE of any-severity caused by any serotype was 69.3% (95% CI: 54.5, 79.7). The secondary efficacy analysis showed an efficacy of: 78.9% (95% CI: 59.1, 90.1) against severe RVGE caused by any serotype; 69.9% (95% CI: 55.2, 80.3) and 78.9% (95% CI: 59.1, 90.1) against any-severity and severe RVGE caused by serotypes contained in the vaccine, respectively. Within 30days following any vaccination, 53.5% (1079/2015) and 53.3% (1077/2019) of participants reported at least one AE, and 5.8% (116/2015) and 5.7% (116/2019) reported SAEs in the vaccine and placebo groups, respectively. No SAEs were considered vaccine-related in recipients of RV5. Two intussusception cases were reported in recipients of RV5 who recovered after receiving treatment. Neither was considered vaccine-related. In Chinese infants, RV5 was efficacious against any-severity and severe RVGE caused by any serotype and generally well-tolerated with respect to AEs.

While live oral rotavirus vaccines (LORVs) are effective at preventing severe rotavirus gastroenteritis (SRVGE), they perform sub-optimally in the settings with the highest burden. Parenteral rotavirus vaccines could have greater efficacy by bypassing the gut, where interference with LORVs may occur. A novel parenteral rotavirus subunit vaccine (TV P2-VP8) was evaluated in a Phase 3 study for safety, immunogenicity, and relative efficacy in healthy African infants. Participating infants were randomized at 6–8 weeks of age to receive either three doses of TV P2-VP8 intramuscularly (IM) plus oral placebo or two doses of ROTARIX® (oral) plus IM placebo. The trial was designed to enroll a total of 8200 participants in two stages separated by an interim analysis conducted upon accrual of a predetermined number of SRVGE cases. Data at interim analysis indicated a low probability of demonstrating TV P2-VP8 superiority compared to ROTARIX in prevention of SRVGE, and the study was closed early. 4055 infants were enrolled and provided safety data. TV P2-VP8 was safe and well tolerated, with no safety concerns indicated. Virus neutralizing and IgG binding antibody seroresponses to TV-P2-VP8 were detected in most participants. The crude attack rates of SRVGE in the per-protocol population (n = 3477) were 4.51 % (TV P2-VP8) and 2.57 % (ROTARIX). The relative vaccine efficacy (RVE) against SRVGE for TV P2-VP8 was −77.68 % (95 % CI, −162.38, −21.54). The RVE against SRVGE in the first and second year of life was −91.67 % (95 % CI, −199.20, −24.35) and − 31.97 % (95 % CI, −220.37, 44.49), respectively. The RVE against rotavirus gastroenteritis of any severity was −47.78 % (95 % CI, −89.63, −15.59). TV P2-VP8 provided inferior protection against SRVGE compared to ROTARIX. The vaccine candidate was safe, immunogenic, and well-tolerated by infants. Continued efforts are needed to identify alternative rotavirus vaccines with improved efficacy in LMICs. Trial Registration:NCT04010448; PACTR201907491834482. •The TV P2-VP8 vaccine candidate was safe and immunogenic.•Three doses of TV P2-VP8 were inferior to two doses of ROTARIX® in preventing severe rotavirus gastroenteritis.•Study provides insight to guide future development of rotavirus vaccine candidates.

Background. Rotavirus (RV) is the leading cause of diarrhea-related death in children worldwide and 95% of RV-associated deaths occur in Africa and Asia where RV vaccines (RVVs) have lower efficacy. We hypothesize that differences in intestinal microbiome composition correlate with the decreased RVV efficacy observed in poor settings. Methods. We conducted a nested, case-control study comparing prevaccination, fecal microbiome compositions between 6-week old, matched RVV responders and nonresponders in rural Ghana. These infants' microbiomes were then compared with 154 age-matched, healthy Dutch infants' microbiomes, assumed to be RVV responders. Fecal microbiome analysis was performed in all groups using the Human Intestinal Tract Chip. Results. We analyzed findings in 78 Ghanaian infants, including 39 RVV responder and nonresponder pairs. The overall microbiome composition was significantly different between RVV responders and nonresponders (FDR, 0.12), and Ghanaian responders were more similar to Dutch infants than nonresponders (P = .002). RVV response correlated with an increased abundance of Streptococcus bovis and a decreased abundance of the Bacteroidetes phylum in comparisons between both Ghanaian RVV responders and nonresponders (FDR, 0.008 vs 0.003) and Dutch infants and Ghanaian nonresponders (FDR, 0.002 vs 0.009). Conclusions. The intestinal microbiome composition correlates significantly with RVV immunogenicity and may contribute to the diminished RVV immunogenicity observed in developing countries.

A monovalent, parenteral, subunit rotavirus vaccine was well tolerated and immunogenic in adults in the USA and in toddlers and infants in South Africa, but elicited poor responses against heterotypic rotavirus strains. We aimed to evaluate safety and immunogenicity of a trivalent vaccine formulation (P2-VP8-P[4],[6],[8]). A double-blind, randomised, placebo-controlled, dose-escalation, phase 1/2 study was done at three South African research sites. Healthy adults (aged 18–45 years), toddlers (aged 2–3 years), and infants (aged 6–8 weeks, ≥37 weeks' gestation, and without previous receipt of rotavirus vaccination), all without HIV infection, were eligible for enrolment. In the dose-escalation phase, adults and toddlers were randomly assigned in blocks (block size of five) to receive 30 μg or 90 μg of vaccine, or placebo, and infants were randomly assigned in blocks (block size of four) to receive 15 μg, 30 μg, or 90 μg of vaccine, or placebo. In the expanded phase, infants were randomly assigned in a 1:1:1:1 ratio to receive 15 μg, 30 μg, or 90 μg of vaccine, or placebo, in block sizes of four. Participants, parents of participants, and clinical, data, and laboratory staff were masked to treatment assignment. Adults received an intramuscular injection of vaccine or placebo in the deltoid muscle on the day of randomisation (day 0), day 28, and day 56; toddlers received a single injection of vaccine or placebo in the anterolateral thigh on day 0. Infants in both phases received an injection of vaccine or placebo in the anterolateral thigh on days 0, 28, and 56, at approximately 6, 10, and 14 weeks of age. Primary safety endpoints were local and systemic reactions (grade 2 or worse) within 7 days and adverse events and serious adverse events within 28 days after each injection in all participants who received at least one injection. Primary immunogenicity endpoints were analysed in infants in either phase who received all planned injections, had blood samples analysed at the relevant timepoints, and presented no major protocol violations considered to have an effect on the immunogenicity results of the study, and included serum anti-P2-VP8 IgA, IgG, and neutralising antibody geometric mean titres and responses measured 4 weeks after the final injection in vaccine compared with placebo groups. This trial is registered with ClinicalTrials.gov, NCT02646891. Between Feb 15, 2016, and Dec 22, 2017, 30 adults (12 each in the 30 μg and 90 μg groups and six in the placebo group), 30 toddlers (12 each in the 30 μg and 90 μg groups and six in the placebo group), and 557 infants (139 in the 15 μg group, 140 in the 30 μg group, 139 in the 90 μg group, and 139 in the placebo group) were randomly assigned, received at least one dose, and were assessed for safety. There were no significant differences in local or systemic adverse events, or unsolicited adverse events, between vaccine and placebo groups. There were no serious adverse events within 28 days of injection in adults, whereas one serious adverse event occurred in a toddler (febrile convulsion in the 30 μg group) and 23 serious adverse events (four in placebo, ten in 15 μg, four in 30 μg, and five in 90 μg groups) occurred among 20 infants, most commonly respiratory tract infections. One death occurred in an infant within 28 days of injection due to pneumococcal meningitis. In 528 infants (130 in placebo, 132 in 15 μg, 132 in 30 μg, and 134 in 90 μg groups), adjusted anti-P2-VP8 IgG seroresponses (≥4-fold increase from baseline) to P[4], P[6], and P[8] antigens were significantly higher in the 15 μg, 30 μg, and 90 μg groups (99–100%) than in the placebo group (10–29%; p<0·0001). Although significantly higher than in placebo recipients (9–10%), anti-P2-VP8 IgA seroresponses (≥4-fold increase from baseline) to each individual antigen were modest (20–34%) across the 15 μg, 30 μg, and 90 μg groups. Adjusted neutralising antibody seroresponses in infants (≥2·7-fold increase from baseline) to DS-1 (P[4]), 1076 (P[6]), and Wa (P[8]) were higher in vaccine recipients than in placebo recipients: p<0·0001 for all comparisons. The trivalent P2-VP8 vaccine was well tolerated, with promising anti-P2-VP8 IgG and neutralising antibody responses across the three vaccine P types. Our findings support advancing the vaccine to efficacy testing. Bill & Melinda Gates Foundation.