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•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]).

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.

We sought datasets with granular age distributions of rotavirus-positive disease presentations among children <5 years of age, before the introduction of rotavirus vaccines. We identified 117 datasets and fit parametric age distributions to each country dataset and mortality stratum. We calculated the median age and the cumulative proportion of rotavirus gastroenteritis events expected to occur at ages between birth and 5.0 years. The median age of rotavirus-positive hospital admissions was 38 weeks (interquartile range [IQR], 25–58 weeks) in countries with very high child mortality and 65 weeks (IQR, 40–107 weeks) in countries with very low or low child mortality. In countries with very high child mortality, 69% of rotavirus-positive admissions in children <5 years of age were in the first year of life, with 3% by 10 weeks, 8% by 15 weeks, and 27% by 26 weeks. This information is critical for assessing the potential benefits of alternative rotavirus vaccination schedules in different countries and for monitoring program impact.

•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.

A randomized, double-blind, placebo-controlled multicenter trial was conducted in healthy Chinese infants to assess the efficacy, immunogenicity and safety of a novel trivalent live human-lamb reassortant rotavirus vaccine (LLR3) against rotavirus gastroenteritis (RVGE). Healthy children aged 6–13 weeks were enrolled and randomized (1:1) to either 3 oral doses of LLR3 or placebo according to a 0, 1, 2 month schedule. The objectives were to evaluate vaccine efficacy (VE) against RVGE of any-severity, severe RVGE (sRVGE) and inpatient caused by rotavirus serotypes contained in the vaccine and not contained in the vaccine after the third dose. Immunogenicity was also assayed in a subgroup. All adverse events (AEs) were collected from 30 min after each dose for immediate reaction, even to the entire study period, including the serious AEs (SAEs) and intussusception. VE against RVGE of any-severity, sRVGE and inpatient caused by any serotype was 56.6% (95% CI: 50.7, 61.8), 70.3% (95% CI: 60.6, 77.6) and 74.0% (95% CI: 57.5, 84.1) respectively. VE against RVGE of any-severity, sRVGE caused by serotypes not contained in vaccine were 54.2% (95% CI: 47.5, 60.1) and 70.4% (95% CI: 60.4, 77.9). The rate of seroconversion and four-fold increase of rotavirus serotype G2-, G3-, and G4-specific IgA is 60.8%, 58.0%, and 60.6% in vaccine group, which was higher than 21.35%, 22.7%, and 23.1% in placebo group (p < 0.0001 for G2, G3, G4), as well as the Geometric Mean Titer (GMT). Through the entire trial, 65.91% and 67.79% of participants reported at least one AE, and 0.02% and 0.02% reported SAEs in the vaccine and placebo groups, respectively. Two intussusception cases were reported both in vaccine and placebo group. In Chinese infants, LLR3 provided a substantial protection against RVGE of any-severity, sRVGE and inpatient caused by any serotype, and showed well immunogenicity and safety.

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.

A phase III, randomized, double-blind study evaluated the efficacy, reactogenicity, safety and immunogenicity of a human rotavirus vaccine, RIX4414 in Japanese infants aged 6–14 weeks when administered as two doses (0, 1-month schedule). Efficacy against any and severe rotavirus gastroenteritis leading to medical intervention caused by circulating wild-type rotavirus from two weeks post-Dose 2 until two years of age was 79.3% (95% CI: 60.5–89.8%) and 91.6% (95% CI: 62.4–99.1%), respectively. Solicited, unsolicited symptoms and serious adverse events were reported at a similar frequency in both groups. Serum anti-rotavirus antibody seroconversion rate one-month post-Dose 2 was 85.3% (95% CI: 68.9–95%) in RIXX4414 group. RIX4414 was efficacious, well-tolerated and immunogenic in Japanese infants and introduction of vaccination could help in reducing the disease burden.

Multinational rotavirus vaccines (Rotarix and RotaTeq) are 43 %–65 % effective in preventing hospitalizations due to rotavirus disease in African countries. The Rotasiil vaccine (Serum Institute of India) offers a potentially cost-effective option but lacks vaccine effectiveness (VE) estimates in African settings. We estimated Rotasiil VE against rotavirus hospitalizations in the Democratic Republic of Congo (DRC) using unconditional multivariate logistic regression and inverse probability of treatment weighting (IPTW) to adjust confounding. We examined sentinel surveillance data from two hospitals in Kinshasa (January 1, 2020 to December 31, 2023) for children aged ≤59 months who sought care for acute diarrhea. We used a test-negative case-control design and calculated VE as [1 – adjusted odds ratio (OR) × 100] using unconditional multivariate logistic regression. We compared two approaches to adjust the OR for confounding. First, the OR was adjusted by including the covariates in the model. Second, the OR was adjusted using stabilized IPTW. In total, 310 children aged 6 to 30 months were included in the full rotavirus vaccine dose analysis, of which 118 (38 %) were rotavirus positive. The median age was 10 months (range: 8–14), and the proportion of fully vaccinated children was 87 %. The VE measured between fully vaccinated versus unvaccinated children was 60 % (95 % CI: 20–80) by multivariate logistic regression and 79 % (95 % CI: 71–85) by IPTW. Rotasiil vaccination under conditions of routine use effectively reduces rotavirus-associated diarrhea hospitalizations among children, supporting the ongoing use of rotavirus vaccine. The IPTW VE estimate was more precise than multivariate logistic regression but the confidence intervals overlapped, suggesting that the resulting VE estimates are not statistically different and the methods are complementary.

Since August 2009, the Democratic Republic of Congo (DRC) has implemented sentinel site surveillance for rotavirus gastroenteritis. Limited hospital studies have been carried out, in DRC, describing the epidemiology of rotavirus diarrhea before rotavirus vaccine introduction in October 2019. This analysis describes the epidemiology of rotavirus gastroenteritis and characteristics of circulating viral strains from 2009 to 2019. We analyzed demographic and clinic data collected from children < 5 years old enrolled at three rotavirus sentinel surveillance sites in DRC during 2009–2019, prior to rotavirus vaccine introduction in 2019. Data have been described and presented as mean ± standard deviation for quantitative variables with normal distribution, or as median with an interquartile range [Q1-Q3] for quantitative variables with non-normal distribution, or as absolute value with percentage for qualitative variables. Between August 2009 and December 2019, 4,928 children < 5 years old were admitted to sentinel surveillance sites for gastroenteritis in the DRC; the rotavirus positivity rate was 60 %. There was a slight male gender predominance (56 %), and the majority of children (79 %) were 0–11 months of age. Every year, the incidence was highest between May and September corresponding to the dry and cool season. Genotyping was performed for 50 % of confirmed rotavirus cases. The most common G genotypes were G1 (39 %) and G2 (24 %) and most common P genotypes were P[6] (49 %) and P[8] (37 %). The most common G-P genotype combinations were G1P[8] (22 %), G2P[6] (16 %) and G1P[6] (14 %). Genotype distribution varied by site, age group, and year. From 2009 to 2019, rotavirus-associated gastroenteritis represented a significant burden among DRC children under 5 who were admitted to sentinel sites. G1P[8] was the most commonly identified genotype. Continued monitoring after the introduction of rotavirus vaccine will be essential to monitor any changes in epidemiology.

Introduction Afghanistan added ROTARIX to the routine national immunization programme in 2018. We aimed to estimate the cost-effectiveness and benefit-risk of ROTARIX and compare its continued use with other rotavirus vaccines that could be used in the future. Methods We used a static cohort model with a finely disaggregated age structure (weeks of age < 5 years) to assess the use of ROTARIX (1-dose vial) over a seven-year period (2018–2024) in Afghanistan. The primary outcome measure was the discounted cost (2022 US$) per Disability Adjusted Life Year (DALY) averted (from government and societal perspectives) compared to no vaccination. We also calculated the benefit-risk ratio i.e., the number of RVGE deaths prevented per one excess intussusception death. Model inputs were informed by pre- and post-licensure surveillance data, new analyses of household survey data, and updated estimates from the international literature. We ran a separate analysis to compare the potential cost-effectiveness and benefit-risk of ROTARIX (1-dose vial), ROTASIIL (1-dose vial), ROTASIIL (2-dose vial), and ROTAVAC (5-dose vial) over a ten-year period (2025–2034). Each product was compared to no rotavirus vaccination and each other. We ran deterministic and probabilistic uncertainty analyses and interpreted our results over a range of cost-effectiveness thresholds. Findings We estimated that routine use of ROTARIX between 2018 and 2024 has prevented 4,600 RVGE deaths (a 41% reduction), 86,400 hospital admissions, and 1.72 million RVGE cases. For every 1,493 RVGE deaths prevented by the vaccine, we estimated one potential excess intussusception death. With a heavily reduced vaccine dose cost (due to support from Gavi) the net cost to the Afghanistan government vaccine programme was estimated to be US$ 4.4 million per year. The cost per DALY averted was US$ 125 (0.25 times the national GDP per capita) when using a Gavi-subsidised vaccine cost and including household costs averted by vaccination. This increased to US$ 471 (0.94 times the national GDP per capita) when incorporating the full vaccine price without Gavi’s subsidy and excluding household costs averted by vaccination. When assuming continued Gavi support over the period 2025–2034, the dominant product would be ROTARIX. Without Gavi support, ROTASIIL (2-dose vial) dominates. Conclusion Our study supports the sustained use of rotavirus vaccination in Afghanistan. The health benefits of the vaccine greatly exceed the potential risks.