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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 . . .

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], . . .

► 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.

Abstract Background Lewis and secretor histo–blood group antigens (HBGAs) have been associated with decreased susceptibility to P[8] genotype rotavirus (RV) infections. Efficacy of vaccines containing attenuated P[8] strains is decreased in low-income countries. Host phenotype might impact vaccine efficacy (VE) by altering susceptibility to vaccination or RV diarrhea (RVD). We performed a substudy in a monovalent RV vaccine (RV1) efficacy trial in Bangladesh to determine the impact of Lewis and secretor status on risk of RVD and VE. Methods In infants randomized to receive RV1 or no RV1 at 10 and 17 weeks with 1 year of complete active diarrheal surveillance, we performed Lewis and secretor phenotyping and genotyped the infecting strain of each episode of RVD. Results A vaccine containing P[8] RV protected secretors and nonsecretors similarly. However, unvaccinated nonsecretors had a reduced risk of RVD (relative risk, 0.53 [95% confidence interval, .36–.79]) mediated by complete protection from P[4] but not P[8] RVs. This effect reduced VE in nonsecretors to 31.7%, compared to 56.2% among secretors, and decreased VE for the overall cohort. Conclusions Host HBGA status may impact VE estimates by altering susceptibility to RV in unvaccinated children; future trials should therefore account for HBGA status. Clinical Trials Registration NCT01375647. Histo–blood group antigens were associated with genotype-specific susceptibility to rotavirus infections. Nonsecretors were at decreased risk of P[4] infections, while Lewis-negative children were at increased risk of P[6] infections. These effects may impact oral rotavirus vaccine efficacy estimates.

•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.

Peak incidence of rotavirus gastroenteritis is seen in infants between 6 and 24 months of age. We therefore aimed to assess the 2-year efficacy and safety of an oral live attenuated human rotavirus vaccine for prevention of severe gastroenteritis in infants. 15 183 healthy infants aged 6–13 weeks from ten Latin American countries randomly assigned in a 1 to 1 ratio to receive two oral doses of RIX4414 or placebo at about 2 and 4 months of age in a double-blind, placebo-controlled phase III study were followed up until about 2 years of age. Primary endpoint was vaccine efficacy from 2 weeks after dose two until 1 year of age. Treatment allocation was concealed from investigators and parents of participating infants. Efficacy follow-up for gastroenteritis episodes was undertaken from 2 weeks after dose two until about 2 years of age. Analysis was according to protocol. This study is registered with ClinicalTrials.gov, number NCT00140673 (eTrack444563–023). 897 infants were excluded from the according-to-protocol analysis. Fewer cases (p<0·0001) of severe rotavirus gastroenteritis were recorded for the combined 2-year period in the RIX4414 group (32 [0·4%] of 7205; 95% CI 0·3–0·6) than in the placebo group (161 [2·3%] of 7081; 1·9–2·6), resulting in a vaccine efficacy of 80·5% (71·3–87·1) to 82·1% (64·6–91·9) against wild-type G1, 77·5% (64·7–86·2) against pooled non-G1 strains, and 80·5% (67·9–88·8) against pooled non-G1 P[8] strains. Vaccine efficacy for hospital admission for rotavirus gastroenteritis was 83·0% (73·1–89·7) and for admission for diarrhoea of any cause was 39·3% (29·1–48·1). No cases of intussusception were reported during the second year of follow-up. Two doses of RIX4414 were effective against severe rotavirus gastroenteritis during the first 2 years of life in a Latin American setting. Inclusion of RIX4414 in routine paediatric immunisations should reduce the burden of rotavirus gastroenteritis worldwide. GlaxoSmithKline.

► 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]).

Rotavirus gastroenteritis (RVGE) is a leading cause of death in African children. The efficacy of pentavalent rotavirus vaccine (PRV) against severe RVGE evaluated in Ghana, Kenya, and Mali in a randomized, double-blind, placebo-controlled trial, showed a combined regional efficacy of 39.3% (95% confidence interval [CI]: 19.1,54.7) in nearly 2 years of follow-up. This report concentrates on the Kenya findings. Infants received 3 doses of PRV/placebo at approximately 6-, 10-, and 14-weeks of age. HIV testing was offered to all participants. Data on illness symptoms and signs were collected upon presentation to healthcare facilities, where stools were collected, and analyzed by rotavirus-specific enzyme-linked immunosorbent assay. The primary endpoint was severe RVGE (Vesikari score≥11), occurring ≥14 days following the third dose. At monthly home visits, symptoms of illnesses during the past 2 weeks were solicited and limited physical exams were performed; dehydration was defined by WHO's Integrated Management of Childhood Illness. Vaccine efficacy (VE) against severe RVGE through nearly 2 years of follow-up among 1308 Kenyan children was 63.9% (95% CI: −5.9,89.8). Through the first year of life, VE against severe RVGE was 83.4% (95% CI: 25.5,98.2). From home visits, VE against all-cause gastroenteritis with severe dehydration was 34.4% (95% CI: 5.3,54.6) through the first year and 29.7% (95% CI: 2.5,49.3) through the entire follow-up period. The reduction in incidence of gastroenteritis with severe dehydration in the community during the first year of life (19.0 cases/100 person-years) was almost six times greater than the reduction in severe RVGE presenting to the clinic (3.3/100 person-years). Oral rehydration solution use was lower among PRV recipients (VE 23.1%, 95% CI: 8.8,35.1). An estimated 41% of gastroenteritis with severe dehydration in the first year reported at home was rotavirus-related. PRV significantly reduced severe RVGE in Kenya. The impact of PRV might be greatest in rural Africa in protecting the many children who develop severe gastroenteritis and cannot access health facilities.

► The immunogenicity of the pentavalent rotavirus vaccine (PRV) was studied in a sub-cohort of a Phase III efficacy clinical trial conducted in Bangladesh and Vietnam. ► Three oral doses of PRV were immunogenic, with a ≥3-fold increase of serum IgA responses shown in 88% of the subjects in two GAVI-eligible Asian countries. ► Both the serum anti-rotavirus IgA and serum neutralizing antibody responses were higher among infants in Vietnam than in Bangladesh, similar to the pattern illustrated in the efficacy estimates between these two countries. ► While the immunogenicity results among Vietnamese children were comparable to those in Latin America and Europe, the immune responses among Bangladeshi children resemble more those in impoverished populations in Africa. We evaluated the immunogenicity of the pentavalent rotavirus vaccine (PRV) in two GAVI-eligible Asian countries, Bangladesh and Vietnam, nested in a larger randomized, double-blind, placebo-controlled efficacy trial conducted over a two-year period from 2007 through 2009. 2036 infants were randomly assigned, in a 1:1 ratio, to receive three oral doses of PRV or placebo approximately at 6, 10, and 14 weeks of age. Concomitant use of EPI vaccines, including oral poliovirus vaccine (OPV) and diphtheria-tetanus-whole cell pertussis (DTwP) vaccine, was encouraged in accordance to the local EPI schedule. A total of 303 infants were evaluated for immunogenicity and blood samples were collected before the first dose (pD1) and approximately 14 days following the third dose (PD3). The seroresponse rates (≥3-fold rise from pD1 to PD3) and geometric mean titers (GMTs) were measured for anti-rotavirus immunoglobulin A (IgA) and serum neutralizing antibody (SNA) to human rotavirus serotypes G1, G2, G3, G4, and P1A[8], respectively. Nearly 88% of the subjects showed a ≥3-fold increase in serum anti-rotavirus IgA response in the analysis of the two countries combined. When analyzed separately, the IgA response was lower in Bangladeshi children (78.1% [95% CI: 66.0, 87.5]) than in Vietnamese children (97.0% [95% CI: 89.6, 99.6]), with a PD3 GMT of 29.1 (units/mL) and 158.5 (units/mL), respectively. In the combined population, the SNA responses to the individual serotypes tested ranged from 10 (G3) to 50 (G1) percentage points lower than the responses shown in the developed countries. However, the SNA response to G3 in Vietnamese subjects was 37.3% (95% CI: 25.8, 50.0), which was similar to the G3 response rate in developed countries. Three oral doses of PRV were immunogenic in two GAVI-eligible Asian countries: Bangladesh and Vietnam. The GMTs of both the serum anti-rotavirus IgA and SNA responses were generally higher in Vietnamese than in Bangladeshi children. The SNA responses varied by individual serotypes and were lower than the results from developed countries. The clinical significance of these observations is not understood because an immune correlate of protection has not been established.

•BRV-TV manufactured in India, was non-reactogenic, safe and immunogenic.•Choice of antigen is important for immunogenicity assays.•Human and bovine rotavirus antigens resulted in different IgA estimates in the same samples. A single dose of live attenuated tetravalent (G1–G4) bovine human reassortant rotavirus vaccine (BRV-TV) was administered to healthy Indian adult volunteers, who were assessed for safety and immunogenicity of the vaccine with 3:1 randomization to vaccine or placebo. All 20 adult male volunteers in the study had rotavirus specific serum IgA at baseline. There were no side effects or adverse events reported. Administration of BRV-TV was not associated with fever, diarrhea, or altered liver transaminases. Rotavirus IgA seroconversion post single dose administration was 27%. This study shows that BRV-TV is non-reactogenic, safe and immunogenic in adults. The IgA units estimated for the same sample using human G1P[8] rotavirus strain as the antigen were consistently higher than with the bovine G6P[5] WC3 strain and the human G2P[4] DS-1 strain antigen. The use of different human and bovine rotavirus strains as antigens in a quantitative rotavirus specific serum IgA assay resulted in different estimations of IgA antibody in the same sample.