Safety and efficacy of high-dose rhesus-human reassortant rotavirus vaccines--report of the National Multicenter Trial. United States Rotavirus Vaccine Efficacy Group. Efficacy and safety of high-dose rhesus-human reassortant rotavirus vaccine in Native American populations. Randomised placebo-controlled trial of rhesus-human reassortant rotavirus vaccine for prevention of severe rotavirus gastroenteritis. Immunogenicity and safety of rhesus-human rotavirus reassortant vaccines with serotype 1 or 2 VP7 specificity. Immunogenicity, safety and protective efficacy of one dose of the rhesus rotavirus vaccine and serotype 1 and 2 human-rhesus rotavirus reassortants in children from Lima, Peru. Immunogenicity, safety and efficacy of tetravalent rhesus-human, reassortant rotavirus vaccine in Belém, Brazil. Evaluation of safety, immunogenicity and efficacy of an attenuated rotavirus vaccine, RIX4414: A randomized, placebo-controlled trial in Latin American infants. Efficacy of RIX4414 live attenuated human rotavirus vaccine in Finnish infants. Protective efficacy against serotype 1 rotavirus diarrhea by live oral rhesus-human reassortant rotavirus vaccines with human rotavirus VP7 serotype 1 or 2 specificity. Comparison of immunogenicity and efficacy of rhesus rotavirus reassortant vaccines in breastfed and nonbreastfed children. US Rotavirus Vaccine Efficacy Group. Evaluation of rhesus rotavirus monovalent and tetravalent reassortant vaccines in US children. US Rotavirus Vaccine Efficacy Group. Field trial of rhesus rotavirus or human-rhesus rotavirus reassortant vaccine of VP7 serotype 3 or 1 specificity in infants. The Elmwood, Panorama, and Westfall Pediatric Groups. Effects of the potency and composition of the multivalent human-bovine (WC3) reassortant rotavirus vaccine on efficacy, safety and immunogenicity in healthy infants. Efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and young children in Venezuela. Safety and immunogenicity of tetravalent rhesus-based rotavirus vaccine in Bangladesh. Safety, efficacy, and immunogenicity of a live, quadrivalent human-bovine reassortant rotavirus vaccine in healthy infants. Reactions to and antigenicity of two human-rhesus rotavirus reassortant vaccine candidates of serotypes 1 and 2 in Venezuelan infants. Rhesus Rotavirus candidate vaccine. Clinical trial in children vaccinated between 2 and 5 months of age. Safety, immunogenicity, and protective efficacy of one and three doses of the tetravalent rhesus rotavirus vaccine in infants in Lima, Peru. Comparative evaluation of reactogenicity and immunogenicity of two dosages of oral tetravalent rhesus rotavirus vaccine. US Rhesus Rotavirus Vaccine Study Group. Evaluation of RIX4414, a live, attenuated rotavirus vaccine, in a randomized, double-blind, placebo-controlled phase 2 trial involving 2464 Singaporean infants. Evaluation of the protective efficacy of a serotype 1 bovine-human rotavirus reassortant vaccine in infants. Clinical efficacy of the RIT 4237 live attenuated bovine rotavirus vaccine in infants vaccinated before a rotavirus epidemic. Prospective study of diarrheal diseases in Venezuelan children to evaluate the efficacy of rhesus rotavirus vaccine. A field study of the safety and efficacy of two candidate rotavirus vaccines in a Native American population. A comparative trial of rhesus monkey (RRV-1) and bovine (RIT 4237) oral rotavirus vaccines in young children. An efficacy trial of the rhesus rotavirus vaccine in Maryland. The Clinical Study Group. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. Protection of infants against rotavirus diarrhoea by RIT 4237 attenuated bovine rotavirus strain vaccine. Efficacy and immunogenicity of two or three dose rotavirus-vaccine regimen in South African children over two consecutive rotavirus-seasons: a randomized, double-blind, placebo-controlled trial. Concurrent administration of rhesus rotavirus tetravalent (RRV-TV) vaccine with pentavalent diphtheria-pertussis-tetanus-Haemophilus influenzae beta-inactivated polio and hepatitis B vaccines. Field trial of rhesus rotavirus vaccine in infants. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. Safety and immunogenicity of live attenuated human-bovine (UK) reassortant rotavirus vaccines with VP7-specificity for serotypes 1, 2, 3 or 4 in adults, children and infants. Clinical studies of a quadrivalent rotavirus vaccine in Venezuelan infants. Immune protection of infants against rotavirus gastroenteritis by a serotype 1 reassortant of bovine rotavirus WC3. Efficacy, immunogenicity, and safety of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine at the end of shelf life. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial. Effect of human rotavirus vaccine on severe diarrhea in African infants. Safety, immunogenicity and efficacy in healthy infants of G1 and G2 human reassortant rotavirus vaccine in a new stabilizer/buffer liquid formulation. Comparative evaluation of safety and immunogenicity of two dosages of an oral live attenuated human rotavirus vaccine. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial. Reactogenicity and immunogenicity of a high-titer rhesus rotavirus-based quadrivalent rotavirus vaccine. Neonatal rotavirus vaccination with RIT 4237 bovine rotavirus vaccine: a preliminary report. Efficacy of live, attenuated, human rotavirus vaccine 89-12 in infants: a randomised placebo-controlled trial. Reactogenicity and antigenicity of rhesus rotavirus vaccine (MMU-18006) in newborn infants in Venezuela. A comparative evaluation of the safety and immunogenicity of a single dose of unbuffered oral rhesus rotavirus serotype 3, rhesus/human reassortant serotypes 1, 2 and 4 and combined (tetravalent) vaccines in healthy infants. Horizontal transmission of a human rotavirus vaccine strain--a randomized, placebo-controlled study in twins. Secondary efficacy endpoints of the pentavalent rotavirus vaccine against gastroenteritis in sub-Saharan Africa. Efficacy of human rotavirus vaccine against severe gastroenteritis in Malawian children in the first two years of life: a randomized, double-blind, placebo controlled trial. Evaluation of the antigenicity and reactogenicity of varying formulations of the rhesus rotavirus-based quadrivalent and the M37 rotavirus vaccine candidates. Efficacy of pentavalent rotavirus vaccine in a high HIV prevalence population in Kenya. Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study. Efficacy of the oral pentavalent rotavirus vaccine in Mali. Evaluation of rhesus rotavirus vaccine (MMU 18006) in infants and young children. Safety and efficacy of human rotavirus vaccine during the first 2 years of life in Asian infants: randomised, double-blind, controlled study. Comparison of reactogenicity and antigenicity of M37 rotavirus vaccine and rhesus-rotavirus-based quadrivalent vaccine. Protection of Peruvian children against rotavirus diarrhea of specific serotypes by one, two, or three doses of the RIT 4237 attenuated bovine rotavirus vaccine. Immunogenicity of tetravalent rhesus rotavirus vaccine administered with buffer and oral polio vaccine. Efficacy of two doses of RIT 4237 bovine rotavirus vaccine for prevention of rotavirus diarrhoea.
Rotavirus is a leading cause of morbidity and mortality from dehydrating gastroenteritis in infants and young children worldwide. Virtually every child is infected by age 4 years, justifying universal childhood immunization when a safe and effective vaccine is available. We report the results of a multicenter, placebo-controlled field trial in the United States of monovalent serotype 1 and tetravalent (TV) rhesus-human reassortant rotavirus vaccines (RRVs).
                In this randomized, double-blind trial, 1278 healthy infants ages 5 to 25 weeks received three oral doses of RRV serotype 1, RRV-TV, or a placebo at approximately 2, 4, and 6 months of age. Vaccines contained 4 x 10(5) plaque-forming units of virus. Gastroenteritis episodes were monitored, and severity was graded throughout one rotavirus season. Two stool specimens per episode were tested for rotavirus.
                The incidence of reactions did not differ among treatment groups during the 5-day, postvaccination safety surveillance period for any of the three doses. Both vaccines significantly reduced the incidence of rotavirus gastroenteritis. Vaccination was most protective against serious rotavirus illness; RRV-TV prevented 49% of rotavirus episodes, 80% of very severe episodes, and 100% of dehydrating rotavirus illness. Reduction of rotavirus disease by RRV-TV resulted in significantly fewer total episodes of gastroenteritis of all causes and an 82% reduction in all cases of dehydrating diarrhea.
                RRV-TV is highly protective against very severe, dehydrating rotavirus gastroenteritis. We compared the efficacy, safety, and immunogenicity of a rhesus rotavirus tetravalent vaccine (RRV-TV), a rhesus rotavirus monovalent (serotype 1) vaccine (RRV-S1), and placebo in healthy American Indian infants for two rotavirus seasons.
                Infants aged 6 to 24 weeks were enrolled in a randomized, double-blind efficacy study. Infants were orally administered RRV-TV (4 x 10(5) plaque-forming units per dose), RRV-S1 (4 x 10(5) plaque-forming units per dose), or placebo at 2, 4, and 6 months of age. Stools collected during episodes of gastroenteritis were tested for detection of rotavirus antigen. A total of 1185 infants received at least one dose of a study vaccine or placebo, and 1051 received all three doses according to the protocol.
                During the first year of surveillance, the estimates of vaccine efficacy (with 95% confidence interval) for preventing rotaviral gastroenteritis were 50% (26, 67) for RRV-TV and 29% (-1, 50) for RRV-S1. In this population only 6% of rotaviral gastroenteritis episodes among placebo recipients were associated with type G1 disease. For severe disease the estimates of vaccine efficacy were higher: 69% (29, 88) for RRV-TV and 48% (-4, 75) for RRV-S1.
                These data indicate that RRV-TV is moderately efficacious in preventing all episodes of gastroenteritis caused by rotavirus and is most efficacious against the severe disease characteristic of rotaviral illness. Rotavirus is the most common cause of acute childhood gastroenteritis. Vaccination with live oral heterologous rotavirus vaccines may prevent rotavirus gastroenteritis. We assessed the efficacy of rhesus-human reassortant rotavirus tetravalent vaccine (RRV-TV) against severe rotavirus gastroenteritis in Finnish children in a randomised placebo-controlled double-blind trial.
                Placebo or RRV-TV (titre 4x10(5) plaque-forming units) was given to infants at ages 2, 3, and 5 months. The children were followed up for one or two rotavirus epidemic seasons. The main outcome measure was protection against severe rotavirus gastroenteritis (score > or =11 on a 20-point severity scale). 2398 children were enrolled and received at least one dose of RRV-TV (n=1191) or placebo (n=1207). The primary efficacy analysis was based on children who received three doses of RRV-TV (n=1128) or placebo (n=1145).
                256 episodes of rotavirus gastroenteritis occurred at any time during the study; 65 were among 1191 RRV-TV recipients, and 191 among 1207 placebo recipients (vaccine efficacy 66% [95% CI 55-74]; intention-to-treat analysis). 226 episodes were included in the primary efficacy analysis of fully vaccinated children (54 among 1128 RRV-TV recipients, 172 among 1145 placebo recipients; vaccine efficacy 68% [57-76]). 100 episodes were severe, eight in RRV-TV recipients and 92 in placebo recipients (vaccine efficacy 91% [82-96]).
                RRV-TV vaccine was highly effective against severe rotavirus gastroenteritis in young children. Incorporation of this vaccine into routine immunisation schedules of infants could reduce severe rotavirus gastroenteritis by 90% and severe gastroenteritis of all causes in young children by 60%. Rhesus-human rotavirus reassortants incorporating the gene expressing the VP7 surface protein of human rotavirus serotypes 1 or 2, and the remaining ten genes from rhesus rotavirus (RRV) were evaluated as candidate oral vaccines in 2-4-month-old infants. A single dose of the serotype 1 reassortant vaccine which had a titre of 10(4) plaque-forming units (p.f.u.) induced a fourfold or greater antibody response in 81% of the recipients by a combination of ELISA and neutralization assays; 51% of the vaccinees developed a neutralizing antibody response to the vaccine strain. A single dose of the serotype 2 vaccine (10(4) p.f.u.) induced a seroresponse in all vaccinees by the combination of assays whereas 67% developed neutralizing antibodies to the vaccine strain. A combination of these two vaccines (0.5 x 10(4) p.f.u. of each) induced an overall seroresponse in 95% of the recipients but only 48% and 24% response in neutralizing antibodies to serotypes 1 and 2, respectively. A trivalent combination which included the two reassortants and RRV (0.33 x 10(4) p.f.u. of each strain) induced an overall response in 82% of the vaccinees, but only 30%, 20% and 65% developed a neutralizing antibody response to serotype 1, serotype 2, and RRV, respectively. Febrile reactions on days 2-5 after vaccination were seen in 23-45% of the infants receiving the various vaccines and combinations and in 5% of the placebo group. It is concluded that rhesus-human reassortant rotaviruses may be combined with each other and with RRV as a polyvalent vaccine, but the VP7-specific neutralizing antibody responses are likely to be lower after combined vaccination than following vaccination with a single reassortant rotavirus. In a four cell trial, a single 10(4) plaque-forming unit dose of rhesus rotavirus (RRV) vaccine (serotype G3), a human rotavirus-rhesus rotavirus reassortant vaccine with serotype G1 specificity, a similar vaccine with serotype G2 specificity, or a placebo was administered with buffer orally at 2 months of age to 800 Peruvian infants. Only the RRV vaccine was associated with a febrile response (< 38 degrees C) that occurred in 9% of the infants on day 4 after vaccination. Diarrhea or other side-effects were not associated with administration of vaccine. Vaccine strains were shed by only 12-18% of the infants as determined by examination of a single stool specimen obtained on days 4 or 5 after vaccination. Fifty per cent of vaccines developed an IgA ELISA seroresponse; however, a serotype-specific seroresponse by plaque reduction neutralization was demonstrated in < 20% of the participants against each of the three candidate vaccine strains. Vaccine efficacy was evaluated by twice-weekly home surveillance for diarrheal diseases during 24 months post-immunization. Rotavirus diarrheal episodes were identified by ELISA. Only the RRV vaccine had a significant protective efficacy (29%, p = 0.03, chi-square test) against rotavirus diarrhea. Analysis of vaccine efficacy against rotavirus episodes of any severity in which no other enteropathogen was isolated showed a trend towards higher vaccine efficacy. In addition, a similar trend was observed in rotavirus-only episodes in which there was some degree of dehydration or when health services were utilized. Serotype G1 or G2 rotavirus strains were most prevalent during surveillance. Neither serotype G1 or serotype G2 vaccines were protective against serotype 1 or 2 rotavirus diarrhea, respectively. The serotype G2 vaccine was 84% protective against serotype 1 and 2 dehydrating rotavirus diarrhea in the small numbers of individuals evaluated. We conclude that one dose of 10(4) p.f.u. of the RRV, serotype G1, or serotype G2 rotavirus vaccine failed to induce either an adequate serotype-specific seroresponse or serotype-specific protection in children immunized at 2 months of age. Only the RRV vaccine induced a low level of protection against rotavirus diarrhea mainly of serotype G1 specificity. Future studies need to explore whether higher vaccine dose and/or more than one dose would increase the immunogenicity and efficacy of the rotavirus vaccine, especially in developing countries with a high level of baseline rotavirus antibodies. A tetravalent rhesus-human reassortant rotavirus (RRV-TV) vaccine (4 x 10(4) plaque-forming units/dose) was evaluated for safety, immunogenicity and efficacy in a prospective, randomized, double-blind, placebo-controlled trial involving 540 Brazilian infants. Doses of vaccine or placebo were given at ages 1, 3 and 5 months. No significant differences were noted in the occurrence of diarrhoea or vomiting in vaccine and placebo recipients following each dose. Low-grade fever occurred on days 3-5 in 2-3% of vaccinees after the first dose, but not after the second or third doses of vaccine. An IgA antibody response to rhesus rotavirus (RRV) occurred in 58% of vaccinees and 33% of placebo recipients. Neutralizing antibody responses to individual serotypes did not exceed 20% when measured by fluorescent focus reduction, but exceeded 40% when assayed by plaque reduction neutralization. There were 91 cases of rotavirus diarrhoea among the 3-dose (vaccine or placebo) recipients during two years of follow-up, 36 of them among children given the vaccine. Overall vaccine efficacy was 8% (P = 0.005) against any diarrhoea and 35% (P = 0.03) against any rotavirus diarrhoea. Protection during the first year of follow-up, when G serotype 1 rotavirus predominated, was 57% (P = 0.008), but fell to 12% in the second year. Similar results were obtained when analysis was restricted to episodes in which rotavirus was the only identified pathogen. There was a tendency for enhanced protection by vaccine against illness associated with an average of 6 or more stools per day. These results are sufficiently encouraging to warrant further studies of this vaccine in developing countries using a higher dosage in an attempt to improve its immunogenicity and efficacy. A live attenuated monovalent rotavirus vaccine RIX4414 was developed with a human strain of G1P1A P[8] specificity to reduce the rotavirus burden in children.
                A double blind, randomized, placebo-controlled study evaluated the efficacy, immunogenicity, safety and reactogenicity of 2 oral doses of RIX4414 (10(4.7), 10(5.2) or 10(5.8) focus-forming units) at 2 and 4 months coadministered with routine vaccinations and oral poliovirus vaccine given for study purposes at least 14 days apart. The 2155 infants (1618 vaccine/537 placebo) enrolled in Brazil, Mexico and Venezuela were followed until 1 year of age.
                Antirotavirus IgA seroconversion rates 2 months after dose 2 ranged between 61% (10(4.7) ffu group) and 65% (10(5.8) ffu group), and most of the infants had seroprotective levels of antibodies to coadministered routine vaccinations. The reactogenicity profile of RIX4414 was similar to that of the placebo, and no vaccination-related serious adverse events were reported. Protective efficacy against severe and any rotavirus gastroenteritis from 15 days post-dose 2 was highest in the 10(5.8) ffu group [86%; 95% confidence interval (95% CI), 63-96% and 70% (95% CI 46-84%), P < 0.001, 2-sided Fisher's exact test]. The efficacy against hospitalization was 79% (95% CI 48-92%) for pooled vaccine groups. Multiple rotavirus serotypes [G1 (50%), G9 (40%), G2, G3 and G4] were identified from gastroenteritis stools (enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction) during the study period. For severe gastroenteritis caused by G9 serotypes, the protection reached 77% (95% CI 18-96%) in the 10(5.8) ffu group, providing proof of concept that the monovalent G1P1A P[8] human rotavirus vaccine elicits cross-protection against the G9 strain. A reduction in any and severe rotavirus gastroenteritis was already observed at post-dose 1 (period: day of dose 1 to 14 days post-dose 2) in vaccinees compared with placebo recipients.
                Two doses of RIX4414 are highly efficacious, providing cross-protection (G1 and G9 strains, prevalent during this study) and early protection against any and severe rotavirus gastroenteritis and hospitalization to infants in Latin America. Rotavirus gastroenteritis, a major cause of mortality and morbidity worldwide, is a vaccine-preventable disease. New safe and effective candidate rotavirus vaccines are needed to replace the withdrawn rhesus rotavirus-based oral vaccine.
                We evaluated a monovalent human rotavirus vaccine, serotype G1, strain RIX4414, for efficacy, immunogenicity and safety in a randomized, double blind, placebo-controlled trial in Finland. We randomly allocated 405 healthy infants to receive 2 doses of vaccine or placebo (ratio 2:1) at approximately 2 and 4 months of age. The infants were followed during 2 rotavirus epidemic seasons (2000-2002) for acute gastroenteritis. Rotaviruses in diarrheal stool samples were primarily detected by enzyme-linked immunosorbent assay and confirmed and G-typed by reverse transciption-polymerase chain reaction.
                The vaccine was well-tolerated. No vaccine-related serious adverse events were observed during the study period. Rotavirus IgA (enzyme-linked immunosorbent assay) seroconversion rate was 80% after 2 doses. Thirty-eight cases of rotavirus gastroenteritis were detected during the entire follow-up period; 35 of these were of the G1 type. RIX4414 vaccine significantly decreased the occurrence of any rotavirus compared with placebo. Efficacy during the first rotavirus epidemic season was 73% [95% confidence interval (95% CI), 27-91%] and 90% (95% CI 10-100%) against any and severe rotavirus gastroenteritis, respectively, and during the entire follow-up period 72% (95% CI 42-87%) against any and 85% (95% CI 42-97%) against severe rotavirus gastroenteritis (P < 0.05 for all comparisons).
                RIX4414 strain of G1 human rotavirus vaccine was well-tolerated, immunogenic and efficacious in infants against rotavirus gastroenteritis during a 2-year period. To further increase vaccine "take" and efficacy, a higher dose of this vaccine may be considered for future efficacy trials. Rhesus-human rotavirus (RV) reassortant vaccine strains D x RRV or DS 1 x RRV with VP7 serotype 1 or 2 specificity were evaluated for safety, immunogenicity and protective efficacy in a double blind placebo-controlled three cell trial involving 359 infants ages 2 to 5 months. The titer of the D x RRV vaccine was 10(4) and that of the DS 1 x RRV vaccine was 10(5) plaque-forming units/1-ml dose. The vaccines were acceptably reactogenic, each inducing a transient febrile response in fewer than one-third of the vaccinees. Seroconversion by RV enzyme-linked immunosorbent assay IgA antibody was detected in 61 and 75% of the vaccinees receiving a single dose of the serotype 1 or 2 reassortant vaccine, respectively. Efficacy against RV diarrhea was evaluated in two successive epidemic seasons; RV serotype 1 was prevalent in both. Clinical efficacy was observed with both vaccines and was associated with seroconversion after vaccination; considering only such vaccinees both vaccines showed equal efficacy. The overall rates of protection for the two vaccines combined against clinical RV disease in children with seroconversion after vaccination were 92 and 59% in the first and second RV epidemic seasons, respectively. Protection against asymptomatic RV infection, as measured by serologic responses, was 59% in the first season and nil in the second season. It is concluded that each of the reassortant RV vaccines was effective in inducing protection against symptomatic RV disease associated with RV serotype 1. To evaluate whether breastfeeding affected the immunogenicity and/or efficacy of candidate rhesus-human rotavirus reassortant vaccines.
                A total of 989 healthy infants between 4 and 26 weeks of age were enrolled into a 23-center, prospective, randomized, double-masked, controlled study of the safety, immunogenicity, and efficacy of three doses (4 x 10(4) plaque-forming units) of monovalent rhesus-human viral protein 7, or G, serotype 1 reassortant vaccine, (RRV-S1) or tetravalent vaccine (RRV-TV) consisting of rhesus-human reassortant G serotypes 1, 2, and 4, and the parent RRV G serotype 3. Vaccine efficacy was compared in the breastfed and nonbreastfed children as well as seroconversion rates and postvaccination geometric mean titers (GMTs) of neutralizing antibodies to human serotypes 1, 2, 3, and 4, RRV, and immunoglobulin A to RRV. GMTs in the two feeding groups were compared with and without adjustment for age at initiation of vaccination, prevaccination antibody titers, and the age and prevaccination titer interaction.
                The seroconversion rates to both vaccines by one or more assays were similar for the breastfed and the nonbreastfed groups (RRV-S1, 84% and 85%, respectively; RRV-TV, 94% and 93%, respectively). There were no significant differences in postvaccination GMTs to either vaccine, measured by any serologic assay, in the two feeding groups. The efficacy of the RRV-S1 vaccine was not significantly lower among the breastfed children than the nonbreastfed children (28% and 39%, respectively). RRV-TV, which is the vaccine being further evaluated for licensure, was equally protective in breastfed and nonbreastfed infants (50% and 51%, respectively). Logistic regression analysis, taking into account differences in age at vaccination and day 1 titer, revealed no evidence of differential vaccine efficacy in the two feeding groups for either vaccine.
                These results indicate that the RRV-TV vaccine, given as three doses of 4 x 10(4) plaque-forming units, induces similar seroresponses and protection in breastfed and nonbreastfed US children. To determine the safety and relative efficacy of two reassortant rhesus rotavirus vaccines over two rotavirus seasons.
                A prospective, double-masked, placebo-controlled trial.
                Twenty-three centers in the United States.
                A total of 1006 healthy infants between 4 and 26 weeks of age were enrolled, and 898 received three doses of vaccine or placebo.
                Reactogenicity was determined by comparing the incidence of fever, diarrhea, and/or vomiting for 5 days after each dose of vaccine. Rotavirus IgA and neutralizing antibody to rhesus rotavirus and four rotavirus serotypes were measured in a subset of subjects. Relative efficacy was determined by comparing the incidence of rotavirus gastroenteritis after three doses of vaccine or placebo over two rotavirus seasons.
                Adverse reactions were mild and limited to a small but significant increase in the incidence of fever after the first dose of tetravalent but not monovalent vaccine. The relative efficacy against rotavirus disease over the 2 years of observation was 40% (98.3% confidence interval, 7% to 62%) for the monovalent and 57% (98.3% confidence interval, 29% to 74%) for the tetravalent vaccine. In post hoc analyses, the relative efficacy against very severe rotavirus gastroenteritis was 73% and 82% for monovalent and tetravalent vaccine recipients, respectively. Also, a 67% and 78% reduction in medical visits for rotavirus gastroenteritis was observed. Both vaccines protected against disease caused by serotype 1 rotavirus, but only the tetravalent vaccine reduced the incidence of disease caused by non-serotype 1 rotavirus infection detected in the second season. It is unclear, however, whether this result represents serotype-specific protection or a difference in the duration of protection.
                Vaccination with both vaccines was safe and significantly reduced the incidence of rotavirus gastroenteritis, but only the tetravalent vaccine provided protection against disease caused by non-serotype 1 rotaviruses during the second year of follow-up. Orally administered live rhesus monkey rotavirus vaccine (RRV, VP7 serotype 3) and human-rhesus reassortant rotavirus vaccine (DxRRV, VP7 serotype 1) were evaluated in a placebo-controlled field trial of 223 infants 2-4 months old. Both vaccines were mildly reactogenic but were generally well tolerated in the 10 days after vaccination. RRV and DxRRV were immunogenic, inducing serum antibody responses in 78% and 71% of the vaccines, respectively. Efficacy of RRV vaccine was 66% (P = .01) and of DxRRV vaccine 77% (P = .002) against rotavirus-associated illness in the first season after vaccination. Efficacy of RRV vaccine against rotavirus-associated illness over three rotavirus seasons was 51.2% (P = .045) and of DxRRV vaccine was 67.3% (P = .006). RRV vaccine provided heterotypic protection of 58.5% (P = .041) and DxRRV vaccine provided homotypic protection of 72.8% (P = .005) over three seasons against the predominant serotype 1 rotavirus. Rotavirus gastroenteritis, which causes substantial infant mortality and morbidity worldwide, is a vaccine-preventable disease. The purpose of this study was to evaluate different compositions and potencies (vaccine virus titers) of a live multivalent human-bovine (WC3) reassortant rotavirus vaccine in order to select the potency and composition of the vaccine for further development.
                The efficacy, safety, and immunogenicity of a G1, G2, G3, G4, and P1A pentavalent composition at three different potencies, a G1, G2, G3, G4 quadrivalent composition, and a P1A monovalent composition of an oral human-bovine (WC3) reassortant rotavirus vaccine were compared in a blinded, placebo-controlled trial conducted between 1998 and 2001 enrolling 1,946 healthy Finnish infants 2-8 months of age.
                All potencies of the pentavalent and quadrivalent vaccines were efficacious (58-74%) against wild-type rotavirus gastroenteritis of any severity and 100% protective against severe rotavirus disease caused by vaccine G-serotypes through the first rotavirus season post-vaccination. The monovalent P1A vaccine was 53% efficacious against moderate-and-severe rotavirus gastroenteritis. Protection against rotavirus gastroenteritis of any severity was demonstrated through two and three rotavirus seasons for all vaccine compositions. After the third dose, the percentage of infants with >or=3-fold rise in baseline serum neutralizing antibody titers against G1 ranged from 62% to 86% for recipients of the pentavalent vaccine, depending on the potency. The incidence of fever, irritability, vomiting, and diarrhea did not significantly differ between vaccine and placebo groups. A 7-month-old male developed intussusception 9 days after the first dose of the low-potency pentavalent vaccine.
                Based on the results of this trial, a pentavalent composition (G1, G2, G3, G4, and P1A) of human-bovine (WC3) reassortant rotavirus vaccine with a potency similar to that of the middle-potency pentavalent vaccine ( approximately 8 x 10(6) plaque-forming units/dose) was selected for further development. Rotaviruses are the principal known etiologic agents of severe diarrhea among infants and young children worldwide. Although a rhesus rotavirus-based quadrivalent vaccine is highly effective in preventing severe diarrhea in developed countries, in developing countries its efficacy has been less impressive. We thus conducted a catchment study in Venezuela to assess the efficacy of the vaccine against dehydrating diarrhea.
                In this randomized, double-blind, placebo-controlled trial, 2207 infants received three oral doses of the quadrivalent rotavirus vaccine (4x10(5) plaque-forming units per dose) or placebo at about two, three, and four months of age. During approximately 19 to 20 months of passive surveillance, episodes of gastroenteritis were evaluated at the hospital.
                The vaccine was safe, although 15 percent of the vaccinated infants had febrile episodes (rectal temperature, > or =38.1 degrees C) during the six days after the first dose, as compared with 7 percent of the controls (P<0.001). However, the vaccine gave 88 percent protection against severe diarrhea caused by rotavirus and 75 percent protection against dehydration, and produced a 70 percent reduction in hospital admissions. Overall, the efficacy of the vaccine against a first episode of rotavirus diarrhea was 48 percent. Horizontal transmission of vaccine virus was demonstrated in 15 percent of the vaccine recipients and 13 percent of the placebo recipients with rotavirus-positive diarrhea.
                In this study in a developing country, the quadrivalent rhesus rotavirus-based vaccine induced a high level of protection against severe diarrheal illness caused by rotavirus. Rotavirus is the most common cause of severe gastroenteritis among children worldwide.
                To compare the safety, immunogenicity and shedding patterns of rhesus rotavirus (RRV)-tetravalent vaccine vs. placebo among infants in rural Bangladesh.
                A double blinded, placebo-controlled trial was conducted in which infants (n = 120) were randomly assigned to receive three doses of either vaccine or placebo administered at approximately 6, 10 and 14 weeks of age together with routine immunizations. Data on possible adverse effects of vaccinations were collected daily for 7 days after each dose. Stool samples were collected after each dose, and serum samples were obtained before the first and after the third vaccination.
                Fever (> or = 38 degrees C), as measured by study assistants, was noted more frequently among vaccinees (15%) than among placebo recipients (2%) during the 7 days after vaccination but was not reported more frequently by parents of vaccinees vs. placebo recipients. Overall 87% of vaccinees had an antibody response (measured by IgA or anti-RRV-neutralizing antibodies) after vaccination compared with 32% of placebo recipients. Rates of seroconversion were higher among subjects with lower levels of prevaccination antibodies and those who shed rotavirus after vaccination. Vaccine strain viruses were detected in stools from placebo vaccine recipients who had evidence of IgA seroconversion.
                In this population RRV-tetravalent vaccine was comparably immunogenic and safe as in trials conducted in developed countries, where this vaccine has been proved effective in preventing severe rotavirus diarrhea. These data support continued evaluation of rotavirus vaccines in developing countries. To investigate safety, efficacy, and immunogenicity of live quadrivalent rotavirus vaccine (QRV) containing human-bovine (WC3) reassortant rotavirus serotypes G1, G2, G3, and P1a.
                This was a randomized, double-blinded, placebo-controlled trial. During 1993 to 1994, at 10 US study sites, 439 healthy infants approximately 2 to 6 months of age, were enrolled to receive 3 doses of oral QRV or placebo at approximately 8-week intervals.
                The vaccine was generally well tolerated; no serious vaccine-related adverse experiences were reported. Risk differences and 95% confidence intervals suggested no differences between vaccine and placebo recipients in the incidences of fever, irritability, vomiting, or diarrhea during the 14 days after any dose. QRV was 74.6% efficacious (95% CI: 49.5%, 88.3%) in preventing rotavirus acute gastroenteritis (AGE), regardless of severity and 100% efficacious (95% CI: 43.5%, 100%) in preventing severe rotavirus AGE through one rotavirus season. Serotype G1 was identified in most infants with rotavirus AGE. A >or=3-fold rise in serum neutralizing antibody to G1 was observed in 57% (45/79) of vaccinees. A >or=3-fold rise in serum anti-rotavirus IgA and fecal anti-rotavirus IgA was observed in 88% (162/185) and 65% (104/159) of vaccinees, respectively.
                QRV was generally well tolerated, immungenic, and highly effective against rotavirus gastroenteritis. The reactions to and antigenicity of two human-rhesus rotavirus (RRV) reassortants (human rotavirus strain D x RRV and human rotavirus strain DS1 x RRV) with the VP7 neutralization specificity of a serotype 1 or serotype 2 rotavirus were evaluated in a placebo-controlled double-blind trial in 116 1- to 5-month-old infants in Caracas, Venezuela. The children were randomly divided into five groups to receive orally the following inocula: (i) 10(4) PFU of D x RRV reassortant; (ii) 10(4) PFU of DS1 x RRV reassortant; (iii) 10(4) PFU of RRV; (iv) 5 x 10(3) PFU of D x RRV and 5 x 10(3) PFU of RRV; and (v) placebo. The children were examined daily for 7 days following vaccine administration; 8 to 26% of the vaccinated infants developed a mild febrile reaction which in most cases lasted only 1 day. Seroresponses to rotavirus were observed in 39 to 65% of the vaccinees by plaque neutralization assay and in 57 to 88% by an immunoglobulin A enzyme-linked immunosorbent assay. Vaccine shedding was detected in 53 to 86% of the vaccinees. Analysis of neutralization antibody responses indicates that the VP4 protein represents an important component of the response induced by the vaccines. Live attenuated oral rhesus Rotavirus candidate vaccine (strain MMU 18006 [lot RRV-1]) was evaluated for immunogenicity, safety, and clinical protection in a double-blind, placebo-controlled trial involving 200 infants aged 2 to 5 months when vaccinated. Vaccine-induced fourfold or greater rise of Rotavirus antibodies was seen in 62% of the infants. Febrile reactions of short duration on days 3 and/or 4 after vaccination occurred in 26% of the vaccine recipients. The clinical follow-up covered two Rotavirus seasons, in which serotypes 1 and 4 were prevalent. There were 16 cases of confirmed Rotavirus diarrhea in the placebo-treated group and 10 in the vaccine-treated group; from this a vaccine protection rate of 38% was derived. Clinical severity of Rotavirus diarrhea was assessed by a score; 13 cases in the placebo-treated group and 5 in the vaccine-treated group were regarded as severe or moderately severe, giving a vaccine protection rate of 67%. The rhesus Rotavirus vaccine induces partial protection against heterotypic Rotavirus disease, but the level of protection achieved with the present vaccine dose in this age group appears to be insufficient for a general Rotavirus vaccination. An oral rhesus-human rotavirus tetravalent (RRV-TV) vaccine (10(4) pfu of rhesus rotavirus [type G3] and of 3 human-rhesus reassortants [G1, G2, and G4]) was evaluated in a field trial in Lima, Peru. At 2, 3, and 4 months of age, infants received either a dose of RRV-TV, an initial dose of vaccine followed by a dose of placebo at 3 and 4 months, or a dose of placebo. Rotavirus-specific IgA responses were detected by ELISA in 75% of the three-dose vaccine group, 59% of the one-dose vaccine group (P = .05), and 24% of the placebo group (P < .001): 64%, 48%, and 12% of each group, respectively, had a neutralizing antibody response to at least 1 serotype. Both one and three doses of vaccine failed to induce a significant level of protection against rotavirus diarrhea; however, they did provide some protection (range, 35%-66%) against more severe rotavirus diarrhea, especially for episodes caused by type G1. To compare the safety and immunogenicity of two dosages of tetravalent rhesus rotavirus vaccine (RRV-TV) and the effect of age at dosing.
                A total of 195 infants were stratified by age into 2 groups, 6 to 12 weeks and 16 to 24 weeks, and randomly assigned to receive a single dose of placebo or RRV-TV containing either 4 x 10(5) or 4 x 10(6) plaque-forming units (pfu). Symptoms were recorded for 5 days after vaccination. Anti-rotavirus IgA and neutralizing antibody to human rotavirus serotypes G1 to G4 and RRV were measured in serum obtained pre- and postvaccination.
                Rates of fever > 38 degrees C (9%), diarrhea (6%) and vomiting (8%) were similar in all groups. IgA (69% vs. 49%, P = 0.02) and RRV (85% vs. 66%, P = 0.004) seroconversion rates were significantly higher in the 4 x 10(6) pfu vaccine group as were antibody titers to RRV (440.2 vs. 263.7, P = 0.04). Older infants demonstrated significantly higher seroconversion rates and antibody titers for IgA (71% vs. 52%, P = 0.03; and 110.6 vs. 54.8, P = 0.004) and RRV (92% vs. 66%, P = 0.05 and 498.3 vs. 205.6, P = 0.01) at either dose level than did the younger infants. There were no significant differences in seroconversion rates or antibody titers to human rotavirus types G1 to G4 between the two vaccination groups.
                RRV-TV at a dose of 4 x 10(6) pfu can be safely administered to infants 6 to 24 weeks of age. A single dose of 4 x 10(6) pfu of RRV-TV was significantly more immunogenic than a single dose of 4 x 10(5) pfu but did not improve responses to the human serotypes. Older vaccine recipients demonstrated significantly higher IgA and neutralizing antibody seroconversion rates and antibody titers than younger infants independent of dosage. At present, no rotavirus vaccine is commercially available for use worldwide. Hence, a live, attenuated monovalent vaccine was developed with human strain RIX4414 (G1P1A P[8] specificity). Vaccination trials involving infants are ongoing in developed and developing countries.
                This study was a randomized, double-blind, placebo-controlled trial conducted at pediatric hospitals and polyclinics in Singapore for the evaluation of the immunogenicity, reactogenicity, and efficacy of 2 oral doses of RIX4414. In total, 2464 healthy infants (who were 11-17 weeks old when the first dose was administered, which is in accordance with the local immunization schedule) were enrolled to receive RIX4414 at 3 concentrations of virus (10(4.7), 10(5.2), or 10(6.1) focus-forming units) or placebo at 1-month intervals, concomitantly with routinely administered infant vaccines.
                The RIX4414 vaccine was highly immunogenic, and virtually all vaccine recipients (98%-100%) experienced "vaccine take" (i.e., a combined immunogenicity end point based on seroconversion and/or shedding of RIX4414 in postvaccination stool samples) after receipt of 2 doses at all 3 dosage levels. Depending on the virus concentration, the anti-rotavirus IgA seroconversion rate varied from 76% (95% confidence interval [CI], 68%-83%) to 91% (95% CI, 85%-95%). Two doses of RIX4414 were well tolerated, with no increase in high fever, severe diarrhea, or vomiting after either dose or with increased viral concentration, compared with placebo. There was no observed interference with routine vaccinations of infants when RIX4414 was coadministered. The calculated efficacy of RIX4414 against rotavirus gastroenteritis was 82% (P = .046); however, this result was considered to be of limited conclusive value because of the low number of rotavirus gastroenteritis episodes identified during the follow-up period.
                The live, attenuated rotavirus vaccine (RIX4414) was well tolerated and highly immunogenic in Singaporean infants. The immunogenicity of routinely administered infant vaccines was not impaired by concomitant administration of RIX4414 vaccine. The objective of this study was to evaluate the efficacy of a live, attenuated bovine (strain WC3) x human (strain WI79, serotype G1) rotavirus reassortant (WI79-9) virus vaccine for prevention of symptomatic rotavirus gastroenteritis in infants. The study was a prospective, randomized, double-blind, placebo-controlled trial, conducted over a single rotavirus season in 325 infants who were 2 to 8 months old at enrollment. Subjects were randomized to receive either placebo or WI79-9 virus vaccine at 10(7.3) plaque-forming units in three oral doses each separated by 2 months. Subjects were followed for 7 days after each dose for occurrence of adverse events and during the subsequent winter for development of rotavirus gastroenteritis. Administration of WI79-9 virus vaccine was well-tolerated, and the rates of low grade fever after each dose were no higher in vaccine recipients (8 to 21%) than in placebo recipients (14 to 19%). The protective efficacy of the WI79-9 vaccine during a subsequent epidemic of predominantly serotype G1 rotavirus was 87.0% (95% confidence limits, 62.6 to 95.5%) against relatively severe rotavirus gastroenteritis (rotavirus gastroenteritis with a clinical severity score of > 8) and was 64.1% (95% confidence limits 35.9 to 79.9%) against all symptomatic rotavirus episodes. The WI79-9 vaccine was safe and effective in prevention of homotypic human rotavirus infection in infants. Further studies of reassortant vaccines based on the bovine WC3 rotavirus should be performed. In a randomized, double-blind, placebo-controlled trial, 331 infants aged 6 to 12 months received orally, at an interval of 1 month, either two doses of live attenuated bovine rotavirus vaccine strain RIT 4237 or equivalent placebo. The vaccinations were carried out during September to November, a non-rotavirus season; only three cases of rotavirus diarrhea occurred in the study group before the vaccinations were completed. During the epidemic season from December to May, 31 patients with clinically significant rotavirus diarrhea required therapy. Five of these were among the 168 vaccine recipients, and 26 among the 160 placebo recipients (P less than 0.001), giving a vaccine protection rate of 82%. The incidence of clinically significant diarrhea from all causes was reduced by 76% in the vaccinees. As determined by an enzyme immunoassay antibody test with homologous virus antigen, seroconversion after vaccination was obtained in 53% of the initially seronegative infants. Clinical protection correlated well with seroconversion, but the vaccinees who failed to seroconvert also had less rotavirus diarrhea than the placebo recipients, suggesting that immunity may be mediated by factors other than serum EIA antibody. Seventeen of the 23 rotavirus isolates in the epidemic season that were typed were of serotype 1, two were of serotype 2, and four were of serotype 3. The protection rates against clinically significant diarrhea were 72%, 100%, and 100% for serotypes 1, 2, and 3, respectively. We conclude that epidemic infantile winter diarrhea associated with human rotaviruses can be significantly reduced by vaccination with the live attenuated RIT 4237 bovine rotavirus vaccine before the epidemic season. The efficacy of a rhesus rotavirus vaccine (MMU 18006, serotype 3) against infantile diarrhea was evaluated by active home surveillance of a group of 320 children 1-10 months of age in Caracas, Venezuela. During a 1 year period following oral administration of vaccine or placebo under a double-masked code, over 600 diarrheal episodes were detected. Etiologic studies revealed that heat-stable toxin (ST) producing enterotoxigenic E. coli (ETEC) was the most common diarrheal agent detected (34%) followed by enteropathogenic E. coli (EPEC, 10.9%), heat-labile toxin (LT) producing ETEC (7.6%), rotavirus (6.9%), Cryptosporidium (4.8%) and Campylobacter (1.3%). ST-producing ETEC were also recovered from over 20% of control stool specimens obtained during diarrhea-free periods, whereas EPEC, rotavirus, Cryptosporidium, and Campylobacter were rarely detected in such control specimens. Rotavirus was responsible for about one-half of the more severe cases of diarrhea. Twenty-two of 151 infants who received placebo (14.6%) and eight of 151 receiving a 10(4) PFU dose of vaccine (5.3%) had rotavirus diarrhea during the follow-up period for an efficacy level of 64% against any rotavirus diarrhea. However, vaccine efficacy reached 90% against the more severe cases of rotavirus diarrhea and was noticeably high in the 1-4 month age group. Serotypic analysis of the rotaviruses detected suggests that the resistance induced by the vaccine was type specific since significant protection was only evident against serotype 3 rotaviruses. A 10(3) PFU dose tested initially in 18 children did not appear to protect against rotavirus diarrhea. A double-blind, randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of a rhesus rotavirus vaccine and RIT 4237, a bovine rotavirus vaccine, in a Navajo population. Infants aged 2-5 months were randomized to receive one dose of either 10(4) pfu of the rhesus rotavirus vaccine or 10(8) pfu of the RIT 4237 vaccine or placebo. Eleven (10.2%) of 108 infants in the rhesus vaccine group, 11 (10.4%) of 106 in the RIT 4237 group, and 9 (8.4%) of 107 in the placebo group experienced rotavirus diarrhea during the follow-up period of 17 months. Thus, in this population, neither vaccine was efficacious in preventing rotavirus diarrhea. Heterologous live, oral rotavirus vaccines of rhesus monkey (RRV-1) and bovine (RIT 4237) origin were tested for immunogenicity, excretion of virus, and clinical reactions in six- to eight-month-old infants. Antibody response, indicating infection with the vaccine virus, was detected in 21 (88%) of 24 children receiving the RRV-1 vaccine and in 18 (75%) of 24 receiving the RIT 4237 vaccine. Excretion of virus in the stools within one week after vaccination was demonstrable in 84% of the RRV-1 and in 21% of the RIT 4237 vaccinees. RRV-1 vaccination was associated with a febrile response (over 38 C) that clustered on days 3 or 4 postvaccination in 64% of the recipient children. In addition, 20% of the RRV-1 vaccinees had watery stools on days 4 or 5. Fever on days 3 and 4 and loose stools were not seen in the RIT 4237 vaccinees. We concluded that in young children the RRV-1 (rhesus monkey) rotavirus vaccine is more immunogenic than the RIT 4237 (bovine) rotavirus vaccine, but vaccination with RRV-1 is associated with significant adverse reactions. A double-blind, placebo-controlled trial of oral rhesus rotavirus vaccine at a dose of 10(4) plaque-forming units was performed in 114 young infants in Maryland. Significantly more vaccinees than controls had fever and vomiting during the week after vaccination, but these reactions were mild. Of the vaccinees, 83% had a fourfold or greater rise in neutralizing antibody to rhesus rotavirus vaccine and 69% shed vaccine virus. Seventeen percent of the vaccinees and 24% of controls had rotavirus-positive diarrhea during the 2 years of surveillance. Vaccine efficacy was therefore 29% (95% confidence limits, -31% to +66%). Stools from 12 of 13 episodes containing sufficient antigen to type were serotype 1. We conclude that rhesus rotavirus vaccine was infective, immunogenic, and probably acceptably attenuated but that this serotype 3 vaccine provided little heterotypic protection during serotype 1 outbreaks in the community. The safety and efficacy of an attenuated G1P[8] human rotavirus (HRV) vaccine were tested in a randomized, double-blind, phase 3 trial.
                We studied 63,225 healthy infants from 11 Latin American countries and Finland who received two oral doses of either the HRV vaccine (31,673 infants) or placebo (31,552 infants) at approximately two months and four months of age. Severe gastroenteritis episodes were identified by active surveillance. The severity of disease was graded with the use of the 20-point Vesikari scale. Vaccine efficacy was evaluated in a subgroup of 20,169 infants (10,159 vaccinees and 10,010 placebo recipients).
                The efficacy of the vaccine against severe rotavirus gastroenteritis and against rotavirus-associated hospitalization was 85 percent (P<0.001 for the comparison with placebo) and reached 100 percent against more severe rotavirus gastroenteritis. Hospitalization for diarrhea of any cause was reduced by 42 percent (95 percent confidence interval, 29 to 53 percent; P<0.001). During the 31-day window after each dose, six vaccine recipients and seven placebo recipients had definite intussusception (difference in risk, -0.32 per 10,000 infants; 95 percent confidence interval, -2.91 to 2.18; P=0.78).
                Two oral doses of the live attenuated G1P[8] HRV vaccine were highly efficacious in protecting infants against severe rotavirus gastroenteritis, significantly reduced the rate of severe gastroenteritis from any cause, and were not associated with an increased risk of intussusception. (ClinicalTrials.gov numbers, NCT00139347 and NCT00263666.)
                Copyright 2006 Massachusetts Medical Society. A randomised, double-blind, placebo-controlled trial was conducted to evaluate the ability of RIT 4237 live attenuated bovine rotavirus (subgroup 1) vaccine strain to protect against natural rotavirus infection in children. 178 infants aged 8 to 11 months received a single oral dose of RIT 4237 vaccine or placebo and were followed up serologically and clinically during a subgroup 2 rotavirus epidemic. No side-effects attributable to the vaccine were observed. During the 5 months' observation after vaccination 2 of the 86 vaccine recipients and 18 of 92 placebo recipients had rotavirus diarrhoea lasting more than 24 h (p less than 0.001). The vaccine-protection rate was thus 88%. The 2 children in the vaccine group with rotavirus diarrhoea were regarded as primary vaccine failures since they had no detectable serum antibody responses after vaccination. Vaccine prepared from RIT 4237 strain of attenuated bovine rotavirus thus seems to protect children against heterologous subgroup 2 rotavirus diarrhoea. 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 14 weeks; HRV_2D) or three (6, 10 and 14 weeks; 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 2 years 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.
                Copyright © 2011 Elsevier Ltd. All rights reserved. To investigate the incorporation of oral rhesus-human reassortant rotavirus tetravalent (RRV-TV) vaccine into a routine immunization programme, RRV-TV or oral placebo was coadministered with a pentavalent diphtheria-tetanus-whole-cell pertussis-Haemophilus influenzae b (Hib)-inactivated polio vaccine and hepatitis B vaccine following a 3-4-5-mo schedule in a double-blind trial involving 249 infants. Seroconversion rates after 3 doses of rotavirus vaccine were 80% for rotavirus immunoglobulin A (IgA) and 93% for RRV neutralizing antibodies. Rotavirus vaccine did not interfere with the immune responses to diphtheria, tetanus, pertussis, Hib, poliovirus 1, 2 and 3, or hepatitis B. Following the first, second and third doses of vaccine, fever >38 degrees C on the day of vaccination was seen in 31%, 24% and 24%, respectively, with no difference between RRV-TV- and placebo-vaccinated children. This fever was presumably due to the whole-cell pertussis vaccine. Those vaccinees who received concomitant RRV-TV vaccine had another peak of fever around d 4 after the first dose, when 25% of them had fever >38 degrees C and 3% >39 degrees C. It is concluded that RRV-TV rotavirus vaccine can be given concurrently with other childhood immunizations following a 3-4-5-mo vaccination schedule. However, febrile reactions to RRV-TV rotavirus vaccine are common when the first dose is given at the age of 3 mo. Orally administered rhesus rotavirus vaccine (RRV) was evaluated in a placebo-controlled study in 176 infants (ages 2 to 4 months). Eighty-eight infants received a dose of 10(4) plaque-forming units of the vaccine, and 88 received the placebo. RRV was well-tolerated but mildly reactogenic in the 10 days after vaccination. There were mild febrile reactions (greater than or equal to 38 degrees C rectally) in 40% of the vaccinees and in 16% of the placebo recipients (P = 0.001). More of the vaccinees had loose stools than did the placebo recipients (P less than 0.05). RRV was immunogenic and induced a 4-fold or greater rise in serum neutralizing antibody responses in 67% of the vaccinees; however, breast-fed infants were less likely to develop a seroresponse than infants who were not breast-fed. Despite the good immunogenicity of RRV the overall incidence of rotavirus-associated illnesses was similar between the vaccine and placebo recipients. The failure of RRV in Rochester may be related to the fact that the circulating rotaviruses were predominantly serotype 1 and RRV is a serotype 3 rotavirus. Because the serotypes of rotavirus that predominate may vary from year to year, a polyvalent preparation may be necessary to provide effective vaccination against rotaviruses. Rotavirus is a leading cause of childhood gastroenteritis and death worldwide.
                We studied healthy infants approximately 6 to 12 weeks old who were randomly assigned to receive three oral doses of live pentavalent human-bovine (WC3 strain) reassortant rotavirus vaccine containing human serotypes G1, G2, G3, G4, and P[8] or placebo at 4-to-10-week intervals in a blinded fashion. Active surveillance was used to identify subjects with serious adverse and other events.
                The 34,035 infants in the vaccine group and 34,003 in the placebo group were monitored for serious adverse events. Intussusception occurred in 12 vaccine recipients and 15 placebo recipients within one year after the first dose including six vaccine recipients and five placebo recipients within 42 days after any dose (relative risk, 1.6; 95 percent confidence interval, 0.4 to 6.4). The vaccine reduced hospitalizations and emergency department visits related to G1-G4 rotavirus gastroenteritis occurring 14 or more days after the third dose by 94.5 percent (95 percent confidence interval, 91.2 to 96.6 percent). In a nested substudy, efficacy against any G1-G4 rotavirus gastroenteritis through the first full rotavirus season after vaccination was 74.0 percent (95 percent confidence interval, 66.8 to 79.9 percent); efficacy against severe gastroenteritis was 98.0 percent (95 percent confidence interval, 88.3 to 100 percent). The vaccine reduced clinic visits for G1-G4 rotavirus gastroenteritis by 86.0 percent (95 percent confidence interval, 73.9 to 92.5 percent).
                This vaccine was efficacious in preventing rotavirus gastroenteritis, decreasing severe disease and health care contacts. The risk of intussusception was similar in vaccine and placebo recipients. (ClinicalTrials.gov number, NCT00090233.)
                Copyright 2006 Massachusetts Medical Society. Live rotavirus vaccine candidates representing VP7 serotypes 1, 2, 3 or 4 derived by reassortment between bovine UK rotavirus and human rotavirus strains D, DS-1, P or ST3 were evaluated for safety and immunogenicity in adults, children and infants. Infection was defined by evidence of rotavirus shed in stools or a 4-fold or greater increase in serum rotavirus-specific IgA or IgG ELISA or plaque reduction neutralization antibody. A single oral dose (10(5.3) or 10(5.8) pfu) of reassortant virus was well tolerated and infected most infants: 10/20 (50%) by D x UK; 9/11 (82%) by DS-1 x UK; 8/10 (80%) by P x UK and 13/14 (93%) by ST3 x UK. All 14 infants given two doses of D x UK were infected. These findings demonstrating satisfactory levels of attenuation, safety, infectivity and immunogenicity of each reassortant in infants warrant additional studies of a candidate vaccine containing these four strains. Phase I studies of an oral quadrivalent rotavirus vaccine were conducted in 130 Venezuelan infants 10 to 20 weeks of age. The vaccine consists of a mixture of equal amounts of rhesus rotavirus (RRV) vaccine (serotype 3 [VP7]) and each of three human rotavirus-RRV reassortant strains: D x RRV (serotype 1 [VP7]), DS1 x RRV (serotype 2 [VP7]), and ST3 x RRV (serotype 4 [VP7]). Three different doses of the quadrivalent vaccine (0.25 x 10(4), 0.5 x 10(4), and 10(4) PFU of each component) were evaluated sequentially for safety and antigenicity in placebo-controlled, double-blind trials. Starting the day after vaccination, the infants were monitored by daily home visits for 7 days. Only minor reactions were observed during this period; these were limited to mild transient febrile episodes which began day 2 or 3 after vaccination and lasted 1 to 2 days in 15 to 30% of the infants. Serological studies demonstrated that 68 to 96% of the infants developed a rotavirus serum immunoglobulin A response following vaccination. However, when tested by plaque reduction neutralization assay against individual human rotavirus serotype 1, 2, 3, or 4, the response rates ranged from 4 to 23% with the low dose, 21 to 33% with the medium dose, and 32 to 58% with the high dose. Most (73 to 79%) infants developed neutralizing antibodies to RRV following administration of each dose schedule. Vaccine virus shedding was analyzed by utilizing tissue culture isolation of virus from stool. All of the infants who received the lower of medium dose and 89% of those fed the high dose shed one or more components of the vaccine. Analyses of rotavirus serotypes isolated from the stool of infants who received the 0.25 x 10(4) -PFU dose revealed that DS1 x RRV was the most commonly shed vaccine component, followed by RRV, D x RRV, and ST3 x RRV in that order. The safety and protective efficacy of a serotype 1 reassortant of bovine rotavirus WC3, disignated strain WI79-9, was evaluated in a double-blind placebo-controlled trial. Rotavirus reassortant WI79-9 contains a gene segment 9 coding for the surface structural protein vp7 of a human serotype 1 rotavirus, with all other gene segments derived from WC3 rotavirus, which had previously been shown to be safe and immunogenic in infants. Infants 2-11 months of age were given two doses of vaccine (10(7.3) plaque-forming units/dose) or of placebo 28 days apart. Adverse reactions to the vaccine were not detected. The incidence of serum plaque reduction neutralization antibody responses to two doses of vaccine was serotype 6, 97%; serotype 3, 68%; and serotype 1, 22%. Active surveillance during the subsequent rotavirus season revealed 8 cases of rotavirus gastroenteritis in 39 placebo control infants and no cases in 38 WI79-9 vaccine recipients (protection = 100%, P = .003). Six cases of rotavirus gastroenteritis were caused by type 1 and two by type 3 virus. Although vaccination with WI79-9 affected only the incidence of rotavirus gastroenteritis, the vaccinated infants exhibited a significantly reduced incidence of total days of diarrhea, fever, and illness associated with gastroenteritis in general. Rotavirus is the leading cause of dehydrating acute gastroenteritis in infants worldwide. Previous studies of a live pentavalent human-bovine reassortant rotavirus vaccine have shown it to be efficacious across a range of potencies.
                Our goal was to evaluate the efficacy, immunogenicity, and safety of pentavalent rotavirus vaccine at the end of shelf life in healthy infants.
                During 2002-2004, 1312 healthy infants approximately 6 to 12 weeks old from the United States (47%) and Finland (53%) were randomly assigned to receive 3 oral doses of vaccine (vaccine at approximately 1.1 x 10(7) infectious U per dose) or placebo approximately 4 to 10 weeks apart. Infants were to be followed for acute gastroenteritis through 1 rotavirus season after vaccination and for adverse events postvaccination.
                Three doses of pentavalent rotavirus vaccine at the end of shelf life demonstrated efficacy against rotavirus gastroenteritis caused by human G-serotypes included in the vaccine (G1-G4). Efficacy against severe rotavirus gastroenteritis was 100%, and efficacy against any rotavirus gastroenteritis regardless of severity was 72.5%. A threefold rise in G1 serum neutralizing was observed in 57% and in anti-rotavirus immunoglobulin A in 96% of pentavalent rotavirus vaccine recipients. No statistically significant increase in vomiting, diarrhea, or irritability was observed among pentavalent rotavirus vaccine recipients compared with placebo recipients within the 7-day period from each dose. A statistically significant increase in fevers (> or = 100.5 degrees F, rectal equivalent) was observed among pentavalent rotavirus vaccine recipients compared with placebo recipients after dose 1.
                This pentavalent human-bovine rotavirus vaccine was generally well tolerated, efficacious, and immunogenic at the end of shelf life. Rotavirus vaccine has proved effective for prevention of severe rotavirus gastroenteritis in infants in developed countries, but no efficacy studies have been done in developing countries in Asia. We assessed the clinical efficacy of live oral pentavalent rotavirus vaccine for prevention of severe rotavirus gastroenteritis in infants in Bangladesh and Vietnam.
                In this multicentre, double-blind, placebo-controlled trial, undertaken in rural Matlab, Bangladesh, and urban and periurban Nha Trang, Vietnam, infants aged 4-12 weeks without symptoms of gastrointestinal disorders were randomly assigned (1:1) to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age, in conjunction with routine infant vaccines including oral poliovirus vaccine. Randomisation was done by computer-generated randomisation sequence in blocks of six. Episodes of gastroenteritis in infants who presented to study medical facilities were reported by clinical staff and from parent recollection. The primary endpoint was severe rotavirus gastroenteritis (Vesikari score >or=11) 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.
                2036 infants were randomly assigned to receive pentavalent rotavirus vaccine (n=1018) or placebo (n=1018). 991 infants assigned to pentavalent rotavirus vaccine and 978 assigned to placebo were included in the per-protocol analysis. Median follow up from 14 days after the third dose of placebo or vaccine until final disposition was 498 days (IQR 480-575). 38 cases of severe rotavirus gastroenteritis (Vesikari score >or=11) were reported during more than 1197 person-years of follow up in the vaccine group, compared with 71 cases in more than 1156 person years in the placebo group, resulting in a vaccine efficacy of 48.3% (95% CI 22.3-66.1) against severe disease (p=0.0005 for efficacy >0%) during nearly 2 years of follow-up. 25 (2.5%) of 1017 infants assigned to receive vaccine and 20 (2.0%) of 1018 assigned to receive placebo had a serious adverse event within 14 days of any dose. The most frequent serious adverse event was pneumonia (vaccine 12 [1.2%]; placebo 15 [1.5%]).
                In infants in developing countries in Asia, pentavalent rotavirus vaccine is safe and efficacious against severe rotavirus gastroenteritis, and our results support expanded WHO recommendations to promote its global use.
                PATH (GAVI Alliance grant) and Merck.
                Copyright 2010 Elsevier Ltd. All rights reserved. Rotavirus is the most common cause of severe gastroenteritis among young children worldwide. Data are needed to assess the efficacy of the rotavirus vaccine in African children.
                We conducted a randomized, placebo-controlled, multicenter trial in South Africa (3166 infants; 64.1% of the total) and Malawi (1773 infants; 35.9% of the total) to evaluate the efficacy of a live, oral rotavirus vaccine in preventing severe rotavirus gastroenteritis. Healthy infants were randomly assigned in a 1:1:1 ratio to receive two doses of vaccine (in addition to one dose of placebo) or three doses of vaccine--the pooled vaccine group--or three doses of placebo at 6, 10, and 14 weeks of age. Episodes of gastroenteritis caused by wild-type rotavirus during the first year of life were assessed through active follow-up surveillance and were graded with the use of the Vesikari scale.
                A total of 4939 infants were enrolled and randomly assigned to one of the three groups; 1647 infants received two doses of the vaccine, 1651 infants received three doses of the vaccine, and 1641 received placebo. Of the 4417 infants included in the per-protocol efficacy analysis, severe rotavirus gastroenteritis occurred in 4.9% of the infants in the placebo group and in 1.9% of those in the pooled vaccine group (vaccine efficacy, 61.2%; 95% confidence interval, 44.0 to 73.2). Vaccine efficacy was lower in Malawi than in South Africa (49.4% vs. 76.9%); however, the number of episodes of severe rotavirus gastroenteritis that were prevented was greater in Malawi than in South Africa (6.7 vs. 4.2 cases prevented per 100 infants vaccinated per year). Efficacy against all-cause severe gastroenteritis was 30.2%. At least one serious adverse event was reported in 9.7% of the infants in the pooled vaccine group and in 11.5% of the infants in the placebo group.
                Human rotavirus vaccine significantly reduced the incidence of severe rotavirus gastroenteritis among African infants during the first year of life. (ClinicalTrials.gov number, NCT00241644.)
                2010 Massachusetts Medical Society A refrigerator-stable rotavirus (RV) vaccine that withstands gastric acid is anticipated to permit more widespread use of RV vaccine.
                We investigated for the first time in infants an oral, liquid formulation of G1 and G2 human bovine reassortant rotavirus vaccine (HRRV) with a new stabilizer/buffer (S/B) containing sucrose, sodium phosphate and sodium citrate.
                During 1997 through 1998, 731 healthy infants approximately 2 to 4 months of age were enrolled at 19 US sites to receive 3 HRRV or placebo doses approximately 6 to 8 weeks apart in a partially double blinded study. Infants were randomized to: (1) HRRV with no S/B but with prefeeding; (2) HRRV plus 1 of 3 different concentrations/volumes of S/B; or (3) placebo.
                No serious vaccine-related adverse experiences or intussusception cases were reported. No statistically significant differences were observed between vaccine and placebo recipients for fever (> or =38.1 degrees C) 0 to 7 days after any dose, irritability, vomiting or diarrhea incidence 0 to 42 days after any dose. Vaccine virus shedding among vaccine recipients was uncommon. Among S/B vaccine groups, proportions of infants with a > or =3-fold titer rise from baseline to Postdose 3 for G1 serum-neutralizing antibody (SNA), G2 SNA, WC3 SNA, serum anti-RV IgA, serum anti-RV IgG and stool anti-RV IgA were generally similar to those of the prefed non-S/B group.
                HRRV with a new S/B was generally well-tolerated; immunogenicity was generally similar to the prefed non-S/B group. No intussusception cases were reported, but the small sample size precluded a definitive conclusion. A large international clinical study is under way to address safety and efficacy of an S/B formulation of a pentavalent version of HRRV. Rotavirus is a major cause of gastroenteritis in children worldwide and is estimated to be responsible for more than 500,000 physician visits, 50,000 hospitalizations and 20 deaths in the United States each year.
                To compare the safety and immunogenicity of 2 dosages of a live attenuated oral monovalent G1 human rotavirus (HRV) vaccine in healthy infants.
                In this randomized, double blind trial conducted in the United States and Canada, 529 healthy infants 5-15 weeks of age received HRV vaccine containing either 10 or 10 focus-forming units or placebo. Two doses were administered orally at a 2-month interval concomitantly with routine childhood vaccines. Symptoms of fever, irritability/fussiness, diarrhea, vomiting, loss of appetite and cough/runny nose were solicited for 15 days postvaccination, nonserious adverse events for 43 days postvaccination and serious adverse events throughout the study. Vaccine take was defined as appearance of serum antirotavirus IgA in postimmunization sera at a titer of > or =20 units/mL or vaccine virus shedding in any stool sample collected between the first dose and 2 months after the second dose.
                No serious adverse events considered related to vaccine were reported. The incidence of solicited symptoms was similar among treatment groups during the 15-day postvaccination surveillance periods. No significant difference in vaccine take after 2 doses (88.0% in high dose group and 81.5% in low dose group) was seen between vaccine groups (P = 0.153).
                Two doses of either dosage level of HRV vaccine administered concurrently with routine childhood vaccines to healthy infants 5-15 weeks of age were well-tolerated and were highly immunogenic. 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 >or=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.
                Copyright 2010 Elsevier Ltd. All rights reserved. We evaluated the reactogenicity and antigenicity of a quadrivalent rotavirus vaccine composed of serotype 3 rhesus rotavirus (RRV) and three single-gene-substitution reassortants of RRV and human strain D (D x RRV, serotype 1), DS1 (DS1 x RRV, serotype 2), or ST3 (ST3 x RRV, serotype 4) in a double-masked study with 302 infants in Caracas, Venezuela. Three doses of the quadrivalent vaccine composed of either 10(5) PFU (low titer) or 10(6) PFU (high titer) of each component were administered to 99 and 101 infants, respectively, at 4-week intervals starting at the second month of age; 102 infants received a placebo. Postvaccination reactions were monitored by home visits every other day during the week postvaccination. The vaccine was associated with the occurrence of mild, short-lived febrile episodes in 26 and 23% of the recipients after the first doses of high- or low-titer vaccine, respectively, in comparison with 13% of the infants receiving the placebo. Febrile reactions occurred less frequently in vaccinees after the second or third dose than after the initial dose. The vaccine was not significantly associated with diarrhea or any additional symptom or sign. Serum specimens obtained shortly before the first, 4 weeks after the first, and 4 weeks after the third dose of vaccine or placebo were tested by an immunoglobulin A enzyme-linked immunosorbent assay and by neutralization assays. Seroresponses occurred significantly more often after 3 doses than after a single dose of either vaccine. Immunoglobulin A responses were observed in 80 and 79% of the infants after 3 doses of high- or low-titer vaccine, respectively. Most of the infants tested developed a neutralization response to RRV after 3 doses of the high- (90%) or low-(88%) titer vaccine. Neutralization response rates to human rotavirus serotypes 1 to 4 after 3 doses were similar in both vaccine and 87 of 90 receiving the high-titer vaccine developed seroresponses, as detected by any of the assays employed. The study indicates that 3 doses of quadrivalent vaccine at a titer of 10(6) PFU of each component offered no advantage over the lower-titer preparation for use in efficacy trials. We vaccinated 244 newborn infants orally with RIT 4237 bovine rotavirus vaccine or placebo and followed them serologically and clinically for 16 months. Initially 39 of the 119 (33%) vaccine recipients compared with 1 of the 120 placebo recipients seroconverted by enzyme-linked immunosorbent assay-immunoglobulin M. After the first winter rotavirus season, at 7 months of age 55% of the vaccinated infants and 37% of the unvaccinated infants were rotavirus-seropositive by enzyme-linked immunosorbent assay-immunoglobulin G (P less than 0.01, chi square test). At 12 months of age, after a low rotavirus prevalence season, 34% of the vaccinated children and 23% of the unvaccinated children remained seropositive. There were 14 confirmed episodes of rotavirus gastroenteritis in the vaccine group and 10 episodes in the placebo group during the first 16 months. However, only 1 of the episodes in the vaccine group was severe, 4 were moderately severe and 9 were mild, whereas 7 episodes in the placebo group were severe and 3 were moderately severe (P less than 0.001 between groups, Fisher's exact test). There was no clear correlation between vaccine-induced clinical protection and initial serologic response (enzyme-linked immunosorbent assay-immunoglobulin M) to vaccination, but during follow-up severe rotavirus gastroenteritis was more likely to occur in children with no serum rotavirus immunoglobulin G antibody at the time of infection. We conclude at the present stage that neonatal rotavirus vaccination with RIT 4237 vaccine gives no protection against rotavirus infection but appears to modify the severity of gastroenteritis. Rotavirus is the most common cause of severe, dehydrating diarrhoea in infants worldwide. We assessed the safety, immunogenicity, and efficacy of a live, oral human rotavirus vaccine, 89-12, in US children in a randomised, placebo-controlled, double-blind multicentre trial.
                215 healthy infants were enrolled, of whom 213 were given two doses of 89-12 (containing 1x10(5) plaque-forming units) or placebo, and 213 were followed up through one rotavirus season. The frequency of side-effects was compared for 7 days after each dose of vaccine. Immune responses to rotavirus were assessed by serum and stool IgA, and by serum 89-12 neutralising titres. The primary outcome variable (protection from rotavirus disease) was evaluated by comparing the frequencies of rotavirus gastroenteritis in an intention-to-treat analysis.
                Adverse reactions were mild. Low-grade fever (> or = 38.1 degrees C) after the first dose was the only side-effect significantly more common in the vaccine group than in the placebo group (21 [19%] vs 5 [5%], p=0.001). An immune response to vaccine was detected in 94.4% of vaccinees. Rotavirus disease occurred in 18 of 107 placebo recipients and two of 108 vaccine recipients (vaccine efficacy 89.0% [95% CI 65.4-94.5]). Ten infants in the placebo group but none in the vaccine group were presented for medical care.
                The 89-12 rotavirus vaccine was safe and immunogenic and provided a high degree of protection against rotavirus disease. Further investigations of this vaccine are needed to confirm these findings in other settings. The reactogenicity and antigenicity of the rhesus rotavirus vaccine, strain MMU18006, developed at the Laboratory of Infectious Diseases (National Institute of Allergy and Infectious Diseases, National Institutes of Health) were examined in a double blind, placebo-controlled study of 40 newborn infants in Caracas, Venezuela. The children were observed for the first few days after birth in the hospital nursery and by home visits for 10 days after vaccination to detect any adverse reactions. No reactions could be attributed to the vaccine. Serologic responses to the vaccine were evaluated in paired sera obtained at birth (cord blood) and 4 weeks after vaccination. Serologic responses to the vaccine were not observed by complement fixation, neutralization or a rhesus rotavirus VP7 epitope-specific competition assay. However, such responses were found in 9 of 14 tested infants by an immunoglobulin A-specific enzyme-linked immunosorbent assay. Seventeen of the 20 vaccinees also shed rhesus rotavirus vaccine in stool during the postvaccination period. To assess safety and immunogenicity, 213 healthy infants aged 6 weeks to 4 months were randomized to receive a single dose of placebo, a 10(4) or 10(5) p.f.u. dose of rhesus rotavirus (RRV) serotype 3, human-RRV reassortant (VP-7 serotypes 1, 2 or 4) or a 10(4) or 10(5) p.f.u. dose of tetravalent rotavirus vaccine (containing equal parts of serotype 1, 2, 3 and 4 strains). The infants were fed ad libitum before and after vaccination; no buffer was used. For 7 days after vaccination, potential vaccine side effects were monitored, and no significant differences were noted for any symptom evaluated among the single serotype, tetravalent or placebo groups. Sera, obtained before and 28 days after vaccination, were measured for antibody to rotavirus by IgG, IgA and IgM enzyme-linked immunosorbent assay in all subjects, and by neutralizing antibody to the individual serotypes by plaque reduction in placebo and tetravalent vaccinees. The serological response rates for serotypes 1, 2, 3, 4 and the tetravalent vaccine were 25, 12, 19, 11 and 22%, respectively, at 10(4) p.f.u.; 47, 50, 35, 29 and 61%, respectively, at 10(5) p.f.u.; and 37% for placebo. The tetravalent vaccine was more immunogenic at 10(5) than at 10(4) p.f.u. (p = 0.04). Grouped together, the vaccines at 10(5) p.f.u. (single serotype and tetravalent) were more immunogenic than the vaccines at 10(4) p.f.u. (38 of 85 versus 17 of 94 seroresponders; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) Transmission of excreted vaccine-derived infectious virus from vaccinated to unvaccinated individuals is possible within close contacts. This randomized (1:1), double-blind study evaluated the potential for transmission of human rotavirus vaccine strain, HRV (Rotarix™) from vaccine recipients to unvaccinated close contacts (twins). 100 pairs of healthy twins aged 6-14 weeks at the time of Dose 1 of HRV vaccine/placebo were enrolled and one randomly selected twin from each pair received two vaccine doses and the other received placebo doses (at 2 and 4 months of age). Presence of vaccine strain in the stool samples of placebo recipients was an indicator of transmission. Serial stool samples were tested for rotavirus using ELISA at pre-determined time points; rotavirus positive stool samples were tested with RT-PCR and reverse hybridization assay to identify G1P[8] vaccine strain. If G1P[8] vaccine strain was detected, the complete genome was sequenced to assess the similarity between viral isolates. Immunogenicity and safety of HRV vaccine in transmission cases was assessed. 15 transmission cases were reported in 80 evaluable twins who received placebo and the transmission rate was 18.8% (95% CI: 10.9-29.0%). None of the transmission cases was associated with gastroenteritis symptoms. Anti-rotavirus IgA seroconversion was 62.5% (95% CI: 51.0-73.1%) (HRV) and 21.3% (95% CI: 12.9-31.8%) (placebo) 7-weeks post-Dose 2; seroconversion in transmission cases was 26.7% (95% CI: 7.8-55.1%). Genetic variations or amino acid substitutions in transmission cases were similar to that seen in corresponding vaccine recipients. Transmission of HRV vaccine strain to unvaccinated twins living in close contact occurred, however, they were not associated with increased of gastroenteritis. Whether transmission leads to indirect protection among unvaccinated individuals remains unknown at this stage.
                Copyright © 2011. Published by Elsevier Ltd. The efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq(®), was evaluated in a double-blind, placebo-controlled, multicenter Phase III clinical trial conducted (April 2007-March 2009) in 3 low-income countries in Africa: Ghana, Kenya, and Mali. In total, 5468 infants were randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age; concomitant administration with routine EPI vaccines, including OPV, was allowed. HIV-infected infants were not excluded. The primary endpoint, vaccine efficacy (VE) against severe-rotavirus gastroenteritis (RVGE), as measured by Vesikari scoring system (VSS, score ≥11), from ≥14 days following Dose 3 through a follow-up period of nearly 2 years in the combined 3 African countries, and secondary endpoints by total follow-up period have been previously reported. In this study, we report post hoc subgroup analyses on secondary endpoints of public health importance. VE against RVGE of any severity was 49.2% (95%CI: 29.9, 63.5) through the first year of life and 30.5% (95%CI: 16.7, 42.2) through the complete follow-up period. VE against severe-gastroenteritis of any etiology was 21.5% (95%CI: <0, 38.4) through the first year of life and 10.6% (95%CI: <0, 24.9) through the complete follow-up period. Through the complete follow-up period, VE against severe-RVGE caused by (i) vaccine-contained G and P types (G1-G4, P1A[8]), (ii) non-vaccine G types (G8, G9, G10), and (iii) non-vaccine P types (P1B[4], P2A[6]) was 34.0% (95%CI:11.2, 51.2), 81.8% (95%CI:16.5, 98.0) and 40.7% (95%CI:8.4, 62.1), respectively. There was a trend towards higher VE with higher disease severity, although in some cases the numbers were small. In African countries with high under-5 mortality rates, PRV significantly reduced RVGE through nearly 2 years of follow-up; more modest reductions were observed against gastroenteritis of any etiology. PRV provides protection against severe-RVGE caused by diverse rotavirus genotypes, including those not contained in the vaccine.
                Copyright © 2012 Elsevier Ltd. All rights reserved. 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.
                Copyright © 2011 Elsevier Ltd. All rights reserved. Three phase I trials of the rhesus rotavirus (RRV)-based quadrivalent vaccine [composed of serotype 3 (RRV), and serotypes 1 (D x RRV), 2 (DS1 x RRV), and 4 (ST3 x RRV) human rotavirus x RRV reassortants] and the M37 (nursery strain) rotavirus vaccine candidates were conducted in an attempt to find a safe and optimally antigenic formulation. Infants 10-20 weeks old received, in trial I, 1) the quadrivalent vaccine as two separate bivalent doses (1 x 10(4) PFU each of D x RRV and RRV, followed 4 weeks later by 1 x 10(4) PFU each of DS1 x RRV and ST3 x RRV) or 2) placebo; in trial II, 1) one dose of quadrivalent vaccine (10(4) PFU of each component), or 2) two doses of quadrivalent vaccine, or 3) a 10(4) PFU dose of M37 vaccine, or 4) M37 vaccine followed by the quadrivalent vaccine, or 5) placebo; in trial III, 1) a dose of a higher-titered quadrivalent vaccine (10(5) PFU of each component), or 2) two doses of higher titered quadrivalent vaccine, or 3) a dose of higher titered M37 vaccine (10(5) PFU) or 4) two doses of M37 vaccine (10(5) PFU), or 5) M37 vaccine (10(5) PFU) followed by the higher titered quadrivalent vaccine, or 6) placebo. A mild, transient fever during the first week postvaccination was associated with the bivalent or quadrivalent vaccines but not with the M37 vaccine. Fourfold or greater serum IgA ELISA responses to rotavirus were observed in 48-92% of the infants receiving quadrivalent vaccine and in 32-50% of those receiving M37 vaccine.(ABSTRACT TRUNCATED AT 250 WORDS) 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.
                Copyright © 2012. Published by Elsevier Ltd. 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 oral, pentavalent rotavirus vaccine (PRV), RotaTeq was assessed for prevention of severe rotavirus gastroenteritis (RVGE) in young children in two multi-site, randomized, placebo-controlled field trials; one in Asia (Vietnam and Bangladesh) and the other in sub-Saharan Africa (Ghana, Kenya and Mali). The efficacy results for the Mali site of the multi-country trial are presented here. We randomly assigned infants in a 1:1 ratio to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age. Gastroenteritis episodes were captured passively at the local health centers and by home visits. The primary study outcome was severe RVGE, as defined by a score of ≥ 11 using the Vesikari Clinical Scoring System occurring ≥ 14 days after the third dose until the end of the study. Other efficacy analyses included efficacy against severe RVGE through the first year and during the second years of life, as well as efficacy after receiving at least one dose of vaccine. In total, 1960 infants were enrolled in the trial at the Mali site and sera were collected on a subset of infants (approximately 150) for immunogenicity testing. In the first year of follow-up, largely due to cultural practices to visit traditional healers as the first point of care, the point estimate of efficacy was unreliable: the per protocol vaccine efficacy against severe RVGE was 1% (95% confidence interval [CI]: -431.7, 81.6); the intention-to-treat vaccine efficacy was 42.9% (95% CI: -125.7, 87.7). During the second year of follow-up, after the surveillance system was modified to adapt to local customs and health care seeking practices, the point estimate of per-protocol vaccine efficacy was 19.2% (95% CI: -23.1,47.3%). 82.5% of Malian infants (95% CI: 70.1,91.3%) who received PRV mounted a seroresponse (≥ 3-fold rise from baseline (prevaccination) to post-dose 3 vaccination) of anti-rotavirus immunoglobulin A antibody, with a post third-dose geometric mean titer (GMT) of 31.3 units/mL. By contrast, only 20.0% of placebo recipients (95% CI: 10.0, 33.7%) developed a seroresponse and the post-third dose GMT was 3.2 units/mL. None of the serious clinical adverse events observed were considered to be vaccine-related.
                Copyright © 2011 Elsevier Ltd. All rights reserved. Orally administered rhesus rotavirus vaccine was evaluated in a placebo-controlled study in young children and infants (ages, eight months to 61 months). Thirteen children received the rotavirus vaccine, and ten children served as the control group. The vaccine was well tolerated. There were no significant differences between the vaccine recipients and the control group in the number of child-days with temperatures greater than or equal to 37.8 C, vomiting, diarrhea, or cough. There were significantly more child-days of rhinorrhea among the vaccine recipients than there were among the control group. The vaccine recipients under two years of age passed a larger number of stools than did the children in the control group, and vaccine recipients had significantly more semiformed and unformed stools than did the children receiving the placebo. All twelve of the children tested were positive for viral shedding. Peak viral shedding occurred on days three and five postvaccination. On day eight, over one-half of the children from whom a stool specimen was obtained were still shedding rotavirus. Children less than two years old shed more rotavirus in their stool than did children more than two years old. All 13 vaccine recipients had a fourfold or greater rise in titer of antibody as measured by plaque reduction, tube neutralization, complement fixation, and/or immune adherence hemagglutination. This study evaluates the safety and efficacy against severe rotavirus gastroenteritis of the oral live attenuated human rotavirus vaccine RIX4414 (Rotarix) during the first 2 years of life in Asian infants from high-income countries. Healthy infants were enrolled to receive 2 doses of RIX4414 (N=5,359) or placebo (N=5,349). From 2 weeks post-dose 2 to 2 years of age, vaccine efficacy was 96.1% (95%CI:85.1%; 99.5%) against severe rotavirus gastroenteritis, 100% (95%CI:80.8%; 100%) against wild-type G1P[8] and 93.6% (95%CI:74.7%; 99.3%) against circulating non-G1 rotavirus types. No intussusception cases were reported within 31 days post-vaccination. RIX4414 shows a good safety profile and offers high protection during the first 2 years of life with potentially significant public health impact in this population. 90 Venezuelan infants aged 10-20 weeks were randomly allocated to four groups which received one of the following: the M37 vaccine (1 x 10(4) pfu [plaque-forming units]); quadrivalent rotavirus vaccine (1 x 10(4) pfu each of serotype 3 rhesus rotavirus [RRV] and human rotavirus-RRV reassortants of serotypes 1, 2, and 4); balanced quadrivalent vaccine consisting of 1 x 10(4) pfu of serotype 1 and 3 components but 5 x 10(4) pfu of serotype 2 and 4 components; or placebo. The frequencies of transient febrile responses in these four groups were 20%, 27%, 30%, and 9%. 50% of 22 infants tested who received M37 vaccine showed a serum rotavirus IgA antibody response, compared with 74% of the 23 quadrivalent and 86% of the 22 balanced-quadrivalent recipients. 64% of the M37 recipients showed a neutralising antibody response to M37; 27% showed such responses to human serotype 1 Wa strain and 27% to serotype 4 neonatal strain ST3. 17-39% of the quadrivalent recipients and 27-41% of the balanced-quadrivalent recipients showed neutralising antibody responses to serotypes 1-4. 70-73% of the quadrivalent and balanced quadrivalent groups also showed neutralising antibody responses to RRV. A randomized placebo-controlled double-blind field trial of RIT 4237 attenuated rotavirus vaccine in Lima, Peru, evaluated the protection against diarrheal illness by one, two, or three doses of vaccine. There were 391 children, 2-18 months old, studied for the occurrence of diarrhea during the 18 months after vaccination. Three doses of the vaccine provided 40% protection against any diarrheal illness associated with rotavirus alone but 58%-75%; protection against the more severe rotaviral illnesses. The vaccine appeared to be more efficacious when it was administered to children in the first year of life. Three doses provided up to 89% efficacy against more severe diseases due to serotype 1 rotavirus, and one dose also afforded significant protection. The protection was lower, even with three doses, against serotype 2 rotavirus. This vaccine trial has provided important insights on how such trials should be conducted and on the serotype-specificity of protection from rotavirus infection. Future vaccines should be able to protect against severe disease caused by all rotavirus serotypes and must work in developing countries where rotavirus is the most important cause of diarrheal mortality. Between January and November 1989, we studied 174 infants aged 6 to 16 weeks in a randomized clinical trial to (1) determine the immunogenicity of a single dose of tetravalent rhesus rotavirus vaccine (RRV-TV) when administered with three different buffer regimens: no antacid buffer and small-volume (2.5-mL) and large-volume (30-mL) antacid buffer; and (2) examine the potential interference of RRV-TV on the immune response to oral polio vaccine. Immunogenicity of RRV-TV, measured as a fourfold rise in antibody titers to rotavirus, was similar in the groups receiving small- and large-dose buffer (45% and 49%, respectively) and significantly less in the group that received RRV-TV alone (23%). Administration of RRV-TV with oral polio vaccine did not significantly interfere with the neutralization response of oral polio vaccine poliovirus serotypes 1, 2, or 3, and overall, 29%, 87%, and 24% of the infants had a fourfold rise in titer to each serotype, respectively. Candidate oral bovine rotavirus vaccine RIT 4237 or placebo was given to 252 Finnish infants at birth and at 7 months of age. No vaccine-associated reactions were observed. Primary rotavirus ELISA IgM responses were detected in 36% of the infants after the first vaccination; after the second dose 68% of the vaccinees were seropositive for rotavirus ELISA IgG antibody. The infants remained in clinical follow-up over two rotavirus epidemic seasons (total 28 months). Counted from child years in follow-up the overall vaccine protection rate was 43%. The clinical severity of rotavirus episodes was assessed using a numerical score 0-20. Vaccine protection rate for cases with a score greater than or equal to 7 was 57% and for cases with a score greater than or equal to 11 it was 89%. It is concluded that vaccination with a bovine rotavirus vaccine at birth and at 7 months of age, with the second dose given shortly before rotavirus epidemic season, protects infants against moderately severe and severe rotavirus diarrhoea in the first 2 years of life.
Current evidence shows that rhesus rotavirus vaccines (particularly RRV-TV) and the human rotavirus vaccine 89-12 are efficacious in preventing diarrhoea caused by rotavirus and all-cause diarrhoea. Evidence about safety, and about mortality or prevention of severe outcomes, is scarce and inconclusive. Bovine rotavirus vaccines were also efficacious, but safety data are not available. Trials of new rotavirus vaccines will hopefully improve the evidence base. Randomized controlled trials should be performed simultaneously in high-, middle-, and low-income countries.

2010 Editor's Note: Several of the vaccines investigated in this review are no longer in routine clinical use (for example, live attenuated rhesus-human reassortant tetravalent vaccine) and further new vaccines have been tested and approved for use since this review was written in 2004. For an up-to-date assessment of rotavirus vaccines currently approved for use, please see : Soares-Weiser K, MacLehose H, Ben-Aharon I, Goldberg E, Pitan F, Cunliffe N. Vaccines for preventing rotavirus diarrhoea: vaccines in use. Cochrane Database of Systematic Reviews 2010, Issue 5. Art. No.: CD008521. DOI: 10.1002/14651858.CD008521.