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Background: A strategy of administering a neonatal rotavirus vaccine at birth to target early prevention of rotavirus gastroenteritis may address some of the barriers to global implementation of a rotavirus vaccine., Methods: We conducted a randomized, double-blind, placebo-controlled trial in Indonesia to evaluate the efficacy of an oral human neonatal rotavirus vaccine (RV3-BB) in preventing rotavirus gastroenteritis. Healthy newborns received three doses of RV3-BB, administered according to a neonatal schedule (0 to 5 days, 8 weeks, and 14 weeks of age) or an infant schedule (8 weeks, 14 weeks, and 18 weeks of age), or placebo. The primary analysis was conducted in the per-protocol population, which included only participants who received all four doses of vaccine or placebo within the visit windows, with secondary analyses performed in the intention-to-treat population, which included all participants who underwent randomization., Results: Among the 1513 participants in the per-protocol population, severe rotavirus gastroenteritis occurred up to the age of 18 months in 5.6% of the participants in the placebo group (28 of 504 babies), in 1.4% in the neonatal-schedule vaccine group (7 of 498), and in 2.7% in the infant-schedule vaccine group (14 of 511). This resulted in a vaccine efficacy of 75% (95% confidence interval [CI], 44 to 91) in the neonatal-schedule group (P<0.001), 51% (95% CI, 7 to 76) in the infant-schedule group (P=0.03), and 63% (95% CI, 34 to 80) in the neonatal-schedule and infant-schedule groups combined (combined vaccine group) (P<0.001). Similar results were observed in the intention-to-treat analysis (1649 participants); the vaccine efficacy was 68% (95% CI, 35 to 86) in the neonatal-schedule group (P=0.001), 52% (95% CI, 11 to 76) in the infant-schedule group (P=0.02), and 60% (95% CI, 31 to 76) in the combined vaccine group (P<0.001). Vaccine response, as evidenced by serum immune response or shedding of RV3-BB in the stool, occurred in 78 of 83 participants (94%) in the neonatal-schedule group and in 83 of 84 participants (99%) in the infant-schedule group. The incidence of adverse events was similar across the groups. No episodes of intussusception occurred within the 21-day risk period after administration of any dose of vaccine or placebo, and one episode of intussusception occurred 114 days after the third dose of vaccine in the infant-schedule group., Conclusions: RV3-BB was efficacious in preventing severe rotavirus gastroenteritis when administered according to a neonatal or an infant schedule in Indonesia. (Funded by the Bill and Melinda Gates Foundation and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612001282875 .).

The Australian Rotavirus Surveillance Program together with collaborating laboratories Australia-wide conducts a laboratory based rotavirus surveillance program. This report describes the genotypes of rotavirus strains responsible for the hospitalisation of children with acute gastroenteritis during 1 July 2010 to 30 June 2011. This report represents the fourth year of surveillance following introduction of rotavirus vaccines into the National Immunisation Program. One thousand one hundred and twenty-seven faecal samples were referred to the centre for G and P genotype analysis using hemi-nested multiplex reverse transcription-polymerase chain reaction. Eight hundred and sixteen samples were confirmed as rotavirus positive. Of these, 551 were collected from children under 5 years of age, while 265 were from older children and adults. Genotype analysis revealed that a change in the dominant type occurred in this reporting period, such that genotype G2P[4] was the dominant type nationally, representing 51% of samples, followed by genotype G1P[8] (26.1%). Genotypes G3P[8] represented 11% of samples while G4P[8] re-emerged as an important genotype, and was identified in 6% of samples. Uncommon rotavirus G and P combinations continue to be identified, with G2P[8] and G9P[4] identified during this survey. Differences in genotype distribution based on vaccine usage continue to be evident in Australian states. This survey continues to highlight the fluctuations in rotavirus genotypes, with an annual change in dominant genotypes suggesting a more dynamic wild-type population.

The Australian Rotavirus Surveillance Program together with 15 collaborating laboratories Australia-wide conducts a laboratory based rotavirus surveillance program. This report describes the genotypes of rotavirus strains responsible for the hospitalisation of children with acute gastroenteritis during the period 1 July 2009 to 30 June 2010, the 3rd year of surveillance following introduction of rotavirus vaccines into the National Immunisation Program. Seven hundred and seventy-eight faecal samples were referred to the centre for G and P genotype analysis using hemi-nested multiplex reverse transcription-polymerase chain reaction. Of the 422 confirmed as rotavirus positive, genotype G1P[8] was the dominant type nationally, representing 49.3%, followed by genotype G2P[4] (21.1%). Genotypes G3P[8], G4P[8] and G9P[8] each represented less than 3% of circulating strains nationally. The dominance of G1P[8] was in part associated with a large outbreak of severe gastroenteritis in the Northern Territory in 2010. The identification of uncommon rotavirus genotype combinations has increased since vaccine introduction, with G1P[4], G2P[8] and G9P[4] identified during this survey. Single strains of G1P[6] and G4P[6] were identified during this study period. This survey continues to highlight the fluctuations in rotavirus genotypes, and results from this survey suggest there is limited genotype selection based on vaccine usage. However, the large G1P[8] outbreak of gastroenteritis in the Northern Territory may have resulted from vaccine pressure on wild-type strains.

Indigenous children living in arid Central Australia experience frequent outbreaks of rotavirus gastroenteritis. A widespread outbreak of G9 rotavirus infection occurred several months after introduction of the RIX4414 rotavirus vaccine. We performed a retrospective case-control study to determine vaccine efficacy during the outbreak. Two doses provided an estimated vaccine efficacy of 77.7% (95% confidence interval, 40.2%-91.7%) against hospitalization for gastroenteritis. Vaccine efficacy was 84.5% (95% confidence interval, 23.4%-96.9%) against confirmed cases of rotavirus infection. Vaccination was effective in this high-burden setting.

The National Rotavirus Reference Centre, together with collaborating laboratories Australia-wide, has conducted rotavirus surveillance since June 1999. This report describes the serotypes of rotavirus strains responsible for the hospitalisation of children with acute gastroenteritis during the period 1 July 2002 to 30 June 2003. We examined 573 faecal samples using monoclonal antibody immunoassays, reverse transcription-polymerase chain reaction, and polyacrylamide gel analysis. For the second consecutive year, serotype G9 strains were the most prevalent type nationally (74.7%) and were found in all seven contributing centres. Serotype G1 strains were the second most prevalent type (11.3%), identified in four of the centres. These findings have implications for vaccine development strategies which have targeted protection of disease due to serotypes G1-G4.

Rotavirus strains that caused severe diarrhea in 4,634 (2,533 male) children aged less than 5 years and admitted to major hospitals in eight centers throughout Australia from 1993 to 1996 were subject to antigenic and genetic analyses. The G serotypes of rotaviruses were identified in 81.9% (3,793 of 4,634) children. They included 67.8% (from 3,143 children) serotype G1 isolates (containing 46 electropherotypes), 11.5% (from 531 children) serotype G2 isolates (27 electropherotypes), 0.8% (from 39 children) serotype G3 isolates (8 electropherotypes), and 1.6% (from 76 children) serotype G4 isolates (9 electropherotypes). G6 (two strains) and G8 (two strains) isolates were identified during the same period. G1 serotypes were predominant in all centers, with intermittent epidemics of G2 serotypes and sporadic detection of G3 and G4 strains. With the exception of two strains (typed as G1P2A[6] and G2P2A[6]) all serotype G1, G3, and G4 strains were P1A[8] and all serotype G2 strains were P1B[4]. Two contrasting epidemiological patterns were identified. In all temperate climates rotavirus incidence peaked during the colder months. The genetic complexity of strains (as judged by electropherotype) was greatest in centers with large populations. Identical electropherotypes appeared each winter in more than one center, apparently indicating the spread of some strains both from west to east and from east to west. Centers caring for children in small aboriginal communities showed unpredictable rotavirus peaks unrelated to climate, with widespread dissemination of a few rotavirus strains over distances of more than 1,000 km. Data from continued comprehensive etiological studies of genetic and antigenic variations in rotaviruses that cause severe disease in young children will serve as baseline data for the study of the effect of vaccination on the incidence of severe rotavirus disease and on the emergence of new strains.

Objective: To determine rates of hospitalisation of young children for acute gastroenteritis in Australia, and to estimate the proportion of these admissions caused by rotavirus infection., Design: Analysis of hospital admission records, and parallel, prospectively collected data on rotavirus-positive admissions., Setting: Hospitals admitting young children in all Australian States and Territories in 1993-1996., Patients: All children under five years admitted to hospital for acute gastroenteritis (International Classification of Diseases, ninth revision principal diagnosis codes 003.0, 004.0-009.3 and 558.9)., Main Outcome Measures: Rate of hospital admission per 1000 children per year by State, and the proportion of admissions caused by rotavirus infection., Results: There were almost 20,000 hospital admissions annually in Australia for acute gastroenteritis in children under five years, at an average rate of 15/1000. An estimated 50% of these were attributable to rotavirus infection, implying a rate of hospitalisation for rotavirus-related gastroenteritis of 7.5/1000/year. Among children under two years this rate was 11.6/1000. Rotavirus incidence rates generally followed a typical seasonal pattern in temperate regions of the country, with sharp peaks in mid to late winter. Rates of hospitalisation varied markedly, even between States with apparently similar patterns of disease, while the incidence in the Northern Territory was 3-5 times higher than other States., Conclusions: Rotavirus-related gastroenteritis is a major cause of hospital admissions in young children, and large savings to the healthcare system are possible if it can be prevented at reasonable cost. Variation in treatment practices between States may be worth studying in greater detail as another source of potential savings.

Acute infectious diarrhea is common in children. Control requires knowledge of causes. Few comprehensive long-term studies of etiology have been undertaken in developed countries. This report is of a 13-year survey of 4,637 children from 0 to 14 years of age, admitted to a large children's hospital for treatment of gastroenteritis, in which viruses, bacteria, and parasites were sought. A recognized enteric pathogen was identified in 56.6% of children. Group A rotaviruses occurred in 39.6% of children overall and in 55% of children 12 to 23 months of age. They were a frequent cause (18.7%) of acute gastroenteritis in children under 6 months and in those aged 5 to 13 years (16%). Rotaviruses were almost entirely responsible for winter admission peaks. Enteric adenovirus types 40 and 41 (6% overall) were more frequent in children under 12 months (9.4%). Salmonella spp. (5.8%) and Campylobacter jejuni (3.4%) were more common in children over 5 years (13.1% and 6.7%, respectively). The 43.5% of cases (60% in children under 6 months) where no enteric pathogen was identified are cause for concern. The involvement of small viruses (including caliciviruses and astroviruses) may be clarified when molecular biology techniques are utilized to address this gap in our knowledge. This comprehensive 13-year study of the cause of acute infectious diarrhea in children in developed countries reinforces the importance of rotavirus and highlights a large group for whom the etiology remains unknown, an issue of particular concern with babies under 6 months of age. New techniques have the potential to identify old and new pathogens causing disease in these vulnerable infants.

Two rotavirus strains, E210 and E212, implicated in epidemics of gastroenteritis in children in central and northern Australia during 1993-1994, exhibited the unusual combination of a 'short' RNA electrophoretic pattern and subgroup II specificity. The outer capsid protein VP7 was found by PCR typing and sequence analysis to be related to that of serotype G2 viruses. Both strains displayed a novel pattern of reactivity to G2-specific monoclonal antibodies that correlated with sequence variation in the antigenic regions of VP7. The VP4 serotype of E210 and E212 was determined as P1B in an enzyme immunoassay, consistent with other G2 viruses. Analysis of the VP6 gene indicated significant identity (98-99%) with other human subgroup II viruses. Northern hybridization analysis of E210 RNA using total genome probes derived from the prototype strains RV4 and RV5 indicated that E210 was derived from multiple gene reassortment between rotaviruses belonging to different genetic types.

During the period 1981 to 1992, 4,473 fecal specimens collected from children hospitalized with acute gastroenteritis at the Royal Children's Hospital, Melbourne, Australia, were examined by electron microscopy. A monoclonal antibody enzyme immunoassay for enteric adenovirus (EAd) types 40 (Ad40) and 41 (Ad41) was used when adenoviruses were visualized. Fecal samples were positive for adenovirus by both electron microscopy and enzyme immunoassay in 138 patients (3.1%). Ad40 was identified in 19 children (14%), and Ad41 was identified in 119 children (86%). These EAd were identified during each of the 12 years surveyed. EAd were present year-round, but the annual number of hospitalizations was not constant. Yearly prevalence varied from 0.7% (1981) to 6.5% (1985). This was associated with monthly fluctuations in Ad41 activity, with overall peak monthly prevalence in May (late autumn). By contrast, Ad40 numbers remained low and constant year-round. The frequency of Ad41 relative to Ad40 increased from 25% in 1981 to exceed 75% after 1983. Children admitted with EAd infection were more likely to have diarrhea for more than 5 days (P < 0.001) but less likely to be febrile or dehydrated (P < 0.05) than children with rotavirus infection. EAd are responsible for enteric symptoms of only a fraction of hospitalized children with infectious diarrhea but result in a more-protracted illness than rotavirus. Their relationship to persistent diarrhea requires further investigation.

The aim of this study was to determine the occurrence of rotavirus infection in infants under 6 months of age who were admitted to hospital in a developed country for treatment of gastroenteritis. Between April 1980 and April 1990, 595 such infants were admitted to the infectious diseases ward at the Royal Children's Hospital, Melbourne, Australia. Faecal specimens were collected within 6 h of admission and were tested for viral, bacterial and protozoal enteric pathogens. Rotaviruses of several serotypes were found in specimens from 15.1% of the infants, adenoviruses in 12.4% and other pathogens in 10.8%. Rotaviruses were found equally often in infants in each 1 month age group. No pathogens were able to be identified in 61.7% of cases. These results show that rotavirus is an important pathogen in infants under 6 months of age who are admitted to hospital with gastroenteritis. Rotavirus vaccination will need to be given during the first 1-3 months of life in developed countries, as is recommended for developing countries. The large group in whom no pathogens were isolated requires further consideration.

In order to facilitate measurement of antirotaviral IgA in large collections of faeces and secretions, adaptations of enzyme immunoassay methods for estimating antirotaviral IgA and IgM in duodenal fluid, saliva, faeces and serum were studied. To quantitate specific IgA, a single dilution of each sample was assayed. Results were expressed as antirotaviral IgA units derived from a standard curve. Units were calculated by log-logit analysis on computer. There was strong correlation between antirotaviral IgA units and end-point titres in 257 faecal samples (correlation coefficient r = 0.92) and in 182 duodenal fluids and salivary samples (correlation coefficient r = 0.74). The assay was validated using acute and convalescent faeces from children with or without rotavirus infection. Immune conversions in IgA were detected in 33 (75%) of the children by units and 34 (77%) by titres. None of nine children with gastroenteritis due to other infectious agents showed immune conversions to rotavirus. A monoclonal capture IgM assay showed similar end-point titres and numbers of immune conversions when compared with a direct assay for antirotaviral IgM in serum and secretions. Use of the capture method eliminated false-positive reactions with the cell control. The assay for antirotaviral IgA units in secretions is simple, rapid, reproducible and reliable, and has proven of value in longitudinal epidemiological studies of rotavirus coproIgA profiles. Both the capture IgM technique and the single dilution IgA method permit analysis of large numbers of specimens and are appropriate for examination of immune responses to natural rotavirus infection or during vaccine trials.

A human rotavirus complement-fixing (CF) antigen, prepared by purification of large volumes of fluid feces collected from children with winter diarrhea, was used to study the development and persistence of antibody in children with diarrhea and the prevalence of rotavirus antibody in Melbourne. In children with diarrhea, antibody rises were detectable within 4 to 6 weeks of the onset of illness, and the titers usually remained elevated for the next 1 to 2 years. CF antibody did not develop in two children with proven rotavirus infection aged less than 6 months, an age at which poor CF responses to other viruses have also been observed. A study of CF antibody levels in the general community showed that in Melbourne, most children have been infected with human rotavirus by the age of 3 years.

The development of mucosal immunity is presumed to be the most important marker of rotavirus infection. The practical difficulties of obtaining small-bowel secretions stimulated this study of the antibody response to acute rotavirus infection at other sites. Forty-four infants admitted to the hospital with rotavirus gastroenteritis had serum, saliva, and feces collected at the acute phase (median, 5.5 days), during convalescence (median, 33.5 days), and 4 months later (median, 12.2 weeks). A subgroup of 19 children also had duodenal juice collected in parallel. Rotavirus-specific immunoglobulin G (IgG), IgA, secretory immunoglobulin, and IgM were measured and compared in all samples. The results showed that the estimation of antirotavirus serum IgM, serum IgG, duodenal juice IgA, and duodenal juice IgM by an enzyme immunoassay indicated an immune response to severe primary rotavirus infection in all children. Four months later, the levels of serum IgG and IgA served as the most sensitive markers of the preceding rotavirus infection. The predictive accuracies of immune responses at different sites in relation to a positive IgA immune response in the duodenum were calculated. Fecal IgA predicted duodenal IgA rotavirus antibodies with accuracies of 86% at 1 month and 92% at 4 months. The high sensitivity of serum IgM and IgG in detecting rotavirus infection and the high predictive accuracy of fecal IgA as an indicator of duodenal IgA abrogates the need for duodenal intubation to detect (or monitor) an immune response to rotavirus infection. This finding has important practical implications for epidemiological studies of acute diarrhea in children and in rotavirus vaccine trials.

Rotavirus infections were detected by electron microscopy examinations in 54 of 66 children (82%) with acute gastroenteritis which necessitated admission to hospital during April to July, 1979, in the Highlands of Papua New Guinea. Longitudinal epidemiological studies may confirm rotavirus infections to be more important aetiolgical agents of childhood gastroenteritis in this region than in many other countries studied to date.