Introduction of rotavirus vaccines into national immunization programs (NIPs) could result in strain selection due to vaccine-induced selective pressure. This study describes the distribution and ...diversity of rotavirus genotypes before and after rotavirus vaccine introduction into the Australian NIP. State-based vaccine selection facilitated a unique comparison of diversity in RotaTeq and Rotarix vaccine states.
From 1995 to 2015, the Australian Rotavirus Surveillance Program conducted genotypic analysis on 13051 rotavirus-positive samples from children <5 years of age, hospitalized with acute gastroenteritis. Rotavirus G and P genotypes were determined using serological and heminested multiplex reverse-transcription polymerase chain reaction assays.
G1P8 was the dominant genotype nationally in the prevaccine era (1995-2006). Following vaccine introduction (2007-2015), greater genotype diversity was observed with fluctuating genotype dominance. Genotype distribution varied based on the vaccine implemented, with G12P8 dominant in states using RotaTeq, and equine-like G3P8 and G2P4 dominant in states and territories using Rotarix.
The increased diversity and differences in genotype dominance observed in states using RotaTeq (G12P8), and in states and territories using Rotarix (equine-like G3P8 and G2P4), suggest that these vaccines exert different immunological pressures that influence the diversity of rotavirus strains circulating in Australia.
Severe diarrhea from rotavirus remains an important cause of illness in infants. In this trial, investigators in Indonesia assessed the potential benefit of a neonatal rotavirus vaccine.
BackgroundRotavirus is the most common cause of severe gastroenteritis among children. We conducted hospital-based surveillance to estimate the burden of hospitalizations for rotavirus among children ...aged <5 years and to describe strain distribution patterns during the 2-year study period MethodsChildren aged <5 years with diarrhea were prospectively enrolled and evaluated by trained pediatricians at representative hospitals in Mongolia and Sri Lanka. Fecal specimens were tested by rotavirus antigen detection enzyme immunoassay. Specimens that tested positive for rotavirus were further characterized to determine the genotype of strains by reverse-transcriptase polymerase chain reaction ResultsFrom 1 March 2005 through 28 February 2007, a total of 1277 hospitalized children with diarrhea were enrolled in Mongolia, and 1916 were enrolled in Sri Lanka. Of the 1152 children in Mongolia who had samples tested, 458 (40%) had results positive for rotavirus, and in Sri Lanka, 428 (24%) of 1806 children with samples tested had positive results. G3P8 was the most common genotype among rotavirus strains in Mongolia (68%) and Sri Lanka (15%) ConclusionsRotavirus causes 40% and 24% of hospitalizations for diarrhea among children in Mongolia and Sri Lanka, respectively. Each study site will continue surveillance of rotavirus, and additional laboratory testing will be performed to provide additional information on the distribution of rotavirus strains by G and P genotype
Rotavirus gastroenteritis is a leading global cause of mortality and morbidity in young children due to diarrhea and dehydration. Over 85% of deaths occur in developing countries. In industrialised ...countries, 2 live oral rotavirus vaccines licensed in 2006 quickly demonstrated high effectiveness, dramatically reducing severe rotavirus gastroenteritis admissions in many settings by more than 90%. In contrast, the same vaccines reduced severe rotavirus gastroenteritis by only 30-60% in developing countries, but have been proven life-saving. Bridging this "efficacy gap" offers the possibility to save many more lives of children under the age of 5. The reduced efficacy of rotavirus vaccines in developing settings may be related to differences in transmission dynamics, as well as host luminal, mucosal and immune factors. This review will examine strategies currently under study to target the issue of reduced efficacy and effectiveness of oral rotavirus vaccines in developing settings.
The RV3-BB human neonatal rotavirus vaccine aims to provide protection from severe rotavirus disease from birth. A phase IIa safety and immunogenicity trial was undertaken in Dunedin, New Zealand ...between January 2012 and April 2014. Healthy, full-term (≥ 36 weeks gestation) babies, who were 0-5 d old were randomly assigned (1:1:1) to receive 3 doses of oral RV3-BB vaccine with the first dose given at 0-5 d after birth (neonatal schedule), or the first dose given at about 8 weeks after birth (infant schedule), or to receive placebo (placebo schedule). Vaccine take (serum immune response or stool shedding of vaccine virus after any dose) was detected after 3 doses of RV3-BB vaccine in >90% of participants when the first dose was administered in the neonatal and infant schedules. The aim of the current study was to characterize RV3-BB shedding and virus replication following administration of RV3-BB in a neonatal and infant vaccination schedule. Shedding was defined as detection of rotavirus by VP6 reverse transcription polymerase chain reaction (RT-PCR) in stool on days 3-7 after administration of RV3-BB. Shedding of rotavirus was highest following vaccination at 8 weeks of age in both neonatal and infant schedules (19/30 and 17/27, respectively). Rotavirus was detected in stool on days 3-7, after at least one dose of RV3-BB, in 70% (21/30) of neonate, 78% (21/27) of infant and 3% (1/32) placebo participants. In participants who shed RV3-BB, rotavirus was detectable in stool on day 1 following RV3-BB administration and remained positive until day 4-5 after administration. The distinct pattern of RV3-BB stool viral load demonstrated using a NSP3 quantitative qRT-PCR in participants who shed RV3-BB, suggests that detection of RV3-BB at day 3-7 was the result of replication rather than passage through the gastrointestinal tract.
Serum rotavirus IgA responses are an imperfect non-mechanistic correlate of protection, and the lack of an accurate serological marker is a challenge to the development of new rotavirus vaccines. ...Serological responses to rotavirus NSP2 occur following wild-type infection; however, it is unknown if serological responses to NSP2 occur following administration of rotavirus vaccines. The phase IIa immunogenicity trial of RV3-BB provided an opportunity to investigate the serological responses to NSP2 following vaccination. Healthy, full-term babies (n = 96) were previously recruited as part of a phase IIa safety and immunogenicity trial in Dunedin, New Zealand between January 2012 and April 2014. Participants received three doses of oral RV3-BB vaccine with the first dose given at 0-5 days after birth (neonatal schedule), or the first dose given at about 8 weeks after birth (infant schedule), or to receive placebo (placebo schedule). Serum IgA and IgG antibody responses to total RV3-BB and NSP2 protein (RV3-BB) were assessed using ELISA. Despite significant serum IgA response against total RV3-BB, we were unable to demonstrate a significant serological response to NSP2 in participants receiving RV3-BB when compared to placebo. Heterotypic antibodies against multiple NSP2 genotypes were detected following RV3-BB vaccination. Our data demonstrates that while serological responses to NSP2 were detectable in a subset of participants, it is a less useful marker when compared to total rotavirus serum IgA response.
Abstract
Background
Histo-blood group antigen (HBGA) status may affect vaccine efficacy due to rotavirus strains binding to HBGAs in a P genotype–dependent manner. This study aimed to determine if ...HBGA status affected vaccine take of the G3P6 neonatal vaccine RV3-BB.
Methods
DNA was extracted from stool samples collected in a subset (n = 164) of the RV3-BB phase IIb trial in Indonesian infants. FUT2 and FUT3 genes were amplified and sequenced, with any single-nucleotide polymorphisms analyzed to infer Lewis and secretor status. Measures of positive cumulative vaccine take were defined as serum immune response (immunoglobulin A or serum-neutralizing antibody) and/or stool excretion of RV3-BB virus. Participants were stratified by HBGA status and measures of vaccine take.
Results
In 147 of 164 participants, Lewis and secretor phenotype were determined. Positive vaccine take was recorded for 144 (97.9%) of 147 participants with the combined phenotype determined. Cumulative vaccine take was not significantly associated with secretor status (relative risk, 1.00 95% CI, .94–1.06; P = .97) or Lewis phenotype (relative risk, 1.03 95% CI, .94–1.14; P = .33), nor was a difference observed when analyzed by each component of vaccine take.
Conclusions
The RV3-BB vaccine produced positive cumulative vaccine take, irrespective of HBGA status in Indonesian infants.
Population differences in histo-blood group antigen status may contribute to the varying performance of oral rotavirus vaccines. This study revealed that the RV3-BB vaccine produced positive cumulative vaccine take, irrespective of histo-blood group antigen status in Indonesian infants.
•Equine-like G3P8 the major cause of gastroenteritis during RV3-BB efficacy trial.•The Indonesian equine-like G3P8 strain was genetically similar to Hungarian and Spanish strains.•Equine-like G3P8 ...strain is an emerging cause of gastroenteritis in Indonesia.
The RV3-BB human neonatal rotavirus vaccine aims to provide protection from severe rotavirus disease from birth. The aim of the current study was to characterise the rotavirus strains causing gastroenteritis during the Indonesian Phase IIb efficacy trial.
A randomized, double-blind placebo-controlled trial involving 1649 participants was conducted from January 2013 to July 2016 in Central Java and Yogyakarta, Indonesia. Participants received three doses of oral RV3-BB vaccine with the first dose given at 0–5 days after birth (neonatal schedule), or the first dose given at ∼8 weeks after birth (infant schedule), or placebo (placebo schedule). Stool samples from episodes of gastroenteritis were tested for rotavirus using EIA testing, positive samples were genotyped by RT-PCR. Full genome sequencing was performed on two representative rotavirus strains.
There were 1110 episodes of acute gastroenteritis of any severity, 105 episodes were confirmed as rotavirus gastroenteritis by EIA testing. The most common genotype identified was G3P8 (90/105), the majority (52/56) of severe (Vesikari score ≥11) rotavirus gastroenteritis episodes were due to the G3P8 strain. Full genome analysis of two representative G3P8 samples demonstrated the strain was an inter-genogroup reassortant, containing an equine-like G3 VP7, P8 VP4 and a genogroup 2 backbone I2-R2-C2-M2-A2-N2-T2-E2-H2. The complete genome of the Indonesian equine-like G3P8 strain demonstrated highest genetic identity to G3P8 strains circulating in Hungary and Spain.
The dominant circulating strain during the Indonesian Phase IIb efficacy trial of the RV3-BB vaccine was an equine-like G3P8 strain. The equine-like G3P8 strain is an emerging cause of severe gastroenteritis in Indonesia and in other regions.