Paediatrics (RCH) - Research Publications
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ItemHisto-blood Group Antigen status of Australian Aboriginal children and seropositivity following oral rotavirus vaccination( 2022)Background: High rates of breakthrough rotavirus gastroenteritis have been reported among Aboriginal children living in rural and remote Australia despite receipt of two doses of oral rotavirus vaccine. Histo-blood group antigens (HBGAs) may mediate rotavirus genotype-dependent differences in susceptibility to rotavirus infection and immune responses to rotavirus vaccination. Methods: HBGA phenotype – Lewis and secretor status - was determined by enzyme immunoassay of saliva samples obtained from Australian Aboriginal children who were enrolled at age 6 to <12 months in a randomised clinical trial of an additional (booster) dose of oral rotavirus vaccine. Participants had received the routine two-dose schedule of oral rotavirus vaccine administered at age 6 weeks and 4 months. Non-secretor phenotype was confirmed by DNA extraction to identify FUT2 ‘G428A’ mutation. Rotavirus seropositivity was defined as serum anti-rotavirus IgA ≥ 20 AU/mL measured by ELISA on enrolment. Results: Of 156 children, 119 (76%) were secretors, 129 (83%) were Lewis antigen positive, and 105 (67%) were rotavirus IgA seropositive. Eighty-seven of 119 (73%) secretors were rotavirus seropositive, versus 4/9 (44%) weak secretors and 13/27 (48%) non-secretors. Eighty-nine of 129 (69%) Lewis antigen positive children were rotavirus seropositive versus 10 of 19 (53%) of those who were Lewis antigen negative. Conclusions Most Australian Aboriginal children were secretor and Lewis antigen positive. Non-secretor children were less likely to be seropositive for rotavirus following vaccination, but this phenotype was less common. HBGA status is unlikely to fully explain the underperformance of rotavirus vaccine at a population level among Australian Aboriginal children.
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ItemThe Challenges and Opportunities of Next-Generation Rotavirus Vaccines: Summary of an Expert Meeting with Vaccine Developers.(MDPI AG, 2022-11-19)The 2nd Next Generation Rotavirus Vaccine Developers Meeting, sponsored by PATH and the Bill and Melinda Gates Foundation, was held in London, UK (7-8 June 2022), and attended by vaccine developers and researchers to discuss advancements in the development of next-generation rotavirus vaccines and to consider issues surrounding vaccine acceptability, introduction, and uptake. Presentations included updates on rotavirus disease burden, the impact of currently licensed oral vaccines, various platforms and approaches for next generation rotavirus vaccines, strategies for combination pediatric vaccines, and the value proposition for novel parenteral rotavirus vaccines. This report summarizes the information shared at the convening and poses various topics worthy of further exploration.
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ItemNo Preview AvailableAustralian Rotavirus Surveillance Program: Annual Report, 2020(AUSTRALIAN GOVERNMENT, DEPT HEALTH & AGEING, 2021-11-30)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.
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ItemIdentification of a novel picornavirus related to cosaviruses in a child with acute diarrhea(BMC, 2008-12-22)Diarrhea, the third leading infectious cause of death worldwide, causes approximately 2 million deaths a year. Approximately 40% of these cases are of unknown etiology. We previously developed a metagenomic strategy for identification of novel viruses from diarrhea samples. By applying mass sequencing to a stool sample collected in Melbourne, Australia from a child with acute diarrhea, one 395 bp sequence read was identified that possessed only limited identity to known picornaviruses. This initial fragment shared only 55% amino acid identity to its top BLAST hit, the VP3 protein of Theiler's-like virus, suggesting that a novel picornavirus might be present in this sample. By using a combination of mass sequencing, RT-PCR, 5' RACE and 3' RACE, 6562 bp of the viral genome was sequenced, which includes the entire putative polyprotein. The overall genomic organization of this virus was similar to known picornaviruses. Phylogenetic analysis of the polyprotein demonstrated that the virus was divergent from previously described picornaviruses and appears to belong to the newly proposed picornavirus genus, Cosavirus. Based on the analysis discussed here, we propose that this virus represents a new species in the Cosavirus genus, and it has tentatively been named Human Cosavirus E1 (HCoSV-E1).
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ItemMetagenomic analysis of human diarrhea: Viral detection and discovery(PUBLIC LIBRARY SCIENCE, 2008-02)Worldwide, approximately 1.8 million children die from diarrhea annually, and millions more suffer multiple episodes of nonfatal diarrhea. On average, in up to 40% of cases, no etiologic agent can be identified. The advent of metagenomic sequencing has enabled systematic and unbiased characterization of microbial populations; thus, metagenomic approaches have the potential to define the spectrum of viruses, including novel viruses, present in stool during episodes of acute diarrhea. The detection of novel or unexpected viruses would then enable investigations to assess whether these agents play a causal role in human diarrhea. In this study, we characterized the eukaryotic viral communities present in diarrhea specimens from 12 children by employing a strategy of "micro-mass sequencing" that entails minimal starting sample quantity (<100 mg stool), minimal sample purification, and limited sequencing (384 reads per sample). Using this methodology we detected known enteric viruses as well as multiple sequences from putatively novel viruses with only limited sequence similarity to viruses in GenBank.
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ItemKlassevirus 1, a previously undescribed member of the family Picornaviridae, is globally widespread(BMC, 2009-06-24)BACKGROUND: Diarrhea is the third leading infectious cause of death worldwide and is estimated to be responsible for approximately 2 million deaths a year. While many infectious causes of diarrhea have been established, approximately 40% of all diarrhea cases are of unknown etiology. In an effort to identify novel viruses that may be causal agents of diarrhea, we used high throughput mass sequencing to analyze stool samples collected from patients with acute diarrhea. RESULTS: Sequences with limited similarity to known picornaviruses were detected in a stool sample collected in Australia from a child with acute diarrhea. Using a combination of mass sequencing, RT-PCR, 5' RACE and 3' RACE, a 6383 bp fragment of the viral genome was sequenced. Phylogenetic analysis demonstrated that this virus was highly divergent from, but most closely related to, members of the genus Kobuvirus. We have tentatively named this novel virus klassevirus 1. We also detected klassevirus 1 by RT-PCR in a diarrhea specimen collected from a patient in St. Louis, United States as well as in untreated sewage collected in Barcelona, Spain. CONCLUSION: Klassevirus 1 is a previously undescribed picornavirus that is globally widespread and present on at least three continents. Further investigations to determine whether klassevirus 1 is a human pathogen are needed.
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ItemImmunogenicity of a Third Scheduled Dose of Rotarix in Australian Indigenous Infants: A Phase IV, Double-blind, Randomized, Placebo-Controlled Clinical Trial(OXFORD UNIV PRESS INC, 2022-11-01)BACKGROUND: Rotarix (GlaxoSmithKline) oral rotavirus vaccine is licensed as 2 doses in the first 6 months of life. In settings with high child mortality rates, clinical protection conferred by 2 doses of Rotarix is reduced. We assessed vaccine immune response when an additional dose of Rotarix was given to Australian Aboriginal children 6 to <12 months old. METHODS: ORVAC is a 2-stage, double-blind, randomized, placebo-controlled trial. Australian Aboriginal children 6 to <12 months old who had received 1 or 2 prior doses of Rotarix rotavirus vaccine were randomized 1:1 to receive an additional dose of Rotarix or matched placebo. The primary immunological end point was seroresponse defined as an anti-rotavirus immunoglobulin A level ≥20 AU/mL, 28-56 days after the additional dose of Rotarix or placebo. RESULTS: Between March 2018 and August 2020, a total of 253 infants were enrolled. Of these, 178 infants (70%) had analyzable serological results after follow-up; 89 were randomized to receive Rotarix, and 89 to receive placebo. The proportion with seroresponse was 85% after Rotarix compared with 72% after placebo. There were no occurrences of intussusception or any serious adverse events. CONCLUSIONS: An additional dose of Rotarix administered to Australian Aboriginal infants 6 to <12 months old increased the proportion with a vaccine seroresponse. CLINICAL TRIALS REGISTRATION: NCT02941107.
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ItemPhylogenetic and immunoinformatic analysis of VP4, VP7, and NSP4 genes of rotavirus strains circulating in children with acute gastroenteritis in Indonesia(WILEY, 2019-10)Rotavirus is a major cause of diarrhea in Indonesian children. However, rotavirus vaccines have not been introduced in the national immunization program of Indonesia. Understanding the genetic diversity and conserved antigenic regions of circulating strains are therefore essential to assess the potential efficacy of rotavirus vaccines. We collected fecal samples from hospitalized children less than 5 years of age with acute diarrhea. Rotavirus genotyping was performed by reverse transcriptase polymerase chain reaction, followed by sequencing of the VP4, VP7, and NSP4 genes of representative strains. Phylogenetic analysis was performed to investigate their relationship with globally circulating strains. Conservational analysis, immunoinformatics, and epitope mapping in comparison to vaccine strains were also performed. The sequence analyses showed that differences of multiple amino acid residues existed between the VP4, VP7, and NSP4 antigenic regions of the vaccine strains and the Indonesian isolates. However, many predicted conserved epitopes with higher antigenicity were observed in the vaccine and Indonesian strains, conferring the importance of these epitopes. The identified epitopes showed a higher potential of rotavirus vaccine to be employed in Indonesia. It could also be helpful to inform the design of a peptide vaccine based on the conserved regions and epitopes in the viral proteins.
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ItemRotavirus vaccine implementation: evidence to fill the gap?(ELSEVIER SCI LTD, 2021-07)
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ItemLuminal microbiota related to Crohn's disease recurrence after surgery(TAYLOR & FRANCIS INC, 2020-11-01)BACKGROUND: Microbial factors are likely to be involved in the recurrence of Crohn's disease (CD) after bowel resection. We investigated the luminal microbiota before and longitudinally after surgery, in relation to disease recurrence, using 16S metagenomic techniques. METHODS: In the prospective Post-Operative Crohn's Endoscopic Recurrence (POCER) study, fecal samples were obtained before surgery and 6, 12, and 18 months after surgery from 130 CD patients. Endoscopy was undertaken to detect disease recurrence, defined as Rutgeerts score ≥i2, at 6 months in two-thirds of patients and all patients at 18 months after surgery. The V2 region of the 16S rRNA gene was sequenced using Illumina MiSeq. Cluster analysis was performed at family level, assessing microbiome community differences between patients with and without recurrence. RESULTS: Six microbial cluster groups were identified. The cluster associated with maintenance of remission was enriched for the Lachnospiraceae family [adjusted OR 0.47 (0.27-0.82), P = .007]. The OTU diversity of Lachnospiraceae within this cluster was significantly greater than in all other clusters. The cluster enriched for Enterobacteriaceae was associated with an increased risk of disease recurrence [adjusted OR 6.35 (1.24-32.44), P = .026]. OTU diversity of Enterobacteriaceae within this cluster was significantly greater than in other clusters. CONCLUSIONS: Luminal bacterial communities are associated with protection from, and the occurrence of, Crohn's disease recurrence after surgery. Recurrence may relate to a higher abundance of facultatively anaerobic pathobionts from the Enterobacteriaceae family. The ecologic change of depleted Lachnospiraceae, a genus of butyrate-producing bacteria, may permit expansion of Enterobacteriaceae through luminal environmental perturbation.
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