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Wagner J, Handley A, Donato CM, Lyons EA, Pavlic D, Ong DS, Bonnici R, Bogdanovic-Sakran N, Parker EPK, Bronowski C, Thobari JA, Satria CD, Nirwati H, Witte D, Jere KC, Mpakiza A, Watts E, Turner A, Boniface K, Mandolo J, Justice F, Bar-Zeev N, Iturriza-Gomara M, Buttery JP, Cunliffe NA, Soenarto Y, Bines JE. Early-life gut microbiome associates with positive vaccine take and shedding in neonatal schedule of the human neonatal rotavirus vaccine RV3-BB. Nat Commun 2025; 16:3432. [PMID: 40210877 PMCID: PMC11986061 DOI: 10.1038/s41467-025-58632-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 03/26/2025] [Indexed: 04/12/2025] Open
Abstract
Rotavirus vaccines are less effective in high mortality regions. A rotavirus vaccine administered at birth may overcome challenges to vaccine uptake posed by a complex gut microbiome. We investigated the association between the microbiome and vaccine responses following RV3-BB vaccine (G3P[6]) administered in a neonatal schedule (dose 1: 0-5 days), or infant schedule (dose 1: 6-8 weeks) in Indonesia (Phase 2b efficacy study) (n = 478 samples/193 infants) (ACTRN12612001282875) and in Malawi (Immunigenicity study) (n = 355 samples/186 infants) (NCT03483116). Vaccine responses assessed using anti-rotavirus IgA seroconversion (IgA), stool shedding of vaccine virus and vaccine take (IgA seroconversion and/or shedding). Here we report, high alpha diversity, beta diversity differences and high abundance of Bacteroides is associated with positive vaccine take and shedding following RV3-BB administered in the neonatal schedule, but not with IgA seroconversion, or in the infant schedule. Higher alpha diversity was associated with shedding after three doses of RV3-BB in the neonatal schedule compared to non-shedders, or the placebo group. High abundance of Streptococcus and Staphylococcus is associated with no shedding in the neonatal schedule group. RV3-BB vaccine administered in a neonatal schedule modulates the early microbiome environment and presents a window of opportunity to optimise protection from rotavirus disease.
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Affiliation(s)
- Josef Wagner
- Enteric Diseases, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
- Respiratory Virus and Microbiome Initiative, Wellcome Sanger Institute, Hinxton, UK.
- Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.
| | - Amanda Handley
- Enteric Diseases, Murdoch Children's Research Institute, Parkville, Victoria, Australia
- Medicines Development for Global Health, Melbourne, Victoria, Australia
| | - Celeste M Donato
- Enteric Diseases, Murdoch Children's Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia
| | - Eleanor A Lyons
- Enteric Diseases, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Daniel Pavlic
- Enteric Diseases, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | | | - Rhian Bonnici
- Enteric Diseases, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | | | - Edward P K Parker
- Department of Infectious Disease Epidemiology and International Health, London School of Hygiene and Tropical Medicine, London, UK
| | - Christina Bronowski
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
| | - Jarir At Thobari
- Department of Pharmacology and Therapy, Faculty of Medicine, Nursing and Universitas Gadjah Mada, Yogyakarta, Indonesia
- Pediatric Research Office, Department of Pediatrics, Faculty of Medicine, Nursing and Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Cahya Dewi Satria
- Pediatric Research Office, Department of Pediatrics, Faculty of Medicine, Nursing and Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Hera Nirwati
- Department of Microbiology, Faculty of Medicine, Nursing and Universitas Gadjah Mada, Yogyakarta, Indonesia, Faculty of Medicine, Nursing and Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Desiree Witte
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
- Malawi Liverpool Wellcome Programme, Blantyre, P.O. Box 30096, Chichiri, Malawi
| | - Khuzwayo C Jere
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
- Malawi Liverpool Wellcome Programme, Blantyre, P.O. Box 30096, Chichiri, Malawi
| | - Ashley Mpakiza
- Malawi Liverpool Wellcome Programme, Blantyre, P.O. Box 30096, Chichiri, Malawi
| | - Emma Watts
- Enteric Diseases, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Ann Turner
- Malawi Liverpool Wellcome Programme, Blantyre, P.O. Box 30096, Chichiri, Malawi
| | - Karen Boniface
- Enteric Diseases, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Jonathan Mandolo
- Malawi Liverpool Wellcome Programme, Blantyre, P.O. Box 30096, Chichiri, Malawi
- Department of Clinical Science, Liverpool School of Tropical Medicine, Liverpool, UK
| | - Frances Justice
- Enteric Diseases, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Naor Bar-Zeev
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
| | - Miren Iturriza-Gomara
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
- GSK Vaccines for Global Health Institute, Sienna, Italy
| | - Jim P Buttery
- Enteric Diseases, Murdoch Children's Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia
- Department of Infectious Diseases, Royal Children's Hospital, Parkville, Australia
| | - Nigel A Cunliffe
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
| | - Yati Soenarto
- Pediatric Research Office, Department of Pediatrics, Faculty of Medicine, Nursing and Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Julie E Bines
- Enteric Diseases, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
- Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.
- Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Parkville, Australia.
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Morgan B, Lyons EA, Handley A, Bogdanovic-Sakran N, Pavlic D, Witte D, Mandolo J, Turner A, Jere KC, Justice F, Ong DS, Bonnici R, Boniface K, Donato CM, Mpakiza A, Meyer A, Bar-Zeev N, Iturriza-Gomara M, Cunliffe NA, Danchin M, Bines JE. Rotavirus-Specific Maternal Serum Antibodies and Vaccine Responses to RV3-BB Rotavirus Vaccine Administered in a Neonatal or Infant Schedule in Malawi. Viruses 2024; 16:1488. [PMID: 39339964 PMCID: PMC11437397 DOI: 10.3390/v16091488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 09/11/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
High titres of rotavirus-specific maternal antibodies may contribute to lower rotavirus vaccine efficacy in low- and middle-income countries (LMICs). RV3-BB vaccine (G3P[6]) is based on a neonatal rotavirus strain that replicates well in the newborn gut in the presence of breast milk. This study investigated the association between maternal serum antibodies and vaccine response in infants administered the RV3-BB vaccine. Serum was collected antenatally from mothers of 561 infants enrolled in the RV3-BB Phase II study conducted in Blantyre, Malawi, and analysed for rotavirus-specific serum IgA and IgG antibodies using enzyme-linked immunosorbent assay. Infant vaccine take was defined as cumulative IgA seroconversion (≥3 fold increase) and/or stool vaccine shedding. Maternal IgA or IgG antibody titres did not have a negative impact on vaccine-like stool shedding at any timepoint. Maternal IgG (but not IgA) titres were associated with reduced take post dose 1 (p < 0.005) and 3 (p < 0.05) in the neonatal vaccine schedule group but not at study completion (week 18). In LMICs where high maternal antibodies are associated with low rotavirus vaccine efficacy, RV3-BB in a neonatal or infant vaccine schedule has the potential to provide protection against severe rotavirus disease.
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Affiliation(s)
- Benjamin Morgan
- Enteric Diseases, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia (A.H.); (N.B.-S.); (D.P.); (F.J.); (D.S.O.); (R.B.); (C.M.D.); (M.D.)
| | - Eleanor A. Lyons
- Enteric Diseases, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia (A.H.); (N.B.-S.); (D.P.); (F.J.); (D.S.O.); (R.B.); (C.M.D.); (M.D.)
| | - Amanda Handley
- Enteric Diseases, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia (A.H.); (N.B.-S.); (D.P.); (F.J.); (D.S.O.); (R.B.); (C.M.D.); (M.D.)
- Medicines Development for Global Health, Melbourne, VIC 3001, Australia
| | - Nada Bogdanovic-Sakran
- Enteric Diseases, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia (A.H.); (N.B.-S.); (D.P.); (F.J.); (D.S.O.); (R.B.); (C.M.D.); (M.D.)
| | - Daniel Pavlic
- Enteric Diseases, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia (A.H.); (N.B.-S.); (D.P.); (F.J.); (D.S.O.); (R.B.); (C.M.D.); (M.D.)
| | - Desiree Witte
- Malawi Liverpool Welcome Trust Programme, Blantyre P.O. Box 30096, Chichi, Malawi; (D.W.); (J.M.); (K.C.J.)
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L69 7ZX, UK; (A.T.); (M.I.-G.); (N.A.C.)
| | - Jonathan Mandolo
- Malawi Liverpool Welcome Trust Programme, Blantyre P.O. Box 30096, Chichi, Malawi; (D.W.); (J.M.); (K.C.J.)
- Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK
| | - Ann Turner
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L69 7ZX, UK; (A.T.); (M.I.-G.); (N.A.C.)
| | - Khuzwayo C. Jere
- Malawi Liverpool Welcome Trust Programme, Blantyre P.O. Box 30096, Chichi, Malawi; (D.W.); (J.M.); (K.C.J.)
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L69 7ZX, UK; (A.T.); (M.I.-G.); (N.A.C.)
| | - Frances Justice
- Enteric Diseases, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia (A.H.); (N.B.-S.); (D.P.); (F.J.); (D.S.O.); (R.B.); (C.M.D.); (M.D.)
| | - Darren Suryawijaya Ong
- Enteric Diseases, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia (A.H.); (N.B.-S.); (D.P.); (F.J.); (D.S.O.); (R.B.); (C.M.D.); (M.D.)
| | - Rhian Bonnici
- Enteric Diseases, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia (A.H.); (N.B.-S.); (D.P.); (F.J.); (D.S.O.); (R.B.); (C.M.D.); (M.D.)
| | - Karen Boniface
- Enteric Diseases, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia (A.H.); (N.B.-S.); (D.P.); (F.J.); (D.S.O.); (R.B.); (C.M.D.); (M.D.)
| | - Celeste M. Donato
- Enteric Diseases, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia (A.H.); (N.B.-S.); (D.P.); (F.J.); (D.S.O.); (R.B.); (C.M.D.); (M.D.)
| | - Ashley Mpakiza
- Malawi Liverpool Welcome Trust Programme, Blantyre P.O. Box 30096, Chichi, Malawi; (D.W.); (J.M.); (K.C.J.)
| | - Anell Meyer
- Enteric Diseases, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia (A.H.); (N.B.-S.); (D.P.); (F.J.); (D.S.O.); (R.B.); (C.M.D.); (M.D.)
- Department of Gastroenterology and Clinical Nutrition, Royal Children’s Hospital, Parkville, VIC 3052, Australia
| | - Naor Bar-Zeev
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L69 7ZX, UK; (A.T.); (M.I.-G.); (N.A.C.)
| | - Miren Iturriza-Gomara
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L69 7ZX, UK; (A.T.); (M.I.-G.); (N.A.C.)
- GSK Vaccines for Global Health Institute, 53100 Sienna, Italy
| | - Nigel A. Cunliffe
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L69 7ZX, UK; (A.T.); (M.I.-G.); (N.A.C.)
| | - Margaret Danchin
- Enteric Diseases, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia (A.H.); (N.B.-S.); (D.P.); (F.J.); (D.S.O.); (R.B.); (C.M.D.); (M.D.)
- GSK Vaccines for Global Health Institute, 53100 Sienna, Italy
- Department of General Medicine, Royal Children’s Hospital, Parkville, VIC 3052, Australia
| | - Julie E. Bines
- Enteric Diseases, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia (A.H.); (N.B.-S.); (D.P.); (F.J.); (D.S.O.); (R.B.); (C.M.D.); (M.D.)
- Department of Gastroenterology and Clinical Nutrition, Royal Children’s Hospital, Parkville, VIC 3052, Australia
- Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia
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Donato CM, Handley A, Byars SG, Bogdanovic-Sakran N, Lyons EA, Watts E, Ong DS, Pavlic D, At Thobari J, Satria CD, Nirwati H, Soenarto Y, Bines JE. Vaccine Take of RV3-BB Rotavirus Vaccine Observed in Indonesian Infants Regardless of HBGA Status. J Infect Dis 2024; 229:1010-1018. [PMID: 37592804 PMCID: PMC11011179 DOI: 10.1093/infdis/jiad351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/19/2023] Open
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 G3P[6] 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.
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Affiliation(s)
- Celeste M Donato
- Enteric Diseases Group, Murdoch Children's Research Institute
- Department of Paediatrics, The University of Melbourne, Parkville
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne
| | - Amanda Handley
- Enteric Diseases Group, Murdoch Children's Research Institute
- Medicines Development for Global Health, Southbank
| | - Sean G Byars
- Florey Institute of Neuroscience and Mental Health, Parkville, Australia
| | | | - Eleanor A Lyons
- Enteric Diseases Group, Murdoch Children's Research Institute
| | - Emma Watts
- Enteric Diseases Group, Murdoch Children's Research Institute
| | - Darren S Ong
- Enteric Diseases Group, Murdoch Children's Research Institute
| | - Daniel Pavlic
- Enteric Diseases Group, Murdoch Children's Research Institute
| | | | | | - Hera Nirwati
- Center for Child Health
- Department of Microbiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada
| | - Yati Soenarto
- Center for Child Health
- Department of Child Health, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr Sardjito Hospital, Yogyakarta, Indonesia
| | - Julie E Bines
- Enteric Diseases Group, Murdoch Children's Research Institute
- Department of Paediatrics, The University of Melbourne, Parkville
- Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Parkville, Australia
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Vaccine evaluation and genotype characterization in children infected with rotavirus in Qatar. Pediatr Res 2023:10.1038/s41390-023-02468-7. [PMID: 36658331 PMCID: PMC10382313 DOI: 10.1038/s41390-023-02468-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 09/29/2022] [Accepted: 12/14/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND We characterized and identified the genetic and antigenic variations of circulating rotavirus strains in comparison to used rotavirus vaccines. METHODS Rotavirus-positive samples (n = 231) were collected and analyzed. The VP7 and VP4 genes were sequenced and analyzed against the rotavirus vaccine strains. Antigenic variations were illustrated on the three-dimensional models of surface proteins. RESULTS In all, 59.7% of the hospitalized children were vaccinated, of which only 57.2% received two doses. There were no significant differences between the vaccinated and non-vaccinated groups in terms of clinical outcome. The G3 was the dominant genotype (40%) regardless of vaccination status. Several amino acid changes were identified in the VP7 and VP4 antigenic epitopes compared to the licensed vaccines. The highest variability was seen in the G3 (6 substitutions) and P[4] (11 substitutions) genotypes in comparison to RotaTeq®. In comparison to Rotarix®, G1 strains possessed three amino acid changes in 7-1a and 7-2 epitopes while P[8] strains possessed five amino acid changes in 8-1 and 8-3 epitopes. CONCLUSIONS The current use of Rotarix® vaccine might not be effective in preventing the infection due to the higher numbers of G3-associated cases. The wide range of mutations in the antigenic epitopes compared to vaccine strains may compromise the vaccine's effectiveness. IMPACT The reduced rotavirus vaccine effectiveness necessitate regular evaluation of the vaccine content to ensure optimal protection. We characterized and identified the genetic and antigenic variations of circulating rotavirus strains in comparison to the Rotarix vaccine strain that is used in Qatar. The study highlight the importance for regular monitoring of emerging rotavirus variants and their impact on vaccine effectiveness in young children.
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Witte D, Handley A, Jere KC, Bogandovic-Sakran N, Mpakiza A, Turner A, Pavlic D, Boniface K, Mandolo J, Ong DS, Bonnici R, Justice F, Bar-Zeev N, Iturriza-Gomara M, Ackland J, Donato CM, Cowley D, Barnes G, Cunliffe NA, Bines JE. Neonatal rotavirus vaccine (RV3-BB) immunogenicity and safety in a neonatal and infant administration schedule in Malawi: a randomised, double-blind, four-arm parallel group dose-ranging study. THE LANCET. INFECTIOUS DISEASES 2022; 22:668-678. [PMID: 35065683 PMCID: PMC9021029 DOI: 10.1016/s1473-3099(21)00473-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/14/2021] [Accepted: 07/30/2021] [Indexed: 11/24/2022]
Abstract
Background Rotavirus vaccines reduce rotavirus-related deaths and hospitalisations but are less effective in high child mortality countries. The human RV3-BB neonatal G3P[6] rotavirus vaccine administered in a neonatal schedule was efficacious in reducing severe rotavirus gastroenteritis in Indonesia but had not yet been evaluated in African infants. Methods We did a phase 2, randomised, double-blind, parallel group dose-ranging study of three doses of oral RV3-BB rotavirus vaccine in infants in three primary health centres in Blantyre, Malawi. Healthy infants less than 6 days of age with a birthweight 2·5 to 4·0 kg were randomly assigned (1:1:1:1) into one of four treatment groups: neonatal vaccine group, which included high-titre (1·0 × 107 focus-forming unit [FFU] per mL), mid-titre (3·0 × 106 FFU per mL), or low-titre (1·0 × 106 FFU per mL); and infant vaccine group, which included high-titre (1·0 × 107 FFU per mL) using a computer generated code (block size of four), stratified by birth (singleton vs multiple). Neonates received their three doses at 0–5 days to 10 weeks and infants at 6–14 weeks. Investigators, participant families, and laboratory staff were masked to group allocation. Anti-rotavirus IgA seroconversion and vaccine take (IgA seroconversion and stool shedding) were evaluated. Safety was assessed in all participants who received at least one dose of vaccine or placebo. The primary outcome was the cumulative IgA seroconversion 4 weeks after three doses of RV3-BB in the neonatal schedule in the high-titre, mid-titre, and low-titre groups in the per protocol population, with its 95% CI. With the high-titre group as the active control group, we did a non-inferiority analysis of the proportion of participants with IgA seroconversion in the mid-titre and low-titre groups, using a non-inferiority margin of less than 20%. This trial is registered at ClinicalTrials.gov (NCT03483116). Findings Between Sept 17, 2018, and Jan 27, 2020, 711 participants recruited were randomly assigned into four treatment groups (neonatal schedule high titre n=178, mid titre n=179, low titre n=175, or infant schedule high titre n=179). In the neonatal schedule, cumulative IgA seroconversion 4 weeks after three doses of RV3-BB was observed in 79 (57%) of 139 participants in the high-titre group, 80 (57%) of 141 participants in the mid-titre group, and 57 (41%) of 138 participants in the low-titre group and at 18 weeks in 100 (72%) of 139 participants in the high-titre group, 96 (67%) of 143 participants in the mid-titre group, and 86 (62%) of 138 of participants in the low-titre. No difference in cumulative IgA seroconversion 4 weeks after three doses of RV3-BB was observed between high-titre and mid-titre groups in the neonatal schedule (difference in response rate 0·001 [95%CI −0·115 to 0·117]), fulfilling the criteria for non-inferiority. In the infant schedule group 82 (59%) of 139 participants had a cumulative IgA seroconversion 4 weeks after three doses of RV3-BB at 18 weeks. Cumulative vaccine take was detected in 483 (85%) of 565 participants at 18 weeks. Three doses of RV3-BB were well tolerated with no difference in adverse events among treatment groups: 67 (39%) of 170 participants had at least one adverse event in the high titre group, 68 (40%) of 172 participants had at least one adverse event in the mid titre group, and 69 (41%) of 169 participants had at least one adverse event in the low titre group. Interpretation RV3-BB was well tolerated and immunogenic when co-administered with Expanded Programme on Immunisation vaccines in a neonatal or infant schedule. A lower titre (mid-titre) vaccine generated similar IgA seroconversion to the high-titre vaccine presenting an opportunity to enhance manufacturing capacity and reduce costs. Neonatal administration of the RV3-BB vaccine has the potential to improve protection against rotavirus disease in children in a high-child mortality country in Africa. Funding Bill & Melinda Gates Foundation, Australian Tropical Medicine Commercialisation Grant.
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Affiliation(s)
- Desiree Witte
- Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
| | - Amanda Handley
- Murdoch Children's Research Institute, Parkville, VIC, Australia; Medicines Development for Global Health, Southbank, VIC, Australia
| | - Khuzwayo C Jere
- Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK; Kamuzu University of Health Sciences, Blantyre, Malawi
| | | | - Ashley Mpakiza
- Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi
| | - Ann Turner
- Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
| | - Daniel Pavlic
- Murdoch Children's Research Institute, Parkville, VIC, Australia
| | - Karen Boniface
- Murdoch Children's Research Institute, Parkville, VIC, Australia
| | - Jonathan Mandolo
- Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi
| | | | - Rhian Bonnici
- Murdoch Children's Research Institute, Parkville, VIC, Australia
| | - Frances Justice
- Murdoch Children's Research Institute, Parkville, VIC, Australia
| | - Naor Bar-Zeev
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK; International Vaccine Access Center, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Miren Iturriza-Gomara
- NIHR Health Protection Research Unit in Gastrointestinal Infections, University of Liverpool, Liverpool, UK; Centre for Vaccine Innovation and Access, Program for Appropriate Technology in Health, Seattle, WA, USA
| | - Jim Ackland
- Global BioSolutions, Melbourne, VIC, Australia
| | - Celeste M Donato
- Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia
| | - Daniel Cowley
- Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia
| | - Graeme Barnes
- Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia
| | - Nigel A Cunliffe
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK; NIHR Health Protection Research Unit in Gastrointestinal Infections, University of Liverpool, Liverpool, UK
| | - Julie E Bines
- Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Parkville, VIC, Australia; Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia.
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Ranshing S, Ganorkar N, Ramji S, Gopalkrishna V. Complete genomic analysis of uncommon G12P[11] rotavirus causing a nosocomial outbreak of acute diarrhea in the newborns in New Delhi, India. J Med Virol 2021; 94:2613-2623. [PMID: 34811775 DOI: 10.1002/jmv.27468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 11/19/2021] [Indexed: 11/06/2022]
Abstract
Rotaviruses (RVs) are the major causative agents of acute gastroenteritis in children, but in neonates, RV infections are generally nosocomial in origin and mostly asymptomatic. However, there have been infrequent reports of nosocomial outbreaks of clinical disease in this population. In this study, we describe uncommon RV genotype; G12P[11] associated with an outbreak of acute gastroenteritis in the neonatal ward and neonatal intensive care unit (NICU) in New Delhi, North India. Full-genome analyses of the pathogenic G12P[11] strain was carried out to map the genotype constellation and further to explore the variations in the antigenic epitopes on the immunodominant VP7 and VP4 proteins, the amino acid sequences were compared with neonatal strains; ROTAVAC® (G9P[11]) and asymptomatic G12P[11] and also other G/P-type matched strains. The study revealed G12-P[11]-I1-R1-C1-M1-A1-N1-T1-E1-H1 human Wa-like genotype constellation and highlights evidence of gene reassortment. No significant differences were observed in the sequences of structural (except VP3) and nonstructural encoding genes of G12P[11] strains recovered from symptomatic and asymptomatic neonates. Presence of additional N-linked glycosylation site was noted in the G12 strains, as a consequence of a change from Asp→Asn at amino acid position 238. Interestingly, only two and four amino acids substitution within the 7-1a and 8-1 antigenic epitope were observed, respectively, compared with asymptomatic G12P[11] strain. The study emphasizes the importance of close monitoring of RV outbreaks in neonates for early alarming of novel strain.
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Affiliation(s)
- Sujata Ranshing
- Enteric Viruses Group, ICMR-National Institute of Virology, Pune, India
| | - Nital Ganorkar
- Enteric Viruses Group, ICMR-National Institute of Virology, Pune, India
| | - Siddarth Ramji
- Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India
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Ranshing SS, Cherian SS, Agarwal MS, Jagtap AS, Patil CM, Gopalkrishna V. Full genome based sequence and structural characterization of an unusual group A rotavirus G12P[11] isolated from neonates in Pune, western India. Vaccine 2020; 38:2275-2291. [DOI: 10.1016/j.vaccine.2020.01.081] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 01/24/2020] [Accepted: 01/27/2020] [Indexed: 11/27/2022]
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Gene-edited vero cells as rotavirus vaccine substrates. Vaccine X 2019; 3:100045. [PMID: 31660537 PMCID: PMC6806661 DOI: 10.1016/j.jvacx.2019.100045] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 08/30/2019] [Accepted: 10/04/2019] [Indexed: 12/13/2022] Open
Abstract
Background Rotavirus (RV) is a leading cause of severe gastroenteritis globally and can cause substantial morbidity associated with gastroenteritis in children <5 years of age. Orally administered live-attenuated RV vaccines offer protection against disease but vaccination efforts have been hampered by high manufacturing costs and the need to maintain a cold chain. Methods A subset of Vero cell host genes was identified by siRNA that when knocked down increased RV replication and these anti-viral host genes were individually deleted using CRISPR-Cas9. Results Fully-sequenced gene knockout Vero cell substrates were assessed for increased RV replication and RV vaccine antigen expression compared to wild type Vero cells. The results showed that RV replication and antigen production were logs higher in Vero cells having an EMX2 gene deletion compared to other Vero cell substrates tested. Conclusions We used siRNAs to screen for host genes that negatively affected RV replication, then CRISPR-Cas9 gene editing to delete select genes. The gene editing led to the development of enhanced RV vaccine substrates supporting a potential path forward for improving RV vaccine production.
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Khametova KM, Alekseev KP, Yuzhakov AG, Kostina LV, Raev SA, Musienko MI, Mukhin AN, Aliper TI, Vorkunova GK, Grebennikova TV. EVALUATION OF THE MOLECULAR-BIOLOGICAL PROPERTIES OF HUMAN ROTAVIRUS A STRAIN WA. ACTA ACUST UNITED AC 2019; 64:16-22. [DOI: 10.18821/0507-4088-2019-64-1-16-22] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 10/31/2018] [Indexed: 01/19/2023]
Abstract
Introduction. Rоtaviruses are amоng the leading causes of severe diarrhea in children all over the Wоrld. Vaccination is considered to be the mоst effective way to cоntrоl the disease. Currently available vaccines for prevention of rоtavirus infection are based on live attenuated rotavirus strains human оr animal origin. Objectives and purposes. The aim of this investigation was to study the biological and genetic properties of an actual epidemic human rotavirus A (RVA) strain Wa G1P[8] genotype. Material and methods. RVA Wa reproduction in a monolayer continuous cell lines, purification and concentration of RVA antigen, PAAG electrophoresis and Western-Blot, electrophoresis of viral genomic RNA segments, sequencing. Results. Human RVA G1P[8] Wa strain biological and molecular genetic properties were assessed in the process of the adaptation to MARC145 continuous cell line. Cell cultured RVA antigen was purified, concentrated and then characterized by the method of PAAG electrophoresis and immunoblot. To verify RVA Wa genome identity, electrophoresis of viral genomic RNA segments was performed. The lack of accumulation of changes in the RVA Wa genome during adaptation to various cell cultures and during serial passages was demonstrated by sequencing fragments of the viral genome. Conclusion. RVA Wa strain is stable, it possesses high biological activity: it has been successfully adapted to the MARC145 cell line and RVA Wa virus titer after the adaptation reached 7,5-7,7 lg TCID50/ml. The identity of the cultivated RVA to the original strain Wa G1P[8] was confirmed.
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Affiliation(s)
- K. M. Khametova
- Ivanovsky Virology Institute, «National Research Center for Epidemiology and Microbiology named after the honorary academician NF. Gamaleya»
| | - K. P. Alekseev
- Ivanovsky Virology Institute, «National Research Center for Epidemiology and Microbiology named after the honorary academician NF. Gamaleya»
| | - A. G. Yuzhakov
- Ivanovsky Virology Institute, «National Research Center for Epidemiology and Microbiology named after the honorary academician NF. Gamaleya»
| | - L. V. Kostina
- Ivanovsky Virology Institute, «National Research Center for Epidemiology and Microbiology named after the honorary academician NF. Gamaleya»
| | - S. A. Raev
- Ivanovsky Virology Institute, «National Research Center for Epidemiology and Microbiology named after the honorary academician NF. Gamaleya»
| | - M. I. Musienko
- Ivanovsky Virology Institute, «National Research Center for Epidemiology and Microbiology named after the honorary academician NF. Gamaleya»
| | - A. N. Mukhin
- Ivanovsky Virology Institute, «National Research Center for Epidemiology and Microbiology named after the honorary academician NF. Gamaleya»
| | - T. I. Aliper
- Ivanovsky Virology Institute, «National Research Center for Epidemiology and Microbiology named after the honorary academician NF. Gamaleya»
| | - G. K. Vorkunova
- Ivanovsky Virology Institute, «National Research Center for Epidemiology and Microbiology named after the honorary academician NF. Gamaleya»
| | - T. V. Grebennikova
- Ivanovsky Virology Institute, «National Research Center for Epidemiology and Microbiology named after the honorary academician NF. Gamaleya»; Peoples Frendship University of Russia (RUDN)
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Ghosh S, Malik YS, Kobayashi N. Therapeutics and Immunoprophylaxis Against Noroviruses and Rotaviruses: The Past, Present, and Future. Curr Drug Metab 2018; 19:170-191. [PMID: 28901254 PMCID: PMC5971199 DOI: 10.2174/1389200218666170912161449] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 09/25/2016] [Accepted: 03/19/2017] [Indexed: 12/20/2022]
Abstract
Background: Noroviruses and rotaviruses are important viral etiologies of severe gastroenteritis. Noroviruses are the primary cause of nonbacterial diarrheal outbreaks in humans, whilst rotaviruses are a major cause of childhood diarrhea. Although both enteric pathogens substantially impact human health and economies, there are no approved drugs against noroviruses and rotaviruses so far. On the other hand, whilst the currently licensed rotavirus vaccines have been successfully implemented in over 100 countries, the most advanced norovirus vaccine has recently completed phase-I and II trials. Methods: We performed a structured search of bibliographic databases for peer-reviewed research litera-ture on advances in the fields of norovirus and rotavirus therapeutics and immunoprophylaxis. Results: Technological advances coupled with a proper understanding of viral morphology and replication over the past decade has facilitated pioneering research on therapeutics and immunoprophylaxis against noroviruses and rotaviruses, with promising outcomes in human clinical trials of some of the drugs and vaccines. This review focuses on the various developments in the fields of norovirus and rotavirus thera-peutics and immunoprophylaxis, such as potential antiviral drug molecules, passive immunotherapies (oral human immunoglobulins, egg yolk and bovine colostral antibodies, llama-derived nanobodies, and anti-bodies expressed in probiotics, plants, rice grains and insect larvae), immune system modulators, probiot-ics, phytochemicals and other biological substances such as bovine milk proteins, therapeutic nanoparti-cles, hydrogels and viscogens, conventional viral vaccines (live and inactivated whole virus vaccines), and genetically engineered viral vaccines (reassortant viral particles, virus-like particles (VLPs) and other sub-unit recombinant vaccines including multi-valent viral vaccines, edible plant vaccines, and encapsulated viral particles). Conclusions: This review provides important insights into the various approaches to therapeutics and im-munoprophylaxis against noroviruses and rotaviruses..
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Affiliation(s)
- Souvik Ghosh
- Department of Biomedical Sciences, Ross University School of Veterinary Medicine, St. Kitts and Nevis, West Indies.,Department of Hygiene, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
| | - Yashpal Singh Malik
- Indian Veterinary Research Institute, Izatnagar 243 122, Uttar Pradesh, India
| | - Nobumichi Kobayashi
- Department of Hygiene, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
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Wu JY, Zhou Y, Zhang GM, Mu GF, Yi S, Yin N, Xie YP, Lin XC, Li HJ, Sun MS. Isolation and characterization of a new candidate human inactivated rotavirus vaccine strain from hospitalized children in Yunnan, China: 2010-2013. World J Clin Cases 2018; 6:426-440. [PMID: 30294607 PMCID: PMC6163142 DOI: 10.12998/wjcc.v6.i11.426] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 07/23/2018] [Accepted: 08/02/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To determine the distribution of rotavirus VP7 gene in hospitalized children in Yunnan, China.
METHODS A total of 366 stool specimens were collected from hospitalized children in hospitals in Yunnan Province from September 2010 to December 2013. The genomic RNA electropherotypes and the G genotypes of the rotaviruses were determined. A phylogenetic analysis of the VP7 gene was performed. Rotavirus isolation was performed, and characterized by plaque, minimum essential medium, and all genes sequence analysis. Quantification of antibodies for inactivated vaccine prepared with ZTR-68 was examined by enzyme-linked immunosorbent assay and microneutralization assay.
RESULTS Group A human rotavirus was detected in 177 of 366 (48.4%) stool samples using a colloidal gold device assay. The temporal distribution of rotavirus cases showed significant correlation with the mean air temperature. Rotaviruses were isolated from 13% of the rotavirus-positive samples. The predominant genotype was G1 (43.5%), followed by G3 (21.7%), G9 (17.4%), G2 (4.3%), G4 (8.7%), and mixed (4.3%) among a total of 23 rotavirus isolates. A rotavirus strain was isolated from a rotavirus-positive stool sample of a 4-month-old child in The First People’s Hospital of Zhaotong (2010) for use as a candidate human inactivated rotavirus vaccine strain and for further research, and was designated ZTR-68. The genotype of 11 gene segments of strain ZTR-68 (RVA/Human-wt/CHN/ZTR-68/2010/G1P[8]) was characterized. The genotype constellation of strain ZTR-68 was identified as G1-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. The VP7 and VP4 genotypes of strain ZTR-68 were similar to Wa-like strains.
CONCLUSIONS
A high prevalence of the G1, G2, and G3 genotypes was detected from 2010 to 2012. However, a dominant prevalence of the G9 genotype was identified as the cause of gastroenteritis in children in Yunnan, China, in 2013. A candidate human inactivated rotavirus vaccine strain, designated ZTR-68 was isolated, characterized, and showed immunogenicity. Our data will be useful for the future formulation and development of a vaccine in China.
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Affiliation(s)
- Jin-Yuan Wu
- Department of Molecular Biology, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, Yunnan Province, China
| | - Yan Zhou
- Department of Molecular Biology, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, Yunnan Province, China
| | - Guang-Ming Zhang
- Department of Molecular Biology, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, Yunnan Province, China
| | - Guo-Fa Mu
- Pediatrics Department, the First People’s Hospital of Zhaotong City, Zhaotong 657000, Yunnan Province, China
| | - Shan Yi
- Department of Molecular Biology, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, Yunnan Province, China
| | - Na Yin
- Department of Molecular Biology, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, Yunnan Province, China
| | - Yu-Ping Xie
- Department of Molecular Biology, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, Yunnan Province, China
| | - Xiao-Chen Lin
- Department of Molecular Biology, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, Yunnan Province, China
| | - Hong-Jun Li
- Department of Molecular Biology, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, Yunnan Province, China
| | - Mao-Sheng Sun
- Department of Molecular Biology, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, Yunnan Province, China
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Cowley D, Nirwati H, Donato CM, Bogdanovic-Sakran N, Boniface K, Kirkwood CD, Bines JE. Molecular characterisation of rotavirus strains detected during a clinical trial of the human neonatal rotavirus vaccine (RV3-BB) in Indonesia. Vaccine 2018; 36:5872-5878. [PMID: 30145099 PMCID: PMC6143382 DOI: 10.1016/j.vaccine.2018.08.027] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 08/07/2018] [Accepted: 08/10/2018] [Indexed: 12/12/2022]
Abstract
Equine-like G3P[8] the major cause of gastroenteritis during RV3-BB efficacy trial. The Indonesian equine-like G3P[8] strain was genetically similar to Hungarian and Spanish strains. Equine-like G3P[8] strain is an emerging cause of gastroenteritis in Indonesia. Background 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. Methods 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. Results There were 1110 episodes of acute gastroenteritis of any severity, 105 episodes were confirmed as rotavirus gastroenteritis by EIA testing. The most common genotype identified was G3P[8] (90/105), the majority (52/56) of severe (Vesikari score ≥11) rotavirus gastroenteritis episodes were due to the G3P[8] strain. Full genome analysis of two representative G3P[8] samples demonstrated the strain was an inter-genogroup reassortant, containing an equine-like G3 VP7, P[8] VP4 and a genogroup 2 backbone I2-R2-C2-M2-A2-N2-T2-E2-H2. The complete genome of the Indonesian equine-like G3P[8] strain demonstrated highest genetic identity to G3P[8] strains circulating in Hungary and Spain. Conclusions The dominant circulating strain during the Indonesian Phase IIb efficacy trial of the RV3-BB vaccine was an equine-like G3P[8] strain. The equine-like G3P[8] strain is an emerging cause of severe gastroenteritis in Indonesia and in other regions.
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Affiliation(s)
- Daniel Cowley
- Enteric Virus Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Rotavirus Program, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia
| | - Hera Nirwati
- Department of Microbiology, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Celeste M Donato
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria, Australia
| | - Nada Bogdanovic-Sakran
- Enteric Virus Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Rotavirus Program, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Karen Boniface
- Enteric Virus Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Rotavirus Program, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Carl D Kirkwood
- Enteric Virus Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia
| | - Julie E Bines
- Enteric Virus Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Rotavirus Program, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia; Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Parkville, Victoria, Australia.
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Hu L, Sankaran B, Laucirica DR, Patil K, Salmen W, Ferreon ACM, Tsoi PS, Lasanajak Y, Smith DF, Ramani S, Atmar RL, Estes MK, Ferreon JC, Prasad BVV. Glycan recognition in globally dominant human rotaviruses. Nat Commun 2018; 9:2631. [PMID: 29980685 PMCID: PMC6035239 DOI: 10.1038/s41467-018-05098-4] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 06/11/2018] [Indexed: 01/01/2023] Open
Abstract
Rotaviruses (RVs) cause life-threatening diarrhea in infants and children worldwide. Recent biochemical and epidemiological studies underscore the importance of histo-blood group antigens (HBGA) as both cell attachment and susceptibility factors for the globally dominant P[4], P[6], and P[8] genotypes of human RVs. How these genotypes interact with HBGA is not known. Here, our crystal structures of P[4] and a neonate-specific P[6] VP8*s alone and in complex with H-type I HBGA reveal a unique glycan binding site that is conserved in the globally dominant genotypes and allows for the binding of ABH HBGAs, consistent with their prevalence. Remarkably, the VP8* of P[6] RVs isolated from neonates displays subtle structural changes in this binding site that may restrict its ability to bind branched glycans. This provides a structural basis for the age-restricted tropism of some P[6] RVs as developmentally regulated unbranched glycans are more abundant in the neonatal gut. Human rotaviruses (RV) bind to histo-blood group antigens (HBGA) for attachment, but how different viral genotypes interact with HBGA isn’t known. Here, Hu et al. report crystal structures of a prevalent and a neonate-specific RV in complex with HBGA and provide insights into glycan recognition and age-restricted tropism of RVs.
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Affiliation(s)
- Liya Hu
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Banumathi Sankaran
- Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
| | - Daniel R Laucirica
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Ketki Patil
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Wilhelm Salmen
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA
| | | | - Phoebe S Tsoi
- Department of Pharmacology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Yi Lasanajak
- Department of Biochemistry and the Emory Comprehensive Glycomics Core, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - David F Smith
- Department of Biochemistry and the Emory Comprehensive Glycomics Core, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Sasirekha Ramani
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Robert L Atmar
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA.,Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Mary K Estes
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA.,Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Josephine C Ferreon
- Department of Pharmacology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - B V Venkataram Prasad
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. .,Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA.
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Bines JE, At Thobari J, Satria CD, Handley A, Watts E, Cowley D, Nirwati H, Ackland J, Standish J, Justice F, Byars G, Lee KJ, Barnes GL, Bachtiar NS, Viska Icanervilia A, Boniface K, Bogdanovic-Sakran N, Pavlic D, Bishop RF, Kirkwood CD, Buttery JP, Soenarto Y. Human Neonatal Rotavirus Vaccine (RV3-BB) to Target Rotavirus from Birth. N Engl J Med 2018; 378:719-730. [PMID: 29466164 PMCID: PMC5774175 DOI: 10.1056/nejmoa1706804] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
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 .).
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Affiliation(s)
- Julie E Bines
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Jarir At Thobari
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Cahya Dewi Satria
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Amanda Handley
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Emma Watts
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Daniel Cowley
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Hera Nirwati
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - James Ackland
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Jane Standish
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Frances Justice
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Gabrielle Byars
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Katherine J Lee
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Graeme L Barnes
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Novilia S Bachtiar
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Ajeng Viska Icanervilia
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Karen Boniface
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Nada Bogdanovic-Sakran
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Daniel Pavlic
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Ruth F Bishop
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Carl D Kirkwood
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Jim P Buttery
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
| | - Yati Soenarto
- From the RV3 Rotavirus Vaccine Program, Murdoch Children's Research Institute (J.E.B., A.H., E.W., D.C., J.S., F.J., G.B., K.J.L., G.L.B., K.B., N.B.-S., D.P., R.F.B., C.D.K., J.P.B.), the Department of Paediatrics, University of Melbourne (J.E.B., D.C., K.J.L., G.L.B., R.F.B., C.D.K., J.P.B.), and the Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne (J.E.B., J.S.), Parkville, the Departments of Paediatrics and of Epidemiology and Preventive Medicine, Monash University, and the Department of Infection and Immunity, Monash Children's Hospital, Clayton (J.P.B.), and Medicines Development for Global Health (A.H.) and Global BioSolutions (J.A.), Melbourne - all in Victoria, Australia; the Department of Pharmacology and Therapy (J.A.T.), the Pediatric Research Office, Department of Paediatrics (C.D.S., A.V.I., Y.S.), and the Department of Microbiology (H.N.), Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and PT Bio Farma, Bandung (N.S.B.) - all in Indonesia; and the Bill and Melinda Gates Foundation, Seattle (C.D.K.)
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Wu W, Orr-Burks N, Karpilow J, Tripp RA. Development of improved vaccine cell lines against rotavirus. Sci Data 2017; 4:170021. [PMID: 28248921 PMCID: PMC5332008 DOI: 10.1038/sdata.2017.21] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 02/02/2017] [Indexed: 11/09/2022] Open
Abstract
Rotavirus is a major cause of severe gastroenteritis among very young children. In developing countries, rotavirus is the major cause of mortality in children under five years old, causing up to 20% of all childhood deaths in countries with high diarrheal disease burden, with more than 90% of these deaths occurring in Africa and Asia. Rotavirus vaccination mimics the first infection without causing illness, thus inducing strong and broad heterotypic immunity against prospective rotavirus infections. Two live vaccines are available, Rotarix and RotaTeq, but vaccination efforts are hampered by high production costs. Here, we present a dataset containing a genome-wide RNA interference (RNAi) screen that identified silencing events that enhanced rotavirus replication. Evaluated against several rotavirus vaccine strains, hits were validated in a Vero vaccine cell line as well as CRISPR/Cas9 generated cells permanently and stably lacking the genes that affect RV replication. Knockout cells were dramatically more permissive to RV replication and permitted an increase in rotavirus replication. These data show a means to improve manufacturing of rotavirus vaccine.
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Affiliation(s)
- Weilin Wu
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602, USA
| | - Nichole Orr-Burks
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602, USA
| | - Jon Karpilow
- Proventus Bio, 220 Riverbend Rd, Athens, Georgia 30602, USA
| | - Ralph A Tripp
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602, USA
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Mandal P, Mullick S, Nayak MK, Mukherjee A, Ganguly N, Niyogi P, Panda S, Chawla-Sarkar M. Complete genotyping of unusual species A rotavirus G12P[11] and G10P[14] isolates and evidence of frequent in vivo reassortment among the rotaviruses detected in children with diarrhea in Kolkata, India, during 2014. Arch Virol 2016; 161:2773-85. [PMID: 27447463 DOI: 10.1007/s00705-016-2969-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 07/05/2016] [Indexed: 12/17/2022]
Abstract
Species A rotaviruses (RVA) are the most important cause of acute gastroenteritis in the young of humans and many animal species globally. G1P[8], G2P[4], G3P[8], G4P[8], G9P[6/8] and G12P[6/8] are the predominantly isolated genotypes throughout the world including India. Unusual genotypes from different host species such as G5, G6, G8, G10 and G11 have also been reported in humans with low frequency. In the present study, among >650 RVA positive stool samples collected from children with diarrhea in Kolkata, India, during 2014, two isolates each of the genotype G12P[11] and G10P[14] were obtained and their genomes completely sequenced. The full genotype constellations were G12-P[11]-I1-R1-C1-M2-A1-N1-T2-E1-H1 and G12-P[11]-I1-R1-C1-M1-A5-N1-T1-E1-H1 for G12P[11] viruses, suggesting several reassortments between Wa- and DS-1-like human RVA strains, including possible reassortment of a simian NSP1 gene. The G10P[14] viruses (G10-P[14]-I2-R2-C2-M2-A11-N2-T6-E2-H3) were found to contain multiple genes closely related to RVAs of artiodactyl origin, highlighting the role of inter-host species transmissions of RVAs. From the G/P constellation of all RVA isolates, it could be concluded that approximately one quarter had likely arisen from reassortment events in vivo among RVAs of 'usual' genotypes.
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Affiliation(s)
- Paulami Mandal
- National Institute of Cholera and Enteric Diseases, Kolkata, 700010, India
| | - Satarupa Mullick
- National Institute of Cholera and Enteric Diseases, Kolkata, 700010, India
| | - Mukti Kant Nayak
- National Institute of Cholera and Enteric Diseases, Kolkata, 700010, India
| | - Anupam Mukherjee
- National Institute of Cholera and Enteric Diseases, Kolkata, 700010, India
| | | | | | - Samiran Panda
- National Institute of Cholera and Enteric Diseases, Kolkata, 700010, India
| | - Mamta Chawla-Sarkar
- Division of Virology, National Institute of Cholera and Enteric Diseases, P-33 C.I.T. Road, Scheme XM, Beliaghata, Kolkata, 700010, West Bengal, India.
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Silva FDF, Gregori F, McDonald SM. Distinguishing the genotype 1 genes and proteins of human Wa-like rotaviruses vs. porcine rotaviruses. INFECTION GENETICS AND EVOLUTION 2016; 43:6-14. [PMID: 27180895 DOI: 10.1016/j.meegid.2016.05.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 05/02/2016] [Accepted: 05/10/2016] [Indexed: 11/16/2022]
Abstract
Group A rotaviruses (RVAs) are 11-segmented, double-stranded RNA viruses and important causes of gastroenteritis in the young of many animal species. Previous studies have suggested that human Wa-like RVAs share a close evolutionary relationship with porcine RVAs. Specifically, the VP1-VP3 and NSP2-5/6 genes of these viruses are usually classified as genotype 1 with >81% nucleotide sequence identity. Yet, it remains unknown whether the genotype 1 genes and proteins of human Wa-like strains are distinguishable from those of porcine strains. To investigate this, we performed comprehensive bioinformatic analyses using all known genotype 1 gene sequences. The RVAs analyzed represent wildtype strains isolated from humans or pigs at various geographical locations during the years of 2004-2013, including 11 newly-sequenced porcine RVAs from Brazil. We also analyzed archival strains that were isolated during the years of 1977-1992 as well as atypical strains involved in inter-species transmission between humans and pigs. We found that, in general, the genotype 1 genes of typical modern human Wa-like RVAs clustered together in phylogenetic trees and were separate from those of typical modern porcine RVAs. The only exception was for the NSP5/6 gene, which showed no host-specific phylogenetic clustering. Using amino acid sequence alignments, we identified 34 positions that differentiated the VP1-VP3, NSP2, and NSP3 genotype 1 proteins of typical modern human Wa-like RVAs versus typical modern porcine RVAs and documented how these positions vary in the archival/unusual isolates. No host-specific amino acid positions were identified for NSP4, NSP5, or NSP6. Altogether, the results of this study support the notion that human Wa-like RVAs and porcine RVAs are evolutionarily related, but indicate that some of their genotype 1 genes and proteins have diverged over time possibly as a reflection of sequestered replication and protein co-adaptation in their respective hosts.
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Affiliation(s)
- Fernanda D F Silva
- Department of Preventive Veterinary Medicine and Animal Health, College of Veterinary Medicine, University of São Paulo, Brazil
| | - F Gregori
- Department of Preventive Veterinary Medicine and Animal Health, College of Veterinary Medicine, University of São Paulo, Brazil
| | - Sarah M McDonald
- Virginia Tech Carilion School of Medicine and Research Institute, Roanoke, VA, USA; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA.
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Franco MA, Angel J, Greenberg HB. Rotaviruses. CLINICAL VIROLOGY 2016:853-872. [DOI: 10.1128/9781555819439.ch36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Ianiro G, Delogu R, Fiore L, Ruggeri FM. Genomic characterization of uncommon human G3P[6] rotavirus strains causing diarrhea in children in Italy in 2009. INFECTION GENETICS AND EVOLUTION 2015; 33:143-9. [PMID: 25913157 DOI: 10.1016/j.meegid.2015.04.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Revised: 03/31/2015] [Accepted: 04/23/2015] [Indexed: 10/23/2022]
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Mullick S, Mandal P, Nayak MK, Ghosh S, De P, Rajendran K, Bhattacharya MK, Mitra U, Ramamurthy T, Kobayashi N, Chawla-Sarkar M. Hospital based surveillance and genetic characterization of rotavirus strains in children (<5 years) with acute gastroenteritis in Kolkata, India, revealed resurgence of G9 and G2 genotypes during 2011-2013. Vaccine 2015; 32 Suppl 1:A20-8. [PMID: 25091674 DOI: 10.1016/j.vaccine.2014.03.018] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION India accounts for an estimated 457,000-884,000 hospitalizations and 2 million outpatient visits for diarrhea. In spite of the huge burden of rotavirus (RV) disease, RV vaccines have not been introduced in national immunization programme of India. Therefore, continuous surveillance for prevalence and monitoring of the circulating genotypes is needed to assess the disease burden prior to introduction of vaccines in this region. METHODS During January 2011 through December 2013, 830 and 1000 stool samples were collected from hospitalized and out-patient department (OPD) patients, respectively, in two hospitals in Kolkata, Eastern India. After primary screening, the G-P typing was done by multiplex semi-nested PCR using type specific primers followed by sequencing. Phylogenetic analysis for the VP7 gene of 25 representative strains was done. RESULTS Among hospitalized and OPD patients, 53.4% and 47.5% cases were positive for rotaviruses, respectively. Unlike previous studies where G1 was predominant, in hospitalized cases G9 rotavirus strains were most prevalent (40%), followed by G2 (39.6%) whereas G1 and G12 occurred at 16.4% and 5.6% frequency. In OPD cases, the most prevalent strain was G2 (40.3%), followed by G1, G9 and G12 at 25.5%, 22.8%, 9.3%, respectively. Phylogenetically the G1, G2 and G9 strains from Kolkata did not cluster with corresponding genotypes of Rotarix, RotaTeq and Rotavac (116E) vaccine strains. CONCLUSION The study highlights the high prevalence of RV in children with gastroenteritis in Kolkata. The circulating genotypes have changed over the time with predominance of G9 and G2 strains during 2011-2013. The current G2, G9 and G1 Kolkata strains shared low amino acid homologies with current vaccine strains. Although there is substantial evidence for cross protection of vaccines against a variety of strains, still the strain variation should be monitored post vaccine introduction to determine if it has any impact on vaccine effectiveness.
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Affiliation(s)
- Satarupa Mullick
- National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Paulami Mandal
- National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Mukti Kant Nayak
- National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Souvik Ghosh
- Department of Hygiene, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Papiya De
- National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - K Rajendran
- National Institute of Cholera and Enteric Diseases, Kolkata, India
| | | | - Utpala Mitra
- National Institute of Cholera and Enteric Diseases, Kolkata, India
| | | | - Nobumichi Kobayashi
- Department of Hygiene, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
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Böhm R, Fleming FE, Maggioni A, Dang VT, Holloway G, Coulson BS, von Itzstein M, Haselhorst T. Revisiting the role of histo-blood group antigens in rotavirus host-cell invasion. Nat Commun 2015; 6:5907. [PMID: 25556995 DOI: 10.1038/ncomms6907] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2014] [Accepted: 11/20/2014] [Indexed: 12/16/2022] Open
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Dennis FE, Fujii Y, Haga K, Damanka S, Lartey B, Agbemabiese CA, Ohta N, Armah GE, Katayama K. Identification of novel Ghanaian G8P[6] human-bovine reassortant rotavirus strain by next generation sequencing. PLoS One 2014; 9:e100699. [PMID: 24971993 PMCID: PMC4074113 DOI: 10.1371/journal.pone.0100699] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 05/25/2014] [Indexed: 01/17/2023] Open
Abstract
Group A rotaviruses (RVAs) are the most important etiological agent of acute gastroenteritis in children <5 years of age worldwide. The monovalent rotavirus vaccine Rotarix was introduced into the national Expanded Programme on Immunization (EPI) in Ghana in May 2012. However, there is a paucity of genetic and phylogenetic data on the complete genomes of human RVAs in circulation pre-vaccine introduction. The common bovine rotavirus VP7 genotype G8 has been sporadically detected in Ghanaian children, usually in combination with the VP4 genotype P[6]. To investigate the genomic constellations and phylogeny of RVA strains in circulation prior to vaccine introduction, the full genomes of two unusual G8P[6] strains, GH018-08 and GH019-08, detected during burden of disease surveillance, were characterized by Illumina MiSeq sequencing. The Ghanaian isolates, GH018-08 and GH019-08, exhibited the unusual, previously unreported genotype constellation G8-P[6]-I2-R2-C2-M2-A2-N2-T2-E2-H3. Phylogenetic analyses confirmed that 10 out of the 11 genes of GH018-08 and GH019-08 were identical/nearly identical, with significant variation detected only in their VP1 genes, and clearly established the occurrence of multiple independent interspecies transmission and reassortment events between co-circulating bovine/ovine/caprine rotaviruses and human DS-1-like RVA strains. These findings highlight the contribution of reassortment and interspecies transmission events to the high rotavirus diversity in this region of Africa, and justify the need for simultaneous monitoring of animal and human rotavirus strains.
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Affiliation(s)
- Francis E. Dennis
- Department of Environmental Parasitology, Tokyo Medical and Dental University, Tokyo, Japan
- Laboratory of Gastroenteritis Viruses, Department of Virology II, National Institute of Infectious Diseases, Musashi-murayama, Tokyo, Japan
- Department of Electron Microscopy and Histopathology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Ghana
| | - Yoshiki Fujii
- Laboratory of Gastroenteritis Viruses, Department of Virology II, National Institute of Infectious Diseases, Musashi-murayama, Tokyo, Japan
| | - Kei Haga
- Laboratory of Gastroenteritis Viruses, Department of Virology II, National Institute of Infectious Diseases, Musashi-murayama, Tokyo, Japan
| | - Susan Damanka
- Department of Electron Microscopy and Histopathology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Ghana
| | - Belinda Lartey
- Department of Electron Microscopy and Histopathology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Ghana
| | - Chantal A. Agbemabiese
- Department of Electron Microscopy and Histopathology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Ghana
| | - Nobuo Ohta
- Department of Environmental Parasitology, Tokyo Medical and Dental University, Tokyo, Japan
| | - George E. Armah
- Department of Electron Microscopy and Histopathology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Ghana
| | - Kazuhiko Katayama
- Laboratory of Gastroenteritis Viruses, Department of Virology II, National Institute of Infectious Diseases, Musashi-murayama, Tokyo, Japan
- * E-mail:
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Absence of genetic differences among G10P[11] rotaviruses associated with asymptomatic and symptomatic neonatal infections in Vellore, India. J Virol 2014; 88:9060-71. [PMID: 24899175 DOI: 10.1128/jvi.01417-14] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
UNLABELLED Rotaviruses (RVs) are leading causes of severe diarrhea and vomiting in infants and young children. RVs with G10P[11] genotype specificity have been associated with symptomatic and asymptomatic neonatal infections in Vellore, India. To identify possible viral genetic determinants responsible for differences in symptomology, the genome sequences of G10P[11] RVs in stool samples of 19 neonates with symptomatic infections and 20 neonates with asymptomatic infections were determined by Sanger and next-generation sequencing. The data showed that all 39 viruses had identical genotype constellations (G10-P[11]-I2-R2-C2-M2-A1-N1-T1-E2-H3), the same as those of the previously characterized symptomatic N155 Vellore isolate. The data also showed that the RNA and deduced protein sequences of all the Vellore G10P[11] viruses were nearly identical; no nucleotide or amino acid differences were found that correlated with symptomatic versus asymptomatic infection. Next-generation sequencing data revealed that some stool samples, both from neonates with symptomatic infections and from neonates with asymptomatic infections, also contained one or more positive-strand RNA viruses (Aichi virus, astrovirus, or salivirus/klassevirus) suspected of being potential causes of pediatric gastroenteritis. However, none of the positive-strand RNA viruses could be causally associated with the development of symptoms. These results indicate that the diversity of clinical symptoms in Vellore neonates does not result from genetic differences among G10P[11] RVs; instead, other undefined factors appear to influence whether neonates develop gastrointestinal disease symptoms. IMPORTANCE Rotavirus (RV) strains have been identified that preferentially replicate in neonates, in some cases, without causing gastrointestinal disease. Surveillance studies have established that G10P[11] RVs are a major cause of neonatal infection in Vellore, India, with half of infected neonates exhibiting symptoms. We used Sanger and next-generation sequencing technologies to contrast G10P[11] RVs recovered from symptomatic and asymptomatic neonates. Remarkably, the data showed that the RNA genomes of the viruses were virtually indistinguishable and lacked any differences that could explain the diversity of clinical outcomes among infected Vellore neonates. The sequencing results also indicated that some symptomatic and some asymptomatic Vellore neonates were infected with other enteric viruses (Aichi virus, astrovirus, salvirus/klassevirus); however, none could be correlated with the presence of symptoms in neonates. Together, our findings suggest that other poorly defined factors, not connected to the genetic makeup of the Vellore G10P[11] viruses, influence whether neonates develop gastrointestinal disease symptoms.
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Böhles N, Böhles N, Busch K, Busch K, Hensel M, Hensel M. Vaccines against human diarrheal pathogens: current status and perspectives. Hum Vaccin Immunother 2014; 10:1522-35. [PMID: 24861668 PMCID: PMC5396248 DOI: 10.4161/hv.29241] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 05/08/2014] [Accepted: 05/15/2014] [Indexed: 12/16/2022] Open
Abstract
Worldwide, nearly 1.7 billion people per year contract diarrheal infectious diseases (DID) and almost 760 000 of infections are fatal. DID are a major problem in developing countries where poor sanitation prevails and food and water may become contaminated by fecal shedding. Diarrhea is caused by pathogens such as bacteria, protozoans and viruses. Important diarrheal pathogens are Vibrio cholerae, Shigella spp. and rotavirus, which can be prevented with vaccines for several years. The focus of this review is on currently available vaccines against these three pathogens, and on development of new vaccines. Currently, various types of vaccines based on traditional (killed, live attenuated, toxoid or conjugate vaccines) and reverse vaccinology (DNA/mRNA, vector, recombinant subunit, plant vaccines) are in development or already available. Development of new vaccines demands high levels of knowledge, experience, budget, and time, yet promising new vaccines often fail in preclinical and clinical studies. Efficacy of vaccination also depends on the route of delivery, and mucosal immunization in particular is of special interest for preventing DID. Furthermore, adjuvants, delivery systems and other vaccine components are essential for an adequate immune response. These aspects will be discussed in relation to the improvement of existing and development of new vaccines against DID.
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Affiliation(s)
| | | | | | | | - Michael Hensel
- Abt. Mikrobiologie; Universität Osnabrück; Osnabrück, Germany
| | - Michael Hensel
- Abt. Mikrobiologie; Universität Osnabrück; Osnabrück, Germany
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Relative roles of GM1 ganglioside, N-acylneuraminic acids, and α2β1 integrin in mediating rotavirus infection. J Virol 2014; 88:4558-71. [PMID: 24501414 DOI: 10.1128/jvi.03431-13] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
UNLABELLED N-acetyl- and N-glycolylneuraminic acids (Sia) and α2β1 integrin are frequently used by rotaviruses as cellular receptors through recognition by virion spike protein VP4. The VP4 subunit VP8*, derived from Wa rotavirus, binds the internal N-acetylneuraminic acid on ganglioside GM1. Wa infection is increased by enhanced internal Sia access following terminal Sia removal from main glycan chains with sialidase. The GM1 ligand cholera toxin B (CTB) reduces Wa infectivity. Here, we found sialidase treatment increased cellular GM1 availability and the infectivity of several other human (including RV-3) and animal rotaviruses, typically rendering them susceptible to methyl α-d-N-acetylneuraminide treatment, but did not alter α2β1 usage. CTB reduced the infectivity of these viruses. Aceramido-GM1 inhibited Wa and RV-3 infectivity in untreated and sialidase-treated cells, and GM1 supplementation increased their infectivity, demonstrating the importance of GM1 for infection. Wa recognition of α2β1 and internal Sia were at least partially independent. Rotavirus usage of GM1 was mapped to VP4 using virus reassortants, and RV-3 VP8* bound aceramido-GM1 by saturation transfer difference nuclear magnetic resonance (STD NMR). Most rotaviruses recognizing terminal Sia did not use GM1, including RRV. RRV VP8* interacted minimally with aceramido-GM1 by STD NMR. Unusually, TFR-41 rotavirus infectivity depended upon terminal Sia and GM1. Competition of CTB, Sia, and/or aceramido-GM1 with cell binding by VP8* from representative rotaviruses showed that rotavirus Sia and GM1 preferences resulted from VP8*-cell binding. Our major finding is that infection by human rotaviruses of commonly occurring VP4 serotypes involves VP8* binding to cell surface GM1 glycan, typically including the internal N-acetylneuraminic acid. IMPORTANCE Rotaviruses, the major cause of severe infantile gastroenteritis, recognize cell surface receptors through virus spike protein VP4. Several animal rotaviruses are known to bind sialic acids at the termini of main carbohydrate chains. Conversely, only a single human rotavirus is known to bind sialic acid. Interestingly, VP4 of this rotavirus bound to sialic acid that forms a branch on the main carbohydrate chain of the GM1 ganglioside. Here, we use several techniques to demonstrate that other human rotaviruses exhibit similar GM1 usage properties. Furthermore, binding by VP4 to cell surface GM1, involving branched sialic acid recognition, is shown to facilitate infection. In contrast, most animal rotaviruses that bind terminal sialic acids did not utilize GM1 for VP4 cell binding or infection. These studies support a significant role for GM1 in mediating host cell invasion by human rotaviruses.
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da Silva Soares L, de Fátima Dos Santos Guerra S, do Socorro Lima de Oliveira A, da Silva Dos Santos F, de Fátima Costa de Menezes EM, Mascarenhas JDP, Linhares AC. Diversity of rotavirus strains circulating in Northern Brazil after introduction of a rotavirus vaccine: high prevalence of G3P[6] genotype. J Med Virol 2013; 86:1065-72. [PMID: 24136444 DOI: 10.1002/jmv.23797] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2013] [Indexed: 12/29/2022]
Abstract
Rotavirus A (RVA) is the most common cause of severe acute gastroenteritis in infants and young children worldwide, causing 453,000 deaths annually. In Brazil, the most frequent genotype identified was G1 during almost three decades in the pre-vaccination period; however, after anti-rotavirus vaccine introduction, there was a predominance of G2 genotype. The aim of this study was to determine the G and P genotypes of rotaviruses isolated from children under 5 years of age with acute gastroenteritis in the Northern region of Brazil, and discuss the emergence of G3P[6] genotype. A total of 783 stool specimens were obtained between January 2011 and March 2012. RVA antigen was detected in 33% (272/783) of samples using a commercial enzyme-linked immunosorbent assay and type-specificity was determined by reverse-transcription polymerase chain reaction. The most common binary combination was G2P[4], representing 41% of cases, followed by G3P[6] (15%), G1P[8] (8%), G3P[8] (4%), G9P[8] (3%), and G12P[6] (2%). G3P[6] strains were analyzed further and phylogenetic analysis of VP7 gene showed that G3 strains clustered into lineage I and showed a high degree of amino acid identity with vaccine strain RV3 (95.1-95.6%). For VP4 sequences, G3P[6] clustered into lineage Ia. It was demonstrated by the first time the emergence of unusual genotype G3P[6] in the Amazon region of Brazil. This genotype shares neither VP7 nor VP4 specificity with the used vaccine and may represent a challenge to vaccination strategies. A continuous monitoring of circulating strains is therefore needed during the post-vaccine era in Brazil.
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Affiliation(s)
- Luana da Silva Soares
- Virology Section, Evandro Chagas Institute, Health Surveillance Secretariat, Brazilian Ministry of Health, Brazil
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McKell AO, Nichols JC, McDonald SM. PCR-based approach to distinguish group A human rotavirus genotype 1 vs. genotype 2 genes. J Virol Methods 2013; 194:197-205. [PMID: 24012969 DOI: 10.1016/j.jviromet.2013.08.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Revised: 08/15/2013] [Accepted: 08/21/2013] [Indexed: 11/30/2022]
Abstract
Group A rotaviruses (RVs) are eleven-segmented, double-stranded RNA viruses and important causes of severe diarrhea in children. A full-genome classification system is readily used to describe the genetic makeup of individual RV strains. In this system, each viral gene is assigned a specific genotype based upon its nucleotide sequence and established percent identity cut-off values. However, a faster and more cost-effective approach to determine RV gene genotypes is to utilize specific oligonucleotide primer sets in RT-PCR/PCR. Such primer sets and PCR-based genotyping methods have already been developed for the VP7-, VP6-, VP4- and NSP4-coding gene segments. In this study, primers were developed for the remaining seven RV gene segments, which encode proteins VP1, VP2, VP3, NSP1, NSP2, NSP3, and NSP5/6. Specifically, primers were designed to distinguish the two most common human RV genotypes (1 vs. 2) for these genes and were validated on several cell culture-adapted human and animal RV strains, as well as on human RVs from clinical fecal specimens. As such, primer sets now exist for all eleven genes of common human RVs, allowing for the identification of reassortant strains with mixed constellations of both genotype 1 and 2 genes using a rapid and economical RT-PCR/PCR method.
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Affiliation(s)
- Allison O McKell
- Virginia Tech Carilion Research Institute, Roanoke, VA 24016, USA; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Blacksburg, VA 24061, USA
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Newell EW, Sigal N, Nair N, Kidd BA, Greenberg HB, Davis MM. Combinatorial tetramer staining and mass cytometry analysis facilitate T-cell epitope mapping and characterization. Nat Biotechnol 2013; 31:623-9. [PMID: 23748502 PMCID: PMC3796952 DOI: 10.1038/nbt.2593] [Citation(s) in RCA: 225] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Accepted: 04/22/2013] [Indexed: 12/19/2022]
Abstract
It is currently not possible to predict which epitopes will be recognized by T cells in different individuals. This is a barrier to the thorough analysis and understanding of T-cell responses after vaccination or infection. Here, by combining mass cytometry with combinatorial peptide-MHC tetramer staining, we have developed a method allowing the rapid and simultaneous identification and characterization of T cells specific for many epitopes. We use this to screen up to 109 different peptide-MHC tetramers in a single human blood sample, while still retaining at least 23 labels to analyze other markers of T-cell phenotype and function. Among 77 candidate rotavirus epitopes, we identified six T-cell epitopes restricted to human leukocyte antigen (HLA)-A*0201 in the blood of healthy individuals. T cells specific for epitopes in the rotavirus VP3 protein displayed a distinct phenotype and were present at high frequencies in intestinal epithelium. This approach should be useful for the comprehensive analysis of T-cell responses to infectious diseases or vaccines.
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Affiliation(s)
- Evan W Newell
- Agency for Science, Technology and Research, Singapore Immunology Network, Singapore.
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Ghosh S, Urushibara N, Chawla-Sarkar M, Krishnan T, Kobayashi N. Whole genomic analyses of asymptomatic human G1P[6], G2P[6] and G3P[6] rotavirus strains reveal intergenogroup reassortment events and genome segments of artiodactyl origin. INFECTION GENETICS AND EVOLUTION 2013; 16:165-73. [DOI: 10.1016/j.meegid.2012.12.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Revised: 12/17/2012] [Accepted: 12/18/2012] [Indexed: 10/27/2022]
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Matthijnssens J, Nakagomi O, Kirkwood CD, Ciarlet M, Desselberger U, Van Ranst M. Group A rotavirus universal mass vaccination: how and to what extent will selective pressure influence prevalence of rotavirus genotypes? Expert Rev Vaccines 2013; 11:1347-54. [PMID: 23249234 DOI: 10.1586/erv.12.105] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Two human group A rotavirus (RVA) vaccines are available and highly effective in preventing severe gastroenteritis caused by all commonly circulating human RVA genotypes. The effect of universal mass vaccination on the RVA genotype distribution is discussed based on the knowledge of complete RVA genotype constellations, data from clinical efficacy trials and effectiveness studies, and genotype surveillance data from countries with universal mass vaccination programs. The theoretically predicted relative enrichment of RVA strains with the G2P[4] DS-1-like genotype constellation in regions with high coverage by Rotarix(®) (GlaxoSmithKline Biologicals, Rixensart, Belgium) seems to become apparent. A G3P[8] genotype increase, which was noted in several regions with a high coverage of RotaTeq(®) (Merck and Co., Inc., NJ, USA), is more difficult to explain based on the theoretical considerations.
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Affiliation(s)
- Jelle Matthijnssens
- Laboratory of Clinical and Epidemiological Virology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
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Phylogenetic analysis of G1P[6] group A rotavirus strains detected in Northeast Brazilian children fully vaccinated with Rotarix™. INFECTION GENETICS AND EVOLUTION 2013; 19:395-402. [PMID: 23538335 DOI: 10.1016/j.meegid.2013.03.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Revised: 03/15/2013] [Accepted: 03/18/2013] [Indexed: 12/11/2022]
Abstract
In 2009 the World Health Organization recommended the use of group A rotavirus (RVA) vaccines in all national immunization programs (NIPs) in order to control severe RVA gastroenteritis disease. In Brazil, Rotarix™ was introduced in the NIP in March 2006, and a significant reduction in mortality rates among children ≤ 5 years old was observed, especially in the Northern and Northeastern Brazil. In the current study the 11 gene segments of six Brazilian G1P[6] RVA strains, isolated in 2009 and 2010 from vaccinated children, were analyzed in order to investigate if the genetic composition of these strains might help to elucidate why they were able to cause acute gastroenteritis in vaccinated children. All six Brazilian RVA strains revealed a complete Wa-like genotype constellation: G1-P[6]-I1-R1-C1-M1-A1-N1-T1-E1-H1. Phylogenetic analysis showed that all six strains were nearly identical and showed a close genetic relationship with contemporary typical human Wa-like RVA strains. These results suggests that the fact that these strains were able to cause acute gastroenteritis in vaccinated children is likely not due to the genetic background of the strains, but rather to other factors such as host relating factors, co-infecting pathogens or vaccine efficacy. P[6] RVA strains are detected rather occasionally in humans in most regions of the world, except for South Asia and Sub-Saharan Africa. However, recently two studies conducted in Brazil showed the circulation of G12P[6] and G2P[6]. This is the first report on the detection and complete genome analyses of G1P[6] RVA strains in Brazil. Surveillance studies will be crucial to further investigate the prevalence of this genotype in the Brazilian population, and the efficacy of current licensed vaccines, which do not contain the P[6] genotype.
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Zeller M, Heylen E, De Coster S, Van Ranst M, Matthijnssens J. Full genome characterization of a porcine-like human G9P[6] rotavirus strain isolated from an infant in Belgium. INFECTION GENETICS AND EVOLUTION 2012; 12:1492-500. [DOI: 10.1016/j.meegid.2012.03.002] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2011] [Revised: 03/01/2012] [Accepted: 03/02/2012] [Indexed: 10/28/2022]
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Heylen E, Zeller M, Ciarlet M, De Coster S, Van Ranst M, Matthijnssens J. Complete genetic characterization of human G2P[6] and G3P[6] rotavirus strains. INFECTION GENETICS AND EVOLUTION 2012; 13:27-35. [PMID: 22982160 DOI: 10.1016/j.meegid.2012.08.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Revised: 08/29/2012] [Accepted: 08/30/2012] [Indexed: 10/27/2022]
Abstract
During the 2008-2009 rotavirus season, 10 G3P[6] rotavirus strains were isolated for the first time in Belgium, while an outbreak of G2P[6] strains occurred in the USA in 2005-2006. Partial sequencing of the 11 genome segments of the 10 Belgian G3P[6] strains revealed a clonal origin. Two of these strains, and a G2P[6] strain representative of the American outbreak, were selected and sequenced completely to analyze their evolutionary relationships. Genetic analysis revealed that all strains possessed a DS-1-like genotype constellation. The 2 Belgian G3P[6] strains showed >99% sequence identity at the nucleotide level and the American G2P[6] strain was phylogenetically closely related to the Belgian P[6] strains. These data suggest that reassortment(s) involving VP7 occurred recently, and that the prevalence of DS-1-like P[6] rotavirus strains need to be closely monitored because the currently licensed RVA vaccines contain neither the P[6] genotype nor strains with a complete human DS-1 genotype constellation.
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Affiliation(s)
- Elisabeth Heylen
- Laboratory of Clinical Virology, Department of Microbiology and Immunology, Rega Institute for Medical Research, Minderbroedersstraat 10, BE-3000 Leuven, Belgium
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Tate JE, Patel MM, Cortese MM, Lopman BA, Gentsch JR, Fleming J, Steele AD, Parashar UD. Remaining issues and challenges for rotavirus vaccine in preventing global childhood diarrheal morbidity and mortality. Expert Rev Vaccines 2012; 11:211-20. [PMID: 22309669 DOI: 10.1586/erv.11.184] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Rotavirus vaccines have had a dramatic impact on morbidity and mortality from diarrhea among children in high- and middle-income countries that have introduced the vaccine into their national immunization programs. Widespread introduction of rotavirus vaccine in developing countries is imminent and their full potential in reducing the global burden from severe childhood diarrhea may soon be realized. The objectives of this paper are to describe the remaining issues and challenges in ensuring the success of the global rotavirus vaccination program and to discuss further research needed to help address them.
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Affiliation(s)
- Jacqueline E Tate
- Centers for Disease Control and Prevention, 1600 Clifton Road, NE MS-A34, Atlanta, GA 30333, USA.
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Ghosh S, Kobayashi N. Whole-genomic analysis of rotavirus strains: current status and future prospects. Future Microbiol 2011; 6:1049-65. [DOI: 10.2217/fmb.11.90] [Citation(s) in RCA: 120] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Studies on genetic diversity of rotaviruses have been primarily based on the genes encoding the antigenically significant VP7 and VP4 proteins. Since the rotavirus genome has 11 segments of RNA that are vulnerable to reassortment events, analyses of the VP7 and VP4 genes may not be sufficient to obtain conclusive data on the overall genetic diversity, or true origin of strains. In the last few years following the advent of the whole-genome-based genotype classification system, the whole genomes of at least 167 human group A rotavirus strains have been analyzed, providing a plethora of new and important information on the complex origin of strains, inter- and intra-genogroup reassortment events, animal–human reassortment events, zoonosis, and genetic linkages involving different group A rotavirus gene segments. In addition, the whole genomes of a limited number of human group B, C and novel group rotavirus strains have been analyzed. This article briefly reviews the available data on whole-genomic analysis of human rotavirus strains. The significance and future prospects of whole-genome-based studies are also discussed.
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Affiliation(s)
- Souvik Ghosh
- Department of Hygiene, Sapporo Medical University School of Medicine, S 1, W 17, Chuo-Ku, Sapporo, Hokkaido 060-8556, Japan
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Matthijnssens J, Ciarlet M, McDonald SM, Attoui H, Bányai K, Brister JR, Buesa J, Esona MD, Estes MK, Gentsch JR, Iturriza-Gómara M, Johne R, Kirkwood CD, Martella V, Mertens PPC, Nakagomi O, Parreño V, Rahman M, Ruggeri FM, Saif LJ, Santos N, Steyer A, Taniguchi K, Patton JT, Desselberger U, Van Ranst M. Uniformity of rotavirus strain nomenclature proposed by the Rotavirus Classification Working Group (RCWG). Arch Virol 2011; 156:1397-413. [PMID: 21597953 PMCID: PMC3398998 DOI: 10.1007/s00705-011-1006-z] [Citation(s) in RCA: 769] [Impact Index Per Article: 54.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2011] [Accepted: 04/19/2011] [Indexed: 12/31/2022]
Abstract
In April 2008, a nucleotide-sequence-based, complete genome classification system was developed for group A rotaviruses (RVs). This system assigns a specific genotype to each of the 11 genome segments of a particular RV strain according to established nucleotide percent cutoff values. Using this approach, the genome of individual RV strains are given the complete descriptor of Gx-P[x]-Ix-Rx-Cx-Mx-Ax-Nx-Tx-Ex-Hx. The Rotavirus Classification Working Group (RCWG) was formed by scientists in the field to maintain, evaluate and develop the RV genotype classification system, in particular to aid in the designation of new genotypes. Since its conception, the group has ratified 51 new genotypes: as of April 2011, new genotypes for VP7 (G20-G27), VP4 (P[28]-P[35]), VP6 (I12-I16), VP1 (R5-R9), VP2 (C6-C9), VP3 (M7-M8), NSP1 (A15-A16), NSP2 (N6-N9), NSP3 (T8-T12), NSP4 (E12-E14) and NSP5/6 (H7-H11) have been defined for RV strains recovered from humans, cows, pigs, horses, mice, South American camelids (guanaco), chickens, turkeys, pheasants, bats and a sugar glider. With increasing numbers of complete RV genome sequences becoming available, a standardized RV strain nomenclature system is needed, and the RCWG proposes that individual RV strains are named as follows: RV group/species of origin/country of identification/common name/year of identification/G- and P-type. In collaboration with the National Center for Biotechnology Information (NCBI), the RCWG is also working on developing a RV-specific resource for the deposition of nucleotide sequences. This resource will provide useful information regarding RV strains, including, but not limited to, the individual gene genotypes and epidemiological and clinical information. Together, the proposed nomenclature system and the NCBI RV resource will offer highly useful tools for investigators to search for, retrieve, and analyze the ever-growing volume of RV genomic data.
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Affiliation(s)
- Jelle Matthijnssens
- Laboratory of Clinical & Epidemiological Virology, Department of Microbiology & Immunology, Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000, Leuven, Belgium.
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Abstract
The innermost VP2 core shell of the triple-layered, icosahedral rotavirus particle surrounds the viral genome and RNA processing enzymes, including the RNA-dependent RNA polymerase (VP1). In addition to anchoring VP1 within the core, VP2 is also an essential cofactor that triggers the polymerase to initiate double-stranded RNA (dsRNA) synthesis using packaged plus-strand RNA templates. The VP2 requirement effectively couples packaging with genome replication and ensures that VP1 makes dsRNA only within an assembling previrion particle. However, the mechanism by which the rotavirus core shell protein activates the viral polymerase remains very poorly understood. In the current study, we sought to elucidate VP2 regions critical for VP1-mediated in vitro dsRNA synthesis. By comparing the functions of proteins from several different rotaviruses, we found that polymerase activation by the core shell protein is specific. Through truncation and chimera mutagenesis, we demonstrate that the VP2 amino terminus, which forms a decameric, internal hub underneath each 5-fold axis, plays an important but nonspecific role in VP1 activation. Our results indicate that the VP2 residues correlating with polymerase activation specificity are located on the inner face of the core shell, distinct from the amino terminus. Based on these findings, we predict that several regions of VP2 engage the polymerase during the concerted processes of rotavirus core assembly and genome replication.
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