{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:17:13Z","timestamp":1787008633822,"version":"build-2736575974"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2017,7,19]],"date-time":"2017-07-19T00:00:00Z","timestamp":1500422400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1051297"],"award-info":[{"award-number":["APP1051297"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Murdoch Childrens Research Institute of Melbourne, Australia"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,10,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Group AStreptococcus (GAS) skin infections are particularly prevalent in developing nations. The GAS M protein, by which strains are differentiated into &amp;gt;220 differentemm types, is immunogenic and elicits protective antibodies. A major obstacle for vaccine development has been the traditional understanding that immunity following infection is restricted to a singleemm type. However, recent evidence has led to the hypothesis of immune cross-reactivity betweenemm types.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated the human serological response to GAS impetigo in Fijian schoolchildren, focusing on 3 majoremm clusters (E4, E6, and D4). Pre- and postinfection sera were assayed by enzyme-linked immunosorbent assay with N-terminal M peptides and bactericidal assays using the infecting-type strain,emm cluster\u2013related strains, and nonrelated strains.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Twenty of the 53 paired sera demonstrated a \u22654-fold increase in antibody titer against the infecting type. When tested against all cluster-related M peptides, we found that 9 of 17 (53%) paired sera had a \u22654-fold increase in antibody titer to cluster-related strains as well. When grouped by cluster, the mean change to cluster-relatedemm types in E4 and E6 was &amp;gt;4-fold (5.9-fold and 19.5-fold, respectively) but for D4 was 3.8-fold. The 17 paired sera were tested in bactericidal assays against selected cluster-related and nonrelated strains. While the responses were highly variable, numerous instances of cross-reactive killing were observed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These data demonstrate that M type\u2013specific and cross-reactive immune responses occur following skin infection. The cross-reactive immune responses frequently align withemm clusters, raising new opportunities to design multivalent vaccines with broad coverage.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cid\/cix599","type":"journal-article","created":{"date-parts":[[2017,7,6]],"date-time":"2017-07-06T07:10:42Z","timestamp":1499325042000},"page":"1523-1531","source":"Crossref","is-referenced-by-count":54,"title":["Immune Cross-Opsonization Withinemm Clusters Following Group AStreptococcus Skin Infection: Broadening the Scope of Type-Specific Immunity"],"prefix":"10.1093","volume":"65","author":[{"given":"Hannah R","family":"Frost","sequence":"first","affiliation":[{"name":"Group A Streptococcus Research Group, Murdoch Childrens Research Institute,Melbourne,Australia;"},{"name":"Molecular Bacteriology Laboratory, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Laho","sequence":"first","affiliation":[{"name":"Group A Streptococcus Research Group, Murdoch Childrens Research Institute,Melbourne,Australia;"},{"name":"Department of Pediatrics, Academic Children Hospital Queen Fabiola, Universit\u00e9 Libre de Bruxelles,Brussels,Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina L","family":"Sanderson-Smith","sequence":"first","affiliation":[{"name":"Illawarra Health and Medical Research Institute and School of Biological Sciences, University of Wollongong,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Licciardi","sequence":"first","affiliation":[{"name":"Pneumococcal Research Group, Murdoch Childrens Research Institute,Melbourne, and"},{"name":"Department of Paediatrics, University of Melbourne, Royal Children\u2019s Hospital Melbourne,Parkville,Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Donath","sequence":"first","affiliation":[{"name":"Department of Paediatrics, University of Melbourne, Royal Children\u2019s Hospital Melbourne,Parkville,Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel","family":"Curtis","sequence":"first","affiliation":[{"name":"Department of Paediatrics, University of Melbourne, Royal Children\u2019s Hospital Melbourne,Parkville,Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Kado","sequence":"first","affiliation":[{"name":"Department of Paediatrics, Colonial War Memorial Hospital,"},{"name":"College of Medicine, Nursing and Health Sciences, Fiji National University, and"},{"name":"Fiji Rheumatic Heart Disease Control Program,Suva,Fiji;Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James B","family":"Dale","sequence":"first","affiliation":[{"name":"Medicine and"},{"name":"Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, and"},{"name":"Department of Veterans Affairs Medical Center,Memphis, Tennessee; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew C","family":"Steer","sequence":"first","affiliation":[{"name":"Group A Streptococcus Research Group, Murdoch Childrens Research Institute,Melbourne,Australia;"},{"name":"Department of Paediatrics, University of Melbourne, Royal Children\u2019s Hospital Melbourne,Parkville,Australia;"},{"name":"Centre for International Child Health, University of Melbourne,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre R","family":"Smeesters","sequence":"first","affiliation":[{"name":"Group A Streptococcus Research Group, Murdoch Childrens Research Institute,Melbourne,Australia;"},{"name":"Molecular Bacteriology Laboratory, and"},{"name":"Department of Pediatrics, Academic Children Hospital Queen Fabiola, Universit\u00e9 Libre de Bruxelles,Brussels,Belgium;"},{"name":"Centre for International Child Health, University of Melbourne,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,7,19]]},"reference":[{"key":"2020060113300384800_CIT0001","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S1473-3099(05)70267-X","article-title":"The global burden of group A streptococcal diseases","volume":"5","author":"Carapetis","year":"2005","journal-title":"Lancet Infect Dis"},{"key":"2020060113300384800_CIT0002","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0136789","article-title":"The global epidemiology of impetigo: a systematic review of the population prevalence of impetigo and pyoderma","volume":"10","author":"Bowen","year":"2015","journal-title":"PLoS One"},{"key":"2020060113300384800_CIT0003","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pntd.0000467","article-title":"High burden of impetigo and scabies in a tropical country","volume":"3","author":"Steer","year":"2009","journal-title":"PLoS Negl Trop Dis"},{"key":"2020060113300384800_CIT0004","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1172\/JCI106358","article-title":"The influence of the site of infection on the immune response to group A streptococci","volume":"49","author":"Kaplan","year":"1970","journal-title":"J Clin Invest"},{"key":"2020060113300384800_CIT0005","doi-asserted-by":"crossref","first-page":"e1006122","DOI":"10.1371\/journal.ppat.1006122","article-title":"Streptococcal immunity is constrained by lack of immunological memory following a single episode of pyoderma","volume":"12","author":"Pandey","year":"2016","journal-title":"PLoS Pathog"},{"key":"2020060113300384800_CIT0006","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.vaccine.2016.03.073","article-title":"Status of research and development of vaccines forStreptococcus pyogenes","volume":"34","author":"Steer","year":"2016","journal-title":"Vaccine"},{"key":"2020060113300384800_CIT0007","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.tim.2010.02.007","article-title":"The streptococcal M protein: a highly versatile molecule","volume":"18","author":"Smeesters","year":"2010","journal-title":"Trends Microbiol"},{"key":"2020060113300384800_CIT0008","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1084\/jem.30.3.179","article-title":"Studies on the biology of streptococcus: i. antigenic relationships between strains ofStreptococcus haemolyticus","volume":"30","author":"Dochez","year":"1919","journal-title":"J Exp Med"},{"key":"2020060113300384800_CIT0009","doi-asserted-by":"crossref","first-page":"307","DOI":"10.4049\/jimmunol.89.3.307","article-title":"Current knowledge of type-specific M antigens of group A streptococci","volume":"89","author":"Lancefield","year":"1962","journal-title":"J Immunol"},{"key":"2020060113300384800_CIT0010","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1084\/jem.167.3.1114","article-title":"The importance of the location of antibody binding on the M6 protein for opsonization and phagocytosis of group A M6 streptococci","volume":"167","author":"Jones","year":"1988","journal-title":"J Exp Med"},{"key":"2020060113300384800_CIT0011","doi-asserted-by":"crossref","first-page":"E222","DOI":"10.1111\/1469-0691.12134","article-title":"Updated model of group AStreptococcus M proteins based on a comprehensive worldwide study","volume":"19","author":"McMillan","year":"2013","journal-title":"Clin Microbiol Infect"},{"key":"2020060113300384800_CIT0012","doi-asserted-by":"crossref","first-page":"8175","DOI":"10.1016\/j.vaccine.2011.09.005","article-title":"New 30-valent M protein-based vaccine evokes cross-opsonic antibodies against non-vaccine serotypes of group A streptococci","volume":"29","author":"Dale","year":"2011","journal-title":"Vaccine"},{"key":"2020060113300384800_CIT0013","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1016\/j.vaccine.2013.01.019","article-title":"Potential coverage of a multivalent M protein-based group A streptococcal vaccine","volume":"31","author":"Dale","year":"2013","journal-title":"Vaccine"},{"key":"2020060113300384800_CIT0014","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0000010","article-title":"Differences between Belgian and Brazilian group AStreptococcus epidemiologic landscape","volume":"1","author":"Smeesters","year":"2006","journal-title":"PLoS One"},{"key":"2020060113300384800_CIT0015","doi-asserted-by":"crossref","first-page":"5835","DOI":"10.1016\/j.vaccine.2008.08.037","article-title":"Genetic diversity of group AStreptococcus M protein: implications for typing and vaccine development","volume":"26","author":"Smeesters","year":"2008","journal-title":"Vaccine"},{"key":"2020060113300384800_CIT0016","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.vaccine.2009.10.137","article-title":"Theemm-type diversity does not always reflect the M protein genetic diversity\u2014is there a case for designer vaccine against GAS","volume":"28","author":"Smeesters","year":"2010","journal-title":"Vaccine"},{"key":"2020060113300384800_CIT0017","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1093\/infdis\/jiu260","article-title":"A systematic and functional classification ofStreptococcus pyogenes that serves as a new tool for molecular typing and vaccine development","volume":"210","author":"Sanderson-Smith","year":"2014","journal-title":"J Infect Dis"},{"key":"2020060113300384800_CIT0018","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/cid\/ciu649","article-title":"Added value of theemm-cluster typing system to analyze the group AStreptococcus epidemiology in high-income settings","volume":"59","author":"Shulman","year":"2014","journal-title":"Clin Infect Dis"},{"key":"2020060113300384800_CIT0019","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1093\/cid\/ciw807","article-title":"Seasonal, geographic, and temporal trends ofemm clusters associated with invasive group A streptococcal infections in US multistate surveillance","volume":"64","author":"Smeesters","year":"2017","journal-title":"Clin Infect Dis"},{"key":"2020060113300384800_CIT0020","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.vaccine.2016.11.065","article-title":"Structure-based design of broadly protective group a streptococcal M protein-based vaccines","volume":"35","author":"Dale","year":"2017","journal-title":"Vaccine"},{"key":"2020060113300384800_CIT0021","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/S1473-3099(09)70178-1","article-title":"Global emm type distribution of group A streptococci: systematic review and implications for vaccine development","volume":"9","author":"Steer","year":"2009","journal-title":"Lancet Infect Dis"},{"key":"2020060113300384800_CIT0022","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1586\/erv.09.133","article-title":"Differences among group AStreptococcus epidemiological landscapes: consequences for M protein-based vaccines?","volume":"8","author":"Smeesters","year":"2009","journal-title":"Expert Rev Vaccines"},{"key":"2020060113300384800_CIT0023","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1128\/CVI.00291-08","article-title":"Normal ranges of streptococcal antibody titers are similar whether streptococci are endemic to the setting or not","volume":"16","author":"Steer","year":"2009","journal-title":"Clin Vaccine Immunol"},{"key":"2020060113300384800_CIT0024","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.1128\/JCM.00312-09","article-title":"emm and C-repeat region molecular typing of beta-hemolytic streptococci in a tropical country: implications for vaccine development","volume":"47","author":"Steer","year":"2009","journal-title":"J Clin Microbiol"},{"key":"2020060113300384800_CIT0025","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1084\/jem.151.5.1026","article-title":"Heterogeneity of type-specific and cross-reactive antigenic determinants within a single M protein of group A streptococci","volume":"151","author":"Dale","year":"1980","journal-title":"J Exp Med"},{"key":"2020060113300384800_CIT0026","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.vaccine.2007.10.064","article-title":"Development and characterization of a standardized ELISA including a reference serum on each plate to detect antibodies induced by experimental malaria vaccines","volume":"26","author":"Miura","year":"2008","journal-title":"Vaccine"},{"key":"2020060113300384800_CIT0027","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1084\/jem.106.4.525","article-title":"Differentiation of group A streptococci with a common R antigen into three serological types, with special reference to the bactericidal test","volume":"106","author":"Lancefield","year":"1957","journal-title":"J Exp Med"},{"key":"2020060113300384800_CIT0028","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0140784","article-title":"Streptococcus pyogenes sortase mutants are highly susceptible to killing by host factors due to aberrant envelope physiology","volume":"10","author":"Raz","year":"2015","journal-title":"PLoS One"},{"key":"2020060113300384800_CIT0029","doi-asserted-by":"crossref","first-page":"2878","DOI":"10.1128\/JCM.38.8.2878-2884.2000","article-title":"Detection of complement-mediated antibody-dependent bactericidal activity in a fluorescence-based serum bactericidal assay for group BNeisseria meningitidis","volume":"38","author":"Mountzouros","year":"2000","journal-title":"J Clin Microbiol"},{"key":"2020060113300384800_CIT0030","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1128\/CVI.00812-13","article-title":"Development and use of a serum bactericidal assay using pooled human complement to assess responses to a meningococcal group A conjugate vaccine in African toddlers","volume":"21","author":"Bash","year":"2014","journal-title":"Clin Vaccine Immunol"},{"key":"2020060113300384800_CIT0031","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s12866-015-0420-x","article-title":"Development of a serological assay to predict antibody bactericidal activity against non-typeableHaemophilus influenzae","volume":"15","author":"Ercoli","year":"2015","journal-title":"BMC Microbiol"},{"key":"2020060113300384800_CIT0032","doi-asserted-by":"crossref","first-page":"e84","DOI":"10.1093\/cid\/ciu490","article-title":"The emm-cluster typing system for Group AStreptococcus identifies epidemiologic similarities across the Pacific region","volume":"59","author":"Baroux","year":"2014","journal-title":"Clin Infect Dis"},{"key":"2020060113300384800_CIT0033","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1128\/IAI.10.6.1356-1361.1974","article-title":"Type-specific opsonic antibodies in streptococcal pyoderma","volume":"10","author":"Bisno","year":"1974","journal-title":"Infect Immun"},{"key":"2020060113300384800_CIT0034","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1086\/650167","article-title":"The human immune response to streptococcal extracellular antigens: clinical, diagnostic, and potential pathogenetic implications","volume":"15","author":"Johnson","year":"2010","journal-title":"Clin Infect Dis"},{"key":"2020060113300384800_CIT0035","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1093\/jpids\/piw070","article-title":"Prospective longitudinal analysis of immune responses in pediatric subjects after pharyngeal acquisition of group A streptococci","volume":"6","author":"Hysmith","year":"2017","journal-title":"J Pediatric Infect Dis Soc"},{"key":"2020060113300384800_CIT0036","doi-asserted-by":"crossref","first-page":"45","DOI":"10.7774\/cevr.2017.6.1.45","article-title":"Trivalent M-related protein as a component of next generation group A streptococcal vaccines","volume":"6","author":"Courtney","year":"2017","journal-title":"Clin Exp Vaccine Res"},{"key":"2020060113300384800_CIT0037","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1086\/506938","article-title":"Low rates of streptococcal pharyngitis and high rates of pyoderma in Australian aboriginal communities where acute rheumatic fever is hyperendemic","volume":"43","author":"McDonald","year":"2006","journal-title":"Clin Infect Dis"},{"key":"2020060113300384800_CIT0038","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fmicb.2016.01119","article-title":"Serological evidence of immune priming by group A streptococci in patients with acute rheumatic fever","volume":"7","author":"Raynes","year":"2016","journal-title":"Front Microbiol"},{"key":"2020060113300384800_CIT0039","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1097\/QCO.0b013e3283511d27","article-title":"Streptococcal skin infection and rheumatic heart disease","volume":"25","author":"Parks","year":"2012","journal-title":"Curr Opin Infect Dis"},{"key":"2020060113300384800_CIT0040","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1097\/INF.0000000000001558","article-title":"Acute rheumatic fever after group AStreptococcus pyoderma and group GStreptococcus pharyngitis","volume":"36","author":"O\u2019Sullivan","year":"2017","journal-title":"Pediatr Infect Dis J"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/cid\/article-pdf\/65\/9\/1523\/33333279\/cix599.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/cid\/article-pdf\/65\/9\/1523\/33333279\/cix599.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T05:46:31Z","timestamp":1692855991000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/65\/9\/1523\/3979656"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,19]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2017,7,19]]},"published-print":{"date-parts":[[2017,10,16]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/cix599","relation":{},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,11,1]]},"published":{"date-parts":[[2017,7,19]]}}}