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(3)(+0000002): Notifier.trigger('modify', 'item', [51], {"autoSyncDelay":15,"noteEditorID":"3CE58R9I","state":{"metadata": {"schemaVersion":9,"citationItems":[{"uris":["http://zotero.org/users/ local/FhamIvwD/items/7IDZT94H"],"itemData":{"id":"http://zotero.org/ users/local/FhamIvwD/items/7IDZT94H","type":"article- journal","abstract":"Group A Streptococcus (GAS; Streptococcus pyogenes) is a bacterial pathogen for which a commercial vaccine for humans is not available. Employing the advantages of high-throughput DNA sequencing technology to vaccine design, we have analyzed 2,083 globally sampled GAS genomes. The global GAS population structure reveals extensive genomic heterogeneity driven by homologous recombination and overlaid with high levels of accessory gene plasticity. We identified the existence of more than 290 clinically associated genomic phylogroups across 22 countries, highlighting challenges in designing vaccines of global utility. To determine vaccine candidate coverage, we investigated all of the previously described GAS candidate antigens for gene carriage and gene sequence heterogeneity. Only 15 of 28 vaccine antigen candidates were found to have both low naturally occurring sequence variation and high (>99%) coverage across this diverse GAS population. This technological platform for vaccine coverage determination is equally applicable to prospective GAS vaccine antigens identified in future studies.","container-title":"Nature Genetics","DOI":"10.1038/ s41588-019-0417-8","ISSN":"1546-1718","issue":"6","journalAbbreviation":"Nat Genet","language":"en","license":"2019 The Author(s), under exclusive licence to Springer Nature America, Inc.","page":"1035-1043","publisher":"Nature Publishing Group","source":"www.nature.com","title":"Atlas of group A streptococcal vaccine candidates compiled using large-scale comparative genomics","URL":"https://www.nature.com/articles/ s41588-019-0417-8","volume":"51","author": [{"family":"Davies","given":"Mark R."},{"family":"McIntyre","given":"Liam"}, {"family":"Mutreja","given":"Ankur"},{"family":"Lacey","given":"Jake A."},{"family":"Lees","given":"John A."},{"family":"Towers","given":"Rebecca J."},{"family":"Duchêne","given":"Sebastián"}, {"family":"Smeesters","given":"Pierre R."},{"family":"Frost","given":"Hannah R."},{"family":"Price","given":"David J."},{"family":"Holden","given":"Matthew T. 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This review uses the recent publication by Davies et al., 2019 as an updated global framework to address S. pyogenes population genomics, highlighting how genomics is being used to gain new insights into evolutionary processes, transmission pathways, and vaccine design.","container-title":"Infection, Genetics and Evolution","DOI":"10.1016/ j.meegid.2020.104609","ISSN":"15671348","journalAbbreviation":"Infection, Genetics and Evolution","language":"en","page":"104609","source":"DOI.org (Crossref)","title":"Global genomic epidemiology of Streptococcus pyogenes","URL":"https://linkinghub.elsevier.com/retrieve/pii/ S1567134820304408","volume":"86","author": [{"family":"Jespersen","given":"Magnus G."},{"family":"Lacey","given":"Jake A."},{"family":"Tong","given":"Steven Y.C."},{"family":"Davies","given":"Mark R."}],"accessed":{"date-parts":[["2026",2,25]]},"issued":{"date-parts": [["2020",12]]}}},{"uris":["http://zotero.org/users/local/FhamIvwD/ items/3XME8YP2"],"itemData":{"id":"http://zotero.org/users/local/ FhamIvwD/items/3XME8YP2","type":"article-journal","abstract":"M protein is a major virulence determinant for the group A streptococcus by virtue of its ability to allow the organism to resist phagocytosis. Common in eucaryotes, the fibrillar coiled-coil design for the M molecule may prove to be a common motif for surface proteins in gram-positive organisms. This type of structure offers the organism several distinct advantages, ranging from antigenic variation to multiple functional domains. The close resemblance of this molecular design to that of certain mammalian proteins could help explain on a molecular level the formation of epitopes responsible for serological cross-reactions between microbial and mammalian proteins. Many of the approaches described in the elucidation of the M-protein structure may be applied for characterizing similar molecules in other microbial systems.","container-title":"Clinical Microbiology Reviews","DOI":"10.1128/ CMR.2.3.285","ISSN":"0893-8512","issue":"3","journalAbbreviation":"Clin Microbiol Rev","language":"eng","page":"285-314","PMID":"2670192","PMCID":"PMC358122","source":"PubMed","title":"Streptococcal M protein: molecular design and biological behavior","title-short":"Streptococcal M protein","volume":"2","author":[{"family":"Fischetti","given":"V. A."}],"issued":{"date-parts":[["1989",7]]}}},{"uris":["http:// zotero.org/users/local/FhamIvwD/items/N7FXKMYZ"],"itemData": {"id":"http://zotero.org/users/local/FhamIvwD/items/ N7FXKMYZ","type":"article-journal","abstract":"SUMMARY\n Group A streptococci are model extracellular gram-positive pathogens responsible for pharyngitis, impetigo, rheumatic fever, and acute glomerulonephritis. A resurgence of invasive streptococcal diseases and rheumatic fever has appeared in outbreaks over the past 10 years, with a predominant M1 serotype as well as others identified with the outbreaks. emm (M protein) gene sequencing has changed serotyping, and new virulence genes and new virulence regulatory networks have been defined. The emm gene superfamily has expanded to include antiphagocytic molecules and immunoglobulin-binding proteins with common structural features. At least nine superantigens have been characterized, all of which may contribute to toxic streptococcal syndrome. An emerging theme is the dichotomy between skin and throat strains in their epidemiology and genetic makeup. Eleven adhesins have been reported, and surface plasmin-binding proteins have been defined. The strong resistance of the group A streptococcus to phagocytosis is related to factor H and fibrinogen binding by M protein and to disarming complement component C5a by the C5a peptidase. Molecular mimicry appears to play a role in autoimmune mechanisms involved in rheumatic fever, while nephritis strain-associated proteins may lead to immune-mediated acute glomerulonephritis. Vaccine strategies have focused on recombinant M protein and C5a peptidase vaccines, and mucosal vaccine delivery systems are under investigation.","container-title":"Clinical Microbiology Reviews","DOI":"10.1128/CMR.13.3.470","ISSN":"0893-8512, 1098-6618","issue":"3","journalAbbreviation":"Clin Microbiol Rev","language":"en","page":"470-511","source":"DOI.org (Crossref)","title":"Pathogenesis of Group A Streptococcal Infections","URL":"https://journals.asm.org/doi/10.1128/ CMR.13.3.470","volume":"13","author": [{"family":"Cunningham","given":"Madeleine W."}],"accessed":{"date-parts":[["2026",3,5]]},"issued":{"date-parts": [["2000",7]]}}}]},"doc":{"type":"doc","content": [{"type":"heading","attrs": {"level":1,"indent":null,"align":"left","dir":"ltr","id":null},"content": [{"type":"text","marks":[{"type":"strong"}],"text":"Group A "},{"type":"text","marks":[{"type":"strong"}, {"type":"em"}],"text":"Streptococcus"},{"type":"text","marks": [{"type":"strong"}],"text":" (GAS)"}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","marks":[{"type":"em"}],"text":"Streptococcus pyogenes "},{"type":"text","text":"(group A streptococcus) is a gram-positive extracellular bacterial pathogen. GAS colonise the throat or skin and are responsible for a number of suppurative infections (a type of inflammation that produces, discharges, or causes the formation of pus, which consists of neutrophils, dead cells, and tissue debris) and non-suppurative sequelae (a condition which is the consequence of a previous disease or injury) "},{"type":"citation","attrs": {"nodeID":"AgmhjJLy","version":0,"citation":{"citationItems":[{"uris": ["http://zotero.org/users/local/FhamIvwD/items/ N7FXKMYZ"]}],"properties":{}}}},{"type":"text","text":"."}]}, {"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"Infection can cause "},{"type":"text","marks":[{"type":"link","attrs":{"href":"zotero:// note/u/YRFSNA87/? section=Pharyngitis","title":null}}],"text":"pharyngitis"}, {"type":"text","text":" (inflammation of the pharynx), "},{"type":"text","marks":[{"type":"link","attrs":{"href":"zotero:// note/u/YRFSNA87/? section=Scarlet%20Fever","title":null}}],"text":"scarlet fever"},{"type":"text","text":" ("},{"type":"text","marks":[{"type":"textColor","attrs": {"color":"rgb(10, 10, 10)"}},{"type":"backgroundColor","attrs":{"color":"rgb(255, 255, 255)"}}],"text":"featuring a bright red, sandpaper-like rash, high fever, and a \"strawberry tongue\") and impetigo (highly contagious, superficial bacterial skin infection, common in children, causing itchy, red sores that rupture and form characteristic honey-colored, crusty patches, usually on the face or limbs). Other diseases include streptococcal shock syndrome and necrotising fasciitis "},{"type":"citation","attrs": {"nodeID":"fBq1afLg","version":0,"citation":{"citationItems":[{"uris": ["http://zotero.org/users/local/FhamIvwD/items/ N7FXKMYZ"]}],"properties":{}}}},{"type":"text","marks": [{"type":"textColor","attrs":{"color":"rgb(10, 10, 10)"}},{"type":"backgroundColor","attrs":{"color":"rgb(255, 255, 255)"}}],"text":"."}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"Importantly, GAS is known for it’s significant role in the development of post-infection sequelae, including acute rheumatic fever, acute glomerulonephritis (inflammation of the kidney's tiny filters (glomeruli), causing blood/protein in urine, high blood pressure, and swelling), and reactive arthritis. Repeated episodes of rheumatic fever leads to rheumatic heart disease "},{"type":"citation","attrs": {"nodeID":"1hCkLrdH","version":0,"citation":{"citationItems":[{"uris": ["http://zotero.org/users/local/FhamIvwD/items/ N7FXKMYZ"]}],"properties":{}}}},{"type":"text","text":"."}]}, {"type":"paragraph","attrs":{"indent":null,"align":"left","dir":"ltr"}}, {"type":"heading","attrs": {"level":2,"indent":null,"align":"left","dir":"ltr","id":null},"content": [{"type":"text","marks":[{"type":"strong"}],"text":"Typing"}]}, {"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"The Lancefield classification scheme distinguishes serological types based on their group A carbohydrate or their M protein, which confers resistance to phagocytosis by polymorphonuclear leukocytes. Identified by Rebecca Lancefield around 1962. The M protein is a major virulence factor, encoded by the "},{"type":"text","marks":[{"type":"em"}],"text":"emm "},{"type":"text","text":"gene "},{"type":"citation","attrs": {"nodeID":"P1LtHgdM","version":0,"citation":{"citationItems":[{"uris": ["http://zotero.org/users/local/FhamIvwD/ items/3XME8YP2"]}],"properties":{}}}},{"type":"text","text":". The skin and throat serotypes have been divided epidemiologically on the basis of opacity factor production, the presence of the class IC repeat region epitope identified on M proteins by anti-M protein monoclonal antibody (MAb) 10B6, and "},{"type":"text","marks":[{"type":"em"}],"text":"emm "},{"type":"text","text":"(M protein) gene patterns A through E "},{"type":"citation","attrs": {"nodeID":"58ORPiUI","version":0,"citation":{"citationItems":[{"uris": ["http://zotero.org/users/local/FhamIvwD/items/ N7FXKMYZ"]}],"properties":{}}}},{"type":"text","text":"."}]}, {"type":"heading","attrs": {"level":2,"indent":null,"align":null,"dir":null,"id":null},"content": [{"type":"text","marks":[{"type":"strong"}],"text":"Genomic Epidemiology"}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"Classical GAS epidemiological and genotypic markers of differentiation:"}]},{"type":"bulletList","attrs": 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disease"}]},{"type":"bulletList","attrs":{"dir":"ltr"},"content": [{"type":"listItem","content":[{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"text","text":"Mitral and/or aortic regurgitation"}]}]}]}]},{"type":"listItem","content": [{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"citation","attrs":{"nodeID":"veF3peMV","version":0,"citation": {"citationItems":[{"uris":["http://zotero.org/users/local/FhamIvwD/ items/3XME8YP2"],"locator":"286"}],"properties":{}}}}]}]}, {"type":"listItem","content":[{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"citation","attrs":{"nodeID":"fGCtWc7G","version":0,"citation": {"citationItems":[{"uris":["http://zotero.org/users/local/FhamIvwD/ items/7IDZT94H"],"locator":"1035"}],"properties":{}}}}]}]}]}, {"type":"paragraph","attrs":{"indent":null,"align":"left","dir":"ltr"}}, {"type":"heading","attrs": {"level":2,"indent":null,"align":"left","dir":"ltr","id":null},"content": [{"type":"text","marks":[{"type":"strong"}],"text":"Vaccine Options"}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"Types:"}]},{"type":"bulletList","attrs": {"dir":"ltr"},"content":[{"type":"listItem","content": [{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"text","text":"Purified protein"}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"text","text":"mRNA"}]}]},{"type":"listItem","content": [{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"text","text":"LNP"}]}]},{"type":"listItem","content": [{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"text","text":"Synthetic Vaccine-Like Particle"}]}]}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"Non M protein antigen vaccine targets:"}]},{"type":"bulletList","attrs":{"dir":"ltr"},"content": [{"type":"listItem","content":[{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"text","text":"SpyCEP"}]}]},{"type":"listItem","content": [{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"text","text":"ADI - Arginine deiminase"}]}]},{"type":"listItem","content": [{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"text","text":"TF - Trigger factor"}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"text","text":"SCPA"}]}]},{"type":"listItem","content": [{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"text","text":"SLO - Pore forming something"}]}]}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"Combo #5 antigens not implicated in autoimmunity. Detoxified by site-directed mutagenisis to remove catalytic activity. M1 purified protein used as pos control in animal trial (provides good protection but not good as vaccine target due to autoimmune sequelae). This was demonstrated when M3 clinical trial resulted in rheumatic fever in patients. FDA banned using GAS components for 25 years. Could also be group A carbohydrate involved in rheumatic fever. WHO roadmap came out in early 2000’s."}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"Effectiveness was influenced by adjuvant (has a large influence on vaccine effectiveness as measured by colonisation after animal challenge), chosen antigen (new antigens can be identified via Activation Induced Marker Assay to probe human memory CD4+ T cell reactivity) and location of the antigen for mRNA (clustering the antigen on the surface of the cell) and VLP vectors. GAS colonisation was measured by swab and streaking on HBA (beta-haemolytic colonies) followed by agglutination test."}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"/"}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"//"}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"}},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"}},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"}}]}},"changed": {"note":"<div data-citation- items=\"%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F7IDZT94H%22%5D%2C%22itemData%22%3A%7B%22id%22%3A%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F7IDZT94H%22%2C%22type%22%3A%22article- 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%20Vaccine%20strategies%20have%20focused%20on%20recombinant%20M%20protein%20and%20C5a%20peptidase%20vaccines%2C%20and%20mucosal%20vaccine%20delivery%20systems%20are%20under%20investigation. %22%2C%22container- title%22%3A%22Clinical%20Microbiology%20Reviews%22%2C%22DOI%22%3A%2210.1128%2FCMR.13.3.470%22%2C%22ISSN%22%3A%220893-8512%2C%201098-6618%22%2C%22issue%22%3A%223%22%2C%22journalAbbreviation%22%3A%22Clin%20Microbiol%20Rev%22%2C%22language%22%3A%22en%22%2C%22page%22%3A%22470-511%22%2C%22source%22%3A%22DOI.org%20(Crossref)%22%2C%22title%22%3A%22Pathogenesis%20of%20Group%20A%20Streptococcal%20Infections%22%2C%22URL%22%3A%22https%3A%2F%2Fjournals.asm.org%2Fdoi%2F10.1128%2FCMR.13.3.470%22%2C%22volume%22%3A%2213%22%2C%22author%22%3A%5B%7B%22family%22%3A%22Cunningham%22%2C%22given%22%3A%22Madeleine%20W. %22%7D%5D%2C%22accessed%22%3A%7B%22date- parts%22%3A%5B%5B%222026%22%2C3%2C5%5D%5D%7D%2C%22issued%22%3A%7B%22date- parts%22%3A%5B%5B%222000%22%2C7%5D%5D%7D%7D%7D%5D\" data-schema-version=\"9\"><h1 style=\"text-align: left;\" dir=\"ltr\"><strong>Group A <em>Streptococcus</em> (GAS)</strong></h1>\n<p style=\"text-align: left;\" dir=\"ltr\"><em>Streptococcus pyogenes </em>(group A streptococcus) is a gram-positive extracellular bacterial pathogen. GAS colonise the throat or skin and are responsible for a number of suppurative infections (a type of inflammation that produces, discharges, or causes the formation of pus, which consists of neutrophils, dead cells, and tissue debris) and non-suppurative sequelae (a condition which is the consequence of a previous disease or injury) <span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2FN7FXKMYZ%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Cunningham, 2000</span>)</span>.</p>\n<p style=\"text-align: left;\" dir=\"ltr\">Infection can cause <a href=\"zotero://note/u/YRFSNA87/?section=Pharyngitis\" rel=\"noopener noreferrer nofollow\">pharyngitis</a> (inflammation of the pharynx), <a href=\"zotero://note/u/YRFSNA87/?section=Scarlet%20Fever\" rel=\"noopener noreferrer nofollow\">scarlet fever</a> (<span style=\"color: rgb(10, 10, 10);\"><span style=\"background-color: rgb(255, 255, 255);\">featuring a bright red, sandpaper-like rash, high fever, and a \"strawberry tongue\") and impetigo (highly contagious, superficial bacterial skin infection, common in children, causing itchy, red sores that rupture and form characteristic honey-colored, crusty patches, usually on the face or limbs). Other diseases include streptococcal shock syndrome and necrotising fasciitis </span></span><span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2FN7FXKMYZ%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Cunningham, 2000</span>)</span><span style=\"color: rgb(10, 10, 10);\"><span style=\"background-color: rgb(255, 255, 255);\">.</span></span></p>\n<p style=\"text-align: left;\" dir=\"ltr\">Importantly, GAS is known for it’s significant role in the development of post-infection sequelae, including acute rheumatic fever, acute glomerulonephritis (inflammation of the kidney's tiny filters (glomeruli), causing blood/protein in urine, high blood pressure, and swelling), and reactive arthritis. Repeated episodes of rheumatic fever leads to rheumatic heart disease <span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2FN7FXKMYZ%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Cunningham, 2000</span>)</span>.</p>\n<p style=\"text-align: left;\" dir=\"ltr\"></p>\n<h2 style=\"text-align: left;\" dir=\"ltr\"><strong>Typing</strong></h2>\n<p style=\"text-align: left;\" dir=\"ltr\">The Lancefield classification scheme distinguishes serological types based on their group A carbohydrate or their M protein, which confers resistance to phagocytosis by polymorphonuclear leukocytes. Identified by Rebecca Lancefield around 1962. The M protein is a major virulence factor, encoded by the <em>emm </em>gene <span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F3XME8YP2%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Fischetti, 1989</span>)</span>. The skin and throat serotypes have been divided epidemiologically on the basis of opacity factor production, the presence of the class IC repeat region epitope identified on M proteins by anti-M protein monoclonal antibody (MAb) 10B6, and <em>emm </em>(M protein) gene patterns A through E <span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2FN7FXKMYZ%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Cunningham, 2000</span>)</span>.</p> \n<h2><strong>Genomic Epidemiology</strong></h2>\n<p style=\"text-align: left;\" dir=\"ltr\">Classical GAS epidemiological and genotypic markers of differentiation:</p>\n<ul dir=\"ltr\">\n<li>\n<em>emm </em>types\n</li>\n<li>\nM protein clusters\n</li>\n<li>\nMulti locus sequence types (MLST)\n</li>\n</ul>\n<p style=\"text-align: left;\" dir=\"ltr\"></p>\n<h2 style=\"text-align: left;\" dir=\"ltr\"><strong>Clinical</strong></h2>\n<p style=\"text-align: left;\" dir=\"ltr\">GAS ranks within the top 10 infectious disease causes of death worldwide <span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2FAU8ZQCQZ%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Jespersen et al., 2020</span>)</span>.</p>\n<p style=\"text-align: left;\" dir=\"ltr\">There is no vaccine:</p>\n<ul dir=\"ltr\">\n<li>\nSerotype diversity\n</li>\n<li>\nAntigen carriage and variation\n</li>\n<li>\nVaccine safety concerns due to immune sequelae caused by repeat GAS infection\n</li>\n<li>\n<span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F7IDZT94H%22%5D%2C%22locator%22%3A%221035%22%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Davies et al., 2019, p. 1035</span>)</span>\n</li>\n</ul>\n<p style=\"text-align: left;\" dir=\"ltr\">Immune sequelae:</p>\n<ul dir=\"ltr\">\n<li>\nGlomerulonephritis\n</li>\n<li> \nAcute rheumatic fever\n</li>\n<li>\n<p style=\"text-align: left;\" dir=\"ltr\">Rheumatic heart disease</p>\n<ul dir=\"ltr\">\n<li>\nMitral and/or aortic regurgitation\n</li>\n</ul>\n</li>\n<li> \n<span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F3XME8YP2%22%5D%2C%22locator%22%3A%22286%22%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Fischetti, 1989, p. 286</span>)</span>\n</li>\n<li>\n<span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F7IDZT94H%22%5D%2C%22locator%22%3A%221035%22%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Davies et al., 2019, p. 1035</span>)</span>\n</li>\n</ul>\n<p style=\"text-align: left;\" dir=\"ltr\"></p>\n<h2 style=\"text-align: left;\" dir=\"ltr\"><strong>Vaccine Options</strong></h2>\n<p style=\"text-align: left;\" dir=\"ltr\">Types:</p>\n<ul dir=\"ltr\">\n<li>\nPurified protein\n</li>\n<li>\nmRNA\n</li>\n<li> \nLNP\n</li>\n<li>\nSynthetic Vaccine-Like Particle\n</li>\n</ul>\n<p style=\"text-align: left;\" dir=\"ltr\">Non M protein antigen vaccine targets:</p>\n<ul dir=\"ltr\">\n<li>\nSpyCEP\n</li>\n<li>\nADI - Arginine deiminase\n</li>\n<li>\nTF - Trigger factor\n</li>\n<li>\nSCPA\n</li>\n<li>\nSLO - Pore forming something\n</li>\n</ul>\n<p style=\"text-align: left;\" dir=\"ltr\">Combo #5 antigens not implicated in autoimmunity. Detoxified by site-directed mutagenisis to remove catalytic activity. M1 purified protein used as pos control in animal trial (provides good protection but not good as vaccine target due to autoimmune sequelae). This was demonstrated when M3 clinical trial resulted in rheumatic fever in patients. FDA banned using GAS components for 25 years. Could also be group A carbohydrate involved in rheumatic fever. WHO roadmap came out in early 2000’s.</p>\n<p style=\"text-align: left;\" dir=\"ltr\">Effectiveness was influenced by adjuvant (has a large influence on vaccine effectiveness as measured by colonisation after animal challenge), chosen antigen (new antigens can be identified via Activation Induced Marker Assay to probe human memory CD4+ T cell reactivity) and location of the antigen for mRNA (clustering the antigen on the surface of the cell) and VLP vectors. GAS colonisation was measured by swab and streaking on HBA (beta-haemolytic colonies) followed by agglutination test.</p>\n<p style=\"text-align: left;\" dir=\"ltr\">/</p>\n<p style=\"text-align: left;\" dir=\"ltr\">/</p>\n<p style=\"text-align: left;\" dir=\"ltr\"></p>\n<p style=\"text-align: left;\" dir=\"ltr\"></p>\n</div>"}}) queued

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data-schema-version="9"><h1 style="text-align: left;" dir="ltr"><strong>Group A <em>Streptococcus</em> (GAS)</strong></h1> <p style="text-align: left;" dir="ltr"><em>Streptococcus pyogenes </em>(group A streptococcus) is a gram-positive extracellular bacterial pathogen. GAS colonise the throat or skin and are responsible for a number of suppurative infections (a type of inflammation that produces, discharges, or causes the formation of pus, which consists of neutrophils, dead cells, and tissue debris) and non-suppurative sequelae (a condition which is the consequence of a previous disease or injury) <span class="citation" data- citation="%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2FN7FXKMYZ%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D"> (<span class="citation-item">Cunningham, 2000</span>)</span>.</p> <p style="text-align: left;" dir="ltr">Infection can cause <a href="zotero://note/u/YRFSNA87/?section=Pharyngitis" rel="noopener noreferrer nofollow">pharyngitis</a> (inflammation of the pharynx), <a href="zotero://note/u/YRFSNA87/?section=Scarlet%20Fever" rel="noopener noreferrer nofollow">scarlet fever</a> (<span style="color: rgb(10, 10, 10);"><span style="background-color: rgb(255, 255, 255);">featuring a bright red, sandpaper-like rash, high fever, and a "strawberry tongue") and impetigo (highly contagious, superficial bacterial skin infection, common in children, causing itchy, red sores that rupture and form characteristic honey-colored, crusty patches, usually on the face or limbs). Other diseases include streptococcal shock syndrome and necrotising fasciitis </span></span><span class="citation" data- citation="%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2FN7FXKMYZ%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D"> (<span class="citation-item">Cunningham, 2000</span>)</span><span style="color: rgb(10, 10, 10);"><span style="background-color: rgb(255, 255, 255);">.</span></span></p> <p style="text-align: left;" dir="ltr">Importantly, GAS is known for it’s significant role in the development of post-infection sequelae, including acute rheumatic fever, acute glomerulonephritis (inflammation of the kidney's tiny filters (glomeruli), causing blood/protein in urine, high blood pressure, and swelling), and reactive arthritis. Repeated episodes of rheumatic fever leads to rheumatic heart disease <span class="citation" data- citation="%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2FN7FXKMYZ%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D"> (<span class="citation-item">Cunningham, 2000</span>)</span>.</p> <p style="text-align: left;" dir="ltr"></p> <h2 style="text-align: left;" dir="ltr"><strong>Typing</strong></h2> <p style="text-align: left;" dir="ltr">The Lancefield classification scheme distinguishes serological types based on their group A carbohydrate or their M protein, which confers resistance to phagocytosis by polymorphonuclear leukocytes. Identified by Rebecca Lancefield around 1962. The M protein is a major virulence factor, encoded by the <em>emm </em>gene <span class="citation" data- citation="%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F3XME8YP2%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D"> (<span class="citation-item">Fischetti, 1989</span>)</span>. The skin and throat serotypes have been divided epidemiologically on the basis of opacity factor production, the presence of the class IC repeat region epitope identified on M proteins by anti-M protein monoclonal antibody (MAb) 10B6, and <em>emm </em>(M protein) gene patterns A through E <span class="citation" data- citation="%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2FN7FXKMYZ%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D"> (<span class="citation-item">Cunningham, 2000</span>)</span>.</p> <h2><strong>Genomic Epidemiology</strong></h2> <p style="text-align: left;" dir="ltr">Classical GAS epidemiological and genotypic markers of differentiation:</p> <ul dir="ltr"> <li> <em>emm </em>types </li> <li> M protein clusters </li> <li> Multi locus sequence types (MLST) </li> </ul> <p style="text-align: left;" dir="ltr"></p> <h2 style="text-align: left;" dir="ltr"><strong>Clinical</strong></h2> <p style="text-align: left;" dir="ltr">GAS ranks within the top 10 infectious disease causes of death worldwide <span class="citation" data- citation="%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2FAU8ZQCQZ%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D"> (<span class="citation-item">Jespersen et al., 2020</span>)</span>.</p> <p style="text-align: left;" dir="ltr">There is no vaccine:</p> <ul dir="ltr"> <li> Serotype diversity </li> <li> Antigen carriage and variation </li> <li> Vaccine safety concerns due to immune sequelae caused by repeat GAS infection </li> <li> <span class="citation" data- citation="%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F7IDZT94H%22%5D%2C%22locator%22%3A%221035%22%7D%5D%2C%22properties%22%3A%7B%7D%7D"> (<span class="citation-item">Davies et al., 2019, p. 1035</span>)</span> </li> </ul> <p style="text-align: left;" dir="ltr">Immune sequelae:</p> <ul dir="ltr"> <li> Glomerulonephritis </li> <li> Acute rheumatic fever </li> <li> <p style="text-align: left;" dir="ltr">Rheumatic heart disease</p> <ul dir="ltr"> <li> Mitral and/or aortic regurgitation </li> </ul> </li> <li> <span class="citation" data- citation="%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F3XME8YP2%22%5D%2C%22locator%22%3A%22286%22%7D%5D%2C%22properties%22%3A%7B%7D%7D"> (<span class="citation-item">Fischetti, 1989, p. 286</span>)</span> </li> <li> <span class="citation" data- citation="%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F7IDZT94H%22%5D%2C%22locator%22%3A%221035%22%7D%5D%2C%22properties%22%3A%7B%7D%7D"> (<span class="citation-item">Davies et al., 2019, p. 1035</span>)</span> </li> </ul> <p style="text-align: left;" dir="ltr"></p> <h2 style="text-align: left;" dir="ltr"><strong>Vaccine Options</strong></h2> <p style="text-align: left;" dir="ltr">Types:</p> <ul dir="ltr"> <li> Purified protein </li> <li> mRNA </li> <li> LNP </li> <li> Synthetic Vaccine-Like Particle </li> </ul> <p style="text-align: left;" dir="ltr">Non M protein antigen vaccine targets:</p> <ul dir="ltr"> <li> SpyCEP </li> <li> ADI - Arginine deiminase </li> <li> TF - Trigger factor </li> <li> SCPA </li> <li> SLO - Pore forming something </li> </ul> <p style="text-align: left;" dir="ltr">Combo #5 antigens not implicated in autoimmunity. Detoxified by site-directed mutagenisis to remove catalytic activity. M1 purified protein used as pos control in animal trial (provides good protection but not good as vaccine target due to autoimmune sequelae). This was demonstrated when M3 clinical trial resulted in rheumatic fever in patients. FDA banned using GAS components for 25 years. Could also be group A carbohydrate involved in rheumatic fever. WHO roadmap came out in early 2000’s.</p> <p style="text-align: left;" dir="ltr">Effectiveness was influenced by adjuvant (has a large influence on vaccine effectiveness as measured by colonisation after animal challenge), chosen antigen (new antigens can be identified via Activation Induced Marker Assay to probe human memory CD4+ T cell reactivity) and location of the antigen for mRNA (clustering the antigen on the surface of the cell) and VLP vectors. GAS colonisation was measured by swab and streaking on HBA (beta-haemolytic colonies) followed by agglutination test.</p> <p style="text-align: left;" dir="ltr">/</p> <p style="text-align: left;" dir="ltr">//</p> <p style="text-align: left;" dir="ltr"></p> <p style="text-align: left;" dir="ltr"></p> <p style="text-align: left;" dir="ltr"></p> </div></div>', 'Group A Streptococcus (GAS)', 51]

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This technological platform for vaccine coverage determination is equally applicable to prospective GAS vaccine antigens identified in future studies.","container-title":"Nature Genetics","DOI":"10.1038/ s41588-019-0417-8","ISSN":"1546-1718","issue":"6","journalAbbreviation":"Nat Genet","language":"en","license":"2019 The Author(s), under exclusive licence to Springer Nature America, Inc.","page":"1035-1043","publisher":"Nature Publishing Group","source":"www.nature.com","title":"Atlas of group A streptococcal vaccine candidates compiled using large-scale comparative genomics","URL":"https://www.nature.com/articles/ s41588-019-0417-8","volume":"51","author": [{"family":"Davies","given":"Mark R."},{"family":"McIntyre","given":"Liam"}, {"family":"Mutreja","given":"Ankur"},{"family":"Lacey","given":"Jake A."},{"family":"Lees","given":"John A."},{"family":"Towers","given":"Rebecca J."},{"family":"Duchêne","given":"Sebastián"}, {"family":"Smeesters","given":"Pierre R."},{"family":"Frost","given":"Hannah R."},{"family":"Price","given":"David J."},{"family":"Holden","given":"Matthew T. 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C."},{"family":"Dougan","given":"Gordon"}, {"family":"Walker","given":"Mark J."}],"accessed":{"date-parts":[["2026",2,27]]},"issued":{"date-parts": [["2019",6]]}}},{"uris":["http://zotero.org/users/local/FhamIvwD/items/ AU8ZQCQZ"],"itemData":{"id":"http://zotero.org/users/local/FhamIvwD/ items/AU8ZQCQZ","type":"article-journal","abstract":"Streptococcus pyogenes is one of the Top 10 human infectious disease killers worldwide causing a range of clinical manifestations in humans. Colonizing a range of ecological niches within its sole host, the human, is key to the ability of this opportunistic pathogen to cause direct and post-infectious manifestations. The expansion of genome sequencing capabilities and data availability over the last decade has led to an improved understanding of the evolutionary dynamics of this pathogen within a global framework where epidemiological relationships and evolutionary mechanisms may not be universal. This review uses the recent publication by Davies et al., 2019 as an updated global framework to address S. pyogenes population genomics, highlighting how genomics is being used to gain new insights into evolutionary processes, transmission pathways, and vaccine design.","container-title":"Infection, Genetics and Evolution","DOI":"10.1016/ j.meegid.2020.104609","ISSN":"15671348","journalAbbreviation":"Infection, Genetics and Evolution","language":"en","page":"104609","source":"DOI.org (Crossref)","title":"Global genomic epidemiology of Streptococcus pyogenes","URL":"https://linkinghub.elsevier.com/retrieve/pii/ S1567134820304408","volume":"86","author": [{"family":"Jespersen","given":"Magnus G."},{"family":"Lacey","given":"Jake A."},{"family":"Tong","given":"Steven Y.C."},{"family":"Davies","given":"Mark R."}],"accessed":{"date-parts":[["2026",2,25]]},"issued":{"date-parts": [["2020",12]]}}},{"uris":["http://zotero.org/users/local/FhamIvwD/ items/3XME8YP2"],"itemData":{"id":"http://zotero.org/users/local/ FhamIvwD/items/3XME8YP2","type":"article-journal","abstract":"M protein is a major virulence determinant for the group A streptococcus by virtue of its ability to allow the organism to resist phagocytosis. Common in eucaryotes, the fibrillar coiled-coil design for the M molecule may prove to be a common motif for surface proteins in gram-positive organisms. This type of structure offers the organism several distinct advantages, ranging from antigenic variation to multiple functional domains. The close resemblance of this molecular design to that of certain mammalian proteins could help explain on a molecular level the formation of epitopes responsible for serological cross-reactions between microbial and mammalian proteins. Many of the approaches described in the elucidation of the M-protein structure may be applied for characterizing similar molecules in other microbial systems.","container-title":"Clinical Microbiology Reviews","DOI":"10.1128/ CMR.2.3.285","ISSN":"0893-8512","issue":"3","journalAbbreviation":"Clin Microbiol Rev","language":"eng","page":"285-314","PMID":"2670192","PMCID":"PMC358122","source":"PubMed","title":"Streptococcal M protein: molecular design and biological behavior","title-short":"Streptococcal M protein","volume":"2","author":[{"family":"Fischetti","given":"V. A."}],"issued":{"date-parts":[["1989",7]]}}},{"uris":["http:// zotero.org/users/local/FhamIvwD/items/N7FXKMYZ"],"itemData": {"id":"http://zotero.org/users/local/FhamIvwD/items/ N7FXKMYZ","type":"article-journal","abstract":"SUMMARY\n Group A streptococci are model extracellular gram-positive pathogens responsible for pharyngitis, impetigo, rheumatic fever, and acute glomerulonephritis. A resurgence of invasive streptococcal diseases and rheumatic fever has appeared in outbreaks over the past 10 years, with a predominant M1 serotype as well as others identified with the outbreaks. emm (M protein) gene sequencing has changed serotyping, and new virulence genes and new virulence regulatory networks have been defined. The emm gene superfamily has expanded to include antiphagocytic molecules and immunoglobulin-binding proteins with common structural features. At least nine superantigens have been characterized, all of which may contribute to toxic streptococcal syndrome. An emerging theme is the dichotomy between skin and throat strains in their epidemiology and genetic makeup. Eleven adhesins have been reported, and surface plasmin-binding proteins have been defined. The strong resistance of the group A streptococcus to phagocytosis is related to factor H and fibrinogen binding by M protein and to disarming complement component C5a by the C5a peptidase. Molecular mimicry appears to play a role in autoimmune mechanisms involved in rheumatic fever, while nephritis strain-associated proteins may lead to immune-mediated acute glomerulonephritis. Vaccine strategies have focused on recombinant M protein and C5a peptidase vaccines, and mucosal vaccine delivery systems are under investigation.","container-title":"Clinical Microbiology Reviews","DOI":"10.1128/CMR.13.3.470","ISSN":"0893-8512, 1098-6618","issue":"3","journalAbbreviation":"Clin Microbiol Rev","language":"en","page":"470-511","source":"DOI.org (Crossref)","title":"Pathogenesis of Group A Streptococcal Infections","URL":"https://journals.asm.org/doi/10.1128/ CMR.13.3.470","volume":"13","author": [{"family":"Cunningham","given":"Madeleine W."}],"accessed":{"date-parts":[["2026",3,5]]},"issued":{"date-parts": [["2000",7]]}}}]},"doc":{"type":"doc","content": [{"type":"heading","attrs": {"level":1,"indent":null,"align":"left","dir":"ltr","id":null},"content": [{"type":"text","marks":[{"type":"strong"}],"text":"Group A "},{"type":"text","marks":[{"type":"strong"}, {"type":"em"}],"text":"Streptococcus"},{"type":"text","marks": [{"type":"strong"}],"text":" (GAS)"}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","marks":[{"type":"em"}],"text":"Streptococcus pyogenes "},{"type":"text","text":"(group A streptococcus) is a gram-positive extracellular bacterial pathogen. GAS colonise the throat or skin and are responsible for a number of suppurative infections (a type of inflammation that produces, discharges, or causes the formation of pus, which consists of neutrophils, dead cells, and tissue debris) and non-suppurative sequelae (a condition which is the consequence of a previous disease or injury) "},{"type":"citation","attrs": {"nodeID":"AgmhjJLy","version":0,"citation":{"citationItems":[{"uris": ["http://zotero.org/users/local/FhamIvwD/items/ N7FXKMYZ"]}],"properties":{}}}},{"type":"text","text":"."}]}, {"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"Infection can cause "},{"type":"text","marks":[{"type":"link","attrs":{"href":"zotero:// note/u/YRFSNA87/? section=Pharyngitis","title":null}}],"text":"pharyngitis"}, {"type":"text","text":" (inflammation of the pharynx), "},{"type":"text","marks":[{"type":"link","attrs":{"href":"zotero:// note/u/YRFSNA87/? section=Scarlet%20Fever","title":null}}],"text":"scarlet fever"},{"type":"text","text":" ("},{"type":"text","marks":[{"type":"textColor","attrs": {"color":"rgb(10, 10, 10)"}},{"type":"backgroundColor","attrs":{"color":"rgb(255, 255, 255)"}}],"text":"featuring a bright red, sandpaper-like rash, high fever, and a \"strawberry tongue\") and impetigo (highly contagious, superficial bacterial skin infection, common in children, causing itchy, red sores that rupture and form characteristic honey-colored, crusty patches, usually on the face or limbs). Other diseases include streptococcal shock syndrome and necrotising fasciitis "},{"type":"citation","attrs": {"nodeID":"fBq1afLg","version":0,"citation":{"citationItems":[{"uris": ["http://zotero.org/users/local/FhamIvwD/items/ N7FXKMYZ"]}],"properties":{}}}},{"type":"text","marks": [{"type":"textColor","attrs":{"color":"rgb(10, 10, 10)"}},{"type":"backgroundColor","attrs":{"color":"rgb(255, 255, 255)"}}],"text":"."}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"Importantly, GAS is known for it’s significant role in the development of post-infection sequelae, including acute rheumatic fever, acute glomerulonephritis (inflammation of the kidney's tiny filters (glomeruli), causing blood/protein in urine, high blood pressure, and swelling), and reactive arthritis. Repeated episodes of rheumatic fever leads to rheumatic heart disease "},{"type":"citation","attrs": {"nodeID":"1hCkLrdH","version":0,"citation":{"citationItems":[{"uris": ["http://zotero.org/users/local/FhamIvwD/items/ N7FXKMYZ"]}],"properties":{}}}},{"type":"text","text":"."}]}, {"type":"paragraph","attrs":{"indent":null,"align":"left","dir":"ltr"}}, {"type":"heading","attrs": {"level":2,"indent":null,"align":"left","dir":"ltr","id":null},"content": [{"type":"text","marks":[{"type":"strong"}],"text":"Typing"}]}, {"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"The Lancefield classification scheme distinguishes serological types based on their group A carbohydrate or their M protein, which confers resistance to phagocytosis by polymorphonuclear leukocytes. Identified by Rebecca Lancefield around 1962. The M protein is a major virulence factor, encoded by the "},{"type":"text","marks":[{"type":"em"}],"text":"emm "},{"type":"text","text":"gene "},{"type":"citation","attrs": {"nodeID":"P1LtHgdM","version":0,"citation":{"citationItems":[{"uris": ["http://zotero.org/users/local/FhamIvwD/ items/3XME8YP2"]}],"properties":{}}}},{"type":"text","text":". The skin and throat serotypes have been divided epidemiologically on the basis of opacity factor production, the presence of the class IC repeat region epitope identified on M proteins by anti-M protein monoclonal antibody (MAb) 10B6, and "},{"type":"text","marks":[{"type":"em"}],"text":"emm "},{"type":"text","text":"(M protein) gene patterns A through E "},{"type":"citation","attrs": {"nodeID":"58ORPiUI","version":0,"citation":{"citationItems":[{"uris": ["http://zotero.org/users/local/FhamIvwD/items/ N7FXKMYZ"]}],"properties":{}}}},{"type":"text","text":"."}]}, {"type":"heading","attrs": {"level":2,"indent":null,"align":null,"dir":null,"id":null},"content": [{"type":"text","marks":[{"type":"strong"}],"text":"Genomic Epidemiology"}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"Classical GAS epidemiological and genotypic markers of differentiation:"}]},{"type":"bulletList","attrs": 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{"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"Non M protein antigen vaccine targets:"}]},{"type":"bulletList","attrs":{"dir":"ltr"},"content": [{"type":"listItem","content":[{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"text","text":"SpyCEP"}]}]},{"type":"listItem","content": [{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"text","text":"ADI - Arginine deiminase"}]}]},{"type":"listItem","content": [{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"text","text":"TF - Trigger factor"}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"text","text":"SCPA"}]}]},{"type":"listItem","content": [{"type":"paragraph","attrs": {"indent":null,"align":null,"dir":null},"content": [{"type":"text","text":"SLO - Pore forming something"}]}]}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"Combo #5 antigens not implicated in autoimmunity. Detoxified by site-directed mutagenisis to remove catalytic activity. M1 purified protein used as pos control in animal trial (provides good protection but not good as vaccine target due to autoimmune sequelae). This was demonstrated when M3 clinical trial resulted in rheumatic fever in patients. FDA banned using GAS components for 25 years. Could also be group A carbohydrate involved in rheumatic fever. WHO roadmap came out in early 2000’s."}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"Effectiveness was influenced by adjuvant (has a large influence on vaccine effectiveness as measured by colonisation after animal challenge), chosen antigen (new antigens can be identified via Activation Induced Marker Assay to probe human memory CD4+ T cell reactivity) and location of the antigen for mRNA (clustering the antigen on the surface of the cell) and VLP vectors. GAS colonisation was measured by swab and streaking on HBA (beta-haemolytic colonies) followed by agglutination test."}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"/"}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"},"content": [{"type":"text","text":"//"}]},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"}},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"}},{"type":"paragraph","attrs": {"indent":null,"align":"left","dir":"ltr"}}]}},"changed": {"note":"<div data-citation- items=\"%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F7IDZT94H%22%5D%2C%22itemData%22%3A%7B%22id%22%3A%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F7IDZT94H%22%2C%22type%22%3A%22article- 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%20Vaccine%20strategies%20have%20focused%20on%20recombinant%20M%20protein%20and%20C5a%20peptidase%20vaccines%2C%20and%20mucosal%20vaccine%20delivery%20systems%20are%20under%20investigation. %22%2C%22container- title%22%3A%22Clinical%20Microbiology%20Reviews%22%2C%22DOI%22%3A%2210.1128%2FCMR.13.3.470%22%2C%22ISSN%22%3A%220893-8512%2C%201098-6618%22%2C%22issue%22%3A%223%22%2C%22journalAbbreviation%22%3A%22Clin%20Microbiol%20Rev%22%2C%22language%22%3A%22en%22%2C%22page%22%3A%22470-511%22%2C%22source%22%3A%22DOI.org%20(Crossref)%22%2C%22title%22%3A%22Pathogenesis%20of%20Group%20A%20Streptococcal%20Infections%22%2C%22URL%22%3A%22https%3A%2F%2Fjournals.asm.org%2Fdoi%2F10.1128%2FCMR.13.3.470%22%2C%22volume%22%3A%2213%22%2C%22author%22%3A%5B%7B%22family%22%3A%22Cunningham%22%2C%22given%22%3A%22Madeleine%20W. %22%7D%5D%2C%22accessed%22%3A%7B%22date- parts%22%3A%5B%5B%222026%22%2C3%2C5%5D%5D%7D%2C%22issued%22%3A%7B%22date- parts%22%3A%5B%5B%222000%22%2C7%5D%5D%7D%7D%7D%5D\" data-schema-version=\"9\"><h1 style=\"text-align: left;\" dir=\"ltr\"><strong>Group A <em>Streptococcus</em> (GAS)</strong></h1>\n<p style=\"text-align: left;\" dir=\"ltr\"><em>Streptococcus pyogenes </em>(group A streptococcus) is a gram-positive extracellular bacterial pathogen. GAS colonise the throat or skin and are responsible for a number of suppurative infections (a type of inflammation that produces, discharges, or causes the formation of pus, which consists of neutrophils, dead cells, and tissue debris) and non-suppurative sequelae (a condition which is the consequence of a previous disease or injury) <span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2FN7FXKMYZ%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Cunningham, 2000</span>)</span>.</p>\n<p style=\"text-align: left;\" dir=\"ltr\">Infection can cause <a href=\"zotero://note/u/YRFSNA87/?section=Pharyngitis\" rel=\"noopener noreferrer nofollow\">pharyngitis</a> (inflammation of the pharynx), <a href=\"zotero://note/u/YRFSNA87/?section=Scarlet%20Fever\" rel=\"noopener noreferrer nofollow\">scarlet fever</a> (<span style=\"color: rgb(10, 10, 10);\"><span style=\"background-color: rgb(255, 255, 255);\">featuring a bright red, sandpaper-like rash, high fever, and a \"strawberry tongue\") and impetigo (highly contagious, superficial bacterial skin infection, common in children, causing itchy, red sores that rupture and form characteristic honey-colored, crusty patches, usually on the face or limbs). Other diseases include streptococcal shock syndrome and necrotising fasciitis </span></span><span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2FN7FXKMYZ%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Cunningham, 2000</span>)</span><span style=\"color: rgb(10, 10, 10);\"><span style=\"background-color: rgb(255, 255, 255);\">.</span></span></p>\n<p style=\"text-align: left;\" dir=\"ltr\">Importantly, GAS is known for it’s significant role in the development of post-infection sequelae, including acute rheumatic fever, acute glomerulonephritis (inflammation of the kidney's tiny filters (glomeruli), causing blood/protein in urine, high blood pressure, and swelling), and reactive arthritis. Repeated episodes of rheumatic fever leads to rheumatic heart disease <span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2FN7FXKMYZ%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Cunningham, 2000</span>)</span>.</p>\n<p style=\"text-align: left;\" dir=\"ltr\"></p>\n<h2 style=\"text-align: left;\" dir=\"ltr\"><strong>Typing</strong></h2>\n<p style=\"text-align: left;\" dir=\"ltr\">The Lancefield classification scheme distinguishes serological types based on their group A carbohydrate or their M protein, which confers resistance to phagocytosis by polymorphonuclear leukocytes. Identified by Rebecca Lancefield around 1962. The M protein is a major virulence factor, encoded by the <em>emm </em>gene <span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F3XME8YP2%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Fischetti, 1989</span>)</span>. The skin and throat serotypes have been divided epidemiologically on the basis of opacity factor production, the presence of the class IC repeat region epitope identified on M proteins by anti-M protein monoclonal antibody (MAb) 10B6, and <em>emm </em>(M protein) gene patterns A through E <span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2FN7FXKMYZ%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Cunningham, 2000</span>)</span>.</p> \n<h2><strong>Genomic Epidemiology</strong></h2>\n<p style=\"text-align: left;\" dir=\"ltr\">Classical GAS epidemiological and genotypic markers of differentiation:</p>\n<ul dir=\"ltr\">\n<li>\n<em>emm </em>types\n</li>\n<li>\nM protein clusters\n</li>\n<li>\nMulti locus sequence types (MLST)\n</li>\n</ul>\n<p style=\"text-align: left;\" dir=\"ltr\"></p>\n<h2 style=\"text-align: left;\" dir=\"ltr\"><strong>Clinical</strong></h2>\n<p style=\"text-align: left;\" dir=\"ltr\">GAS ranks within the top 10 infectious disease causes of death worldwide <span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2FAU8ZQCQZ%22%5D%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Jespersen et al., 2020</span>)</span>.</p>\n<p style=\"text-align: left;\" dir=\"ltr\">There is no vaccine:</p>\n<ul dir=\"ltr\">\n<li>\nSerotype diversity\n</li>\n<li>\nAntigen carriage and variation\n</li>\n<li>\nVaccine safety concerns due to immune sequelae caused by repeat GAS infection\n</li>\n<li>\n<span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F7IDZT94H%22%5D%2C%22locator%22%3A%221035%22%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Davies et al., 2019, p. 1035</span>)</span>\n</li>\n</ul>\n<p style=\"text-align: left;\" dir=\"ltr\">Immune sequelae:</p>\n<ul dir=\"ltr\">\n<li>\nGlomerulonephritis\n</li>\n<li> \nAcute rheumatic fever\n</li>\n<li>\n<p style=\"text-align: left;\" dir=\"ltr\">Rheumatic heart disease</p>\n<ul dir=\"ltr\">\n<li>\nMitral and/or aortic regurgitation\n</li>\n</ul>\n</li>\n<li> \n<span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F3XME8YP2%22%5D%2C%22locator%22%3A%22286%22%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Fischetti, 1989, p. 286</span>)</span>\n</li>\n<li>\n<span class=\"citation\" data- citation=\"%7B%22citationItems%22%3A%5B%7B%22uris%22%3A%5B%22http%3A%2F%2Fzotero.org%2Fusers%2Flocal%2FFhamIvwD%2Fitems%2F7IDZT94H%22%5D%2C%22locator%22%3A%221035%22%7D%5D%2C%22properties%22%3A%7B%7D%7D\"> (<span class=\"citation-item\">Davies et al., 2019, p. 1035</span>)</span>\n</li>\n</ul>\n<p style=\"text-align: left;\" dir=\"ltr\"></p>\n<h2 style=\"text-align: left;\" dir=\"ltr\"><strong>Vaccine Options</strong></h2>\n<p style=\"text-align: left;\" dir=\"ltr\">Types:</p>\n<ul dir=\"ltr\">\n<li>\nPurified protein\n</li>\n<li>\nmRNA\n</li>\n<li> \nLNP\n</li>\n<li>\nSynthetic Vaccine-Like Particle\n</li>\n</ul>\n<p style=\"text-align: left;\" dir=\"ltr\">Non M protein antigen vaccine targets:</p>\n<ul dir=\"ltr\">\n<li>\nSpyCEP\n</li>\n<li>\nADI - Arginine deiminase\n</li>\n<li>\nTF - Trigger factor\n</li>\n<li>\nSCPA\n</li>\n<li>\nSLO - Pore forming something\n</li>\n</ul>\n<p style=\"text-align: left;\" dir=\"ltr\">Combo #5 antigens not implicated in autoimmunity. Detoxified by site-directed mutagenisis to remove catalytic activity. M1 purified protein used as pos control in animal trial (provides good protection but not good as vaccine target due to autoimmune sequelae). This was demonstrated when M3 clinical trial resulted in rheumatic fever in patients. FDA banned using GAS components for 25 years. Could also be group A carbohydrate involved in rheumatic fever. WHO roadmap came out in early 2000’s.</p>\n<p style=\"text-align: left;\" dir=\"ltr\">Effectiveness was influenced by adjuvant (has a large influence on vaccine effectiveness as measured by colonisation after animal challenge), chosen antigen (new antigens can be identified via Activation Induced Marker Assay to probe human memory CD4+ T cell reactivity) and location of the antigen for mRNA (clustering the antigen on the surface of the cell) and VLP vectors. GAS colonisation was measured by swab and streaking on HBA (beta-haemolytic colonies) followed by agglutination test.</p>\n<p style=\"text-align: left;\" dir=\"ltr\">/</p>\n<p style=\"text-align: left;\" dir=\"ltr\">/</p>\n<p style=\"text-align: left;\" dir=\"ltr\"></p>\n<p style=\"text-align: left;\" dir=\"ltr\"></p>\n</div>"}},"autoSyncDelay":15}) called [observers: 51]

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