{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T02:32:11Z","timestamp":1794018731317,"version":"4.8.0"},"reference-count":46,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,12,3]],"date-time":"2023-12-03T00:00:00Z","timestamp":1701561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator","award":["AI173689"],"award-info":[{"award-number":["AI173689"]}],"id":[{"id":"https:\/\/ror.org\/0381dsh28","id-type":"ROR","asserted-by":"crossref"}]},{"name":"LeDucq Foundation for Cardiovascular Research","award":["AI173689"],"award-info":[{"award-number":["AI173689"]}],"id":[{"id":"https:\/\/ror.org\/0393a9736","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NIH\/NIAID","award":["AI173689"],"award-info":[{"award-number":["AI173689"]}]},{"name":"A.P. Giannini Postdoctoral Fellowship","award":["AI173689"],"award-info":[{"award-number":["AI173689"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Group B Streptococcus (Streptococcus agalactiae or GBS) is the leading infectious cause of neonatal mortality, causing roughly 150,000 infant deaths and stillbirths annually across the globe. Approximately 20% of pregnant women are asymptomatically colonized by GBS, which is a major risk factor for severe fetal and neonatal infections as well as preterm birth, low birth weight, and neurodevelopmental abnormalities. Current clinical interventions for GBS infection are limited to antibiotics, and no vaccine is available. We previously described VAX-A1 as a highly effective conjugate vaccine against group A Streptococcus that is formulated with three antigens, SpyAD, streptolysin O, and C5a peptidase (ScpA). ScpA is a surface-expressed, well-characterized GAS virulence factor that shares nearly identical sequences with the lesser studied GBS homolog ScpB. Here, we show that GBS C5a peptidase ScpB cleaves human complement factor C5a and contributes to disease severity in the murine models of pneumonia and sepsis. Furthermore, antibodies elicited by GAS C5a peptidase bind to GBS in an ScpB-dependent manner, and VAX-A1 immunization protects mice against lethal GBS heterologous challenge. These findings support the contribution of ScpB to GBS virulence and underscore the importance of choosing vaccine antigens; a universal GAS vaccine such as VAX-A1 whose formulation includes GAS C5a peptidase may have additional benefits through some measure of cross-protection against GBS infections.<\/jats:p>","DOI":"10.3390\/vaccines11121811","type":"journal-article","created":{"date-parts":[[2023,12,3]],"date-time":"2023-12-03T04:59:16Z","timestamp":1701579556000},"page":"1811","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The Group A Streptococcal Vaccine Candidate VAX-A1 Protects against Group B Streptococcus Infection via Cross-Reactive IgG Targeting Virulence Factor C5a Peptidase"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1910-9780","authenticated-orcid":false,"given":"Sinead","family":"McCabe","sequence":"first","affiliation":[{"name":"Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2747-7699","authenticated-orcid":false,"given":"Elisabet","family":"Bj\u00e5nes","sequence":"additional","affiliation":[{"name":"Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Hendriks","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[{"name":"Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2695-5863","authenticated-orcid":false,"given":"Nina M.","family":"van Sorge","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Netherlands Reference Laboratory for Bacterial Meningitis, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Pill-Pepe","sequence":"additional","affiliation":[{"name":"Vaxcyte, Inc., San Carlos, CA 94070, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Bautista","sequence":"additional","affiliation":[{"name":"Vaxcyte, Inc., San Carlos, CA 94070, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Chu","sequence":"additional","affiliation":[{"name":"Vaxcyte, Inc., San Carlos, CA 94070, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen D. C.","family":"Cod\u00e9e","sequence":"additional","affiliation":[{"name":"Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Fairman","sequence":"additional","affiliation":[{"name":"Vaxcyte, Inc., San Carlos, CA 94070, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeraj","family":"Kapoor","sequence":"additional","affiliation":[{"name":"Vaxcyte, Inc., San Carlos, CA 94070, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Uchiyama","sequence":"additional","affiliation":[{"name":"Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3847-0422","authenticated-orcid":false,"given":"Victor","family":"Nizet","sequence":"additional","affiliation":[{"name":"Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA"},{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1128\/microbiolspec.GPP3-0028-2018","article-title":"Pneumococcal vaccines","volume":"7","author":"Briles","year":"2019","journal-title":"Microbiol. Spectr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1093\/infdis\/jiad035","article-title":"Malice in chains","volume":"227","author":"Osowicki","year":"2023","journal-title":"J. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/S1473-3099(23)00043-9","article-title":"Surge of invasive group A Streptococcus disease","volume":"23","author":"Bagcchi","year":"2023","journal-title":"Lancet Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Auala, T., Zavale, B.G., Mbakwem, A.\u00c7., and Mocumbi, A.O. (2022). Acute Rheumatic Fever and Rheumatic Heart Disease: Highlighting the role of group A Streptococcus in the global burden of cardiovascular disease. Pathogens, 11.","DOI":"10.3390\/pathogens11050496"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S100","DOI":"10.1093\/cid\/cix658","article-title":"Maternal colonization with group B Streptococcus and serotype distribution worldwide: Systematic review and meta-analyses","volume":"65","author":"Russell","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e807","DOI":"10.1016\/S2214-109X(22)00093-6","article-title":"Group B Streptococcus infection during pregnancy and infancy: Estimates of regional and global burden","volume":"10","author":"Procter","year":"2022","journal-title":"Lancet Glob. Health"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2914","DOI":"10.1016\/j.jmb.2019.01.035","article-title":"The double life of group B Streptococcus: Asymptomatic colonizer and potent pathogen","volume":"431","author":"Armistead","year":"2019","journal-title":"J. Mol. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1038\/219866a0","article-title":"Isolation from heart valves of glycopeptides which share immunological properties with Streptococcus haemolyticus group A polysaccharides","volume":"219","author":"Goldstein","year":"1968","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1161\/01.CIR.50.6.1244","article-title":"Differences in antibody response to streptococcal antigens in children with rheumatic and non-rheumatic mitral valve disease","volume":"50","author":"Shulman","year":"1974","journal-title":"Circulation"},{"key":"ref_10","first-page":"114","article-title":"Specificity of persistence of antibody to the streptococcal group A carbohydrate in rheumatic valvular heart disease","volume":"105","author":"Appleton","year":"1985","journal-title":"J. Lab. Clin. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1172\/JCI7132","article-title":"Cytotoxic mAb from rheumatic carditis recognizes heart valves and laminin","volume":"106","author":"Galvin","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1097\/IM9.0000000000000044","article-title":"Site-specific conjugation of cell wall polyrhamnose to protein SpyAD envisioning a safe universal group A streptococcal vaccine","volume":"3","author":"Gao","year":"2021","journal-title":"Infect. Microbes Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"24111","DOI":"10.1021\/acsomega.1c07360","article-title":"Non-native amino acid click chemistry-based technology for site-specific polysaccharide conjugation to a bacterial protein serving as both carrier and vaccine antigen","volume":"7","author":"Kapoor","year":"2022","journal-title":"ACS Omega"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5219","DOI":"10.1128\/iai.60.12.5219-5223.1992","article-title":"Streptococcal C5a peptidase is a highly specific endopeptidase","volume":"60","author":"Cleary","year":"1992","journal-title":"Infect. Immun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1146\/annurev.immunol.23.021704.115835","article-title":"Role of C5a in inflammatory responses","volume":"23","author":"Guo","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1128\/iai.64.2.503-510.1996","article-title":"C5a peptidase alters clearance and trafficking of group A streptococci by infected mice","volume":"64","author":"Ji","year":"1996","journal-title":"Infect. Immun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1128\/iai.64.7.2387-2390.1996","article-title":"Conservation of the C5a peptidase genes in group A and B streptococci","volume":"64","author":"Chmouryguina","year":"1996","journal-title":"Infect. Immun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1046\/j.1365-2958.2001.02211.x","article-title":"Genetic basis for the beta-haemolytic\/cytolytic activity of group B Streptococcus","volume":"39","author":"Pritzlaff","year":"2001","journal-title":"Mol. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1128\/JB.185.4.1208-1217.2003","article-title":"Molecular genetic analysis of a group A Streptococcus operon encoding serum opacity factor and a novel fibronectin-binding protein, SfbX","volume":"185","author":"Jeng","year":"2003","journal-title":"J. Bacteriol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1021\/jacsau.2c00302","article-title":"Chemical synthesis and immunological evaluation of fragments of the multiantennary group-specific polysaccharide of group B Streptococcus","volume":"2","author":"Wang","year":"2022","journal-title":"JACS Au"},{"key":"ref_21","unstructured":"Wang, Z. (2020). Chemical Synthesis of Fragments of Streptococcal Cell Wall Polysaccharides. [Ph.D. Thesis, Leiden University]. Available online: https:\/\/scholarlypublications.universiteitleiden.nl\/handle\/1887\/137445."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1093\/jac\/dkab421","article-title":"Bicarbonate modulates delafloxacin activity against MDR Staphylococcus aureus and Pseudomonas aeruginosa","volume":"77","author":"Holland","year":"2021","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1093\/femsre\/fuw006","article-title":"Bacterial glycobiology: Rhamnose-containing cell wall polysaccharides in Gram-positive bacteria","volume":"40","author":"Mistou","year":"2016","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13950","DOI":"10.1073\/pnas.0506758102","article-title":"Genome analysis of multiple pathogenic isolates of Streptococcus agalactiae: Implications for the microbial \u201cpan-genome\u201d","volume":"102","author":"Tettelin","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5341","DOI":"10.1021\/bi00414a059","article-title":"Multiantennary group-specific polysaccharide of group B Streptococcus","volume":"27","author":"Michon","year":"1988","journal-title":"Biochemistry"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Gu\u00e9rin, H., Kulakauskas, S., and Chapot-Chartier, M.-P. (2022). Structural variations and roles of rhamnose-rich cell wall polysaccharides in Gram-positive bacteria. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.102488"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1042\/bj2730635","article-title":"Group B streptococci inactivate complement component C5a by enzymic cleavage at the C-terminus","volume":"273","author":"Bohnsack","year":"1991","journal-title":"Biochem. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1128\/IAI.70.5.2408-2413.2002","article-title":"The group B streptococcal C5a peptidase is both a specific protease and an invasin","volume":"70","author":"Cheng","year":"2002","journal-title":"Infect. Immun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-1-0716-0467-0_1","article-title":"Detection of Streptococcus pyogenes virulence gactors","volume":"2136","author":"Sitkiewicz","year":"2020","journal-title":"Methods Mol. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1021\/acsinfecdis.9b00347","article-title":"Group A Streptococcus cell wall oligosaccharide-streptococcal C5a peptidase conjugates as effective antibacterial vaccines","volume":"6","author":"Wang","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1128\/iai.65.4.1422-1430.1997","article-title":"Role of putative virulence factors of Streptococcus pyogenes in mouse models of long-term throat colonization and pneumonia","volume":"65","author":"Husmann","year":"1997","journal-title":"Infect. Immun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5018","DOI":"10.1128\/IAI.68.9.5018-5025.2000","article-title":"Genetic polymorphisms of group B Streptococcus scpB alter functional activity of a cell-associated peptidase that inactivates C5a","volume":"68","author":"Bohnsack","year":"2000","journal-title":"Infect. Immun."},{"key":"ref_33","first-page":"10","article-title":"Emergence and global dissemination of host-specific Streptococcus agalactiae clones","volume":"1","author":"Poulsen","year":"2010","journal-title":"mBio"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"15084","DOI":"10.1038\/nrdp.2015.84","article-title":"Acute rheumatic fever and rheumatic heart disease","volume":"2","author":"Carapetis","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1016\/j.jacc.2018.06.063","article-title":"Rheumatic heart disease worldwide: JACC Scientific Expert Panel","volume":"72","author":"Watkins","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1056\/NEJMoa1603693","article-title":"Global, regional, and national burden of rheumatic heart disease, 1990\u20132015","volume":"377","author":"Watkins","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e13374","DOI":"10.1111\/eci.13374","article-title":"Rheumatic Heart Disease Anno 2020: Impacts of gender and migration on epidemiology and management","volume":"50","author":"Mutagaywa","year":"2020","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3165","DOI":"10.1093\/eurheartj\/ehy340","article-title":"2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy","volume":"39","author":"Bauersachs","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1136\/heartjnl-2013-304888","article-title":"Heart failure in pregnant women with cardiac disease: Data from the ROPAC","volume":"100","author":"Ruys","year":"2014","journal-title":"Heart"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.acvd.2011.04.001","article-title":"Pregnancy in women with heart disease in sub-Saharan Africa","volume":"104","author":"Diao","year":"2011","journal-title":"Arch. Cardiovasc. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s13224-012-0220-2","article-title":"Pregnancy complicated by maternal heart disease: A review of 281 women","volume":"62","author":"Konar","year":"2012","journal-title":"J. Obstet. Gynaecol. India"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"101","DOI":"10.7774\/cevr.2016.5.2.101","article-title":"Accelerating the development of a group A Streptococcus vaccine: An urgent public health need","volume":"5","author":"Excler","year":"2016","journal-title":"Clin. Exp. Vaccine Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1097\/QCO.0000000000000644","article-title":"Update on group A streptococcal vaccine development","volume":"33","author":"Dale","year":"2020","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e00618-16","DOI":"10.1128\/mBio.00618-16","article-title":"Differing efficacies of lead group A streptococcal vaccine candidates and full-length M protein in cutaneous and invasive disease models","volume":"7","author":"Pandey","year":"2016","journal-title":"mBio"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.jinf.2016.02.002","article-title":"Development of a multicomponent vaccine for Streptococcus pyogenes based on the antigenic targets of IVIG","volume":"72","author":"Reglinski","year":"2016","journal-title":"J. Infect."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e00693-19","DOI":"10.1128\/mBio.00693-19","article-title":"An experimental group A Streptococcus vaccine that reduces pharyngitis and tonsillitis in a nonhuman primate model","volume":"10","author":"Carnathan","year":"2019","journal-title":"mBio"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/11\/12\/1811\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:36:51Z","timestamp":1760132211000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/11\/12\/1811"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,3]]},"references-count":46,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["vaccines11121811"],"URL":"https:\/\/doi.org\/10.3390\/vaccines11121811","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,3]]}}}