{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:40:33Z","timestamp":1788972033567,"version":"build-2803163510"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2016,4,1]],"date-time":"2016-04-01T00:00:00Z","timestamp":1459468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cluster of virulence responder\/sensor (CovR\/S) mutant group A streptococci (GAS) are serious human pathogens of multiple M protein strains that upregulate expression of virulence factors, including the IL-8 protease Streptococcus pyogenes cell envelope proteinase (SpyCEP), thus blunting neutrophil-mediated killing and enabling ingress of bacteria from a superficial wound to deep tissue. We previously showed that a combination vaccine incorporating J8-DT (conserved peptide vaccine from the M protein) and a recombinant SpyCEP fragment protects against CovR\/S mutants. To enhance the vaccine\u2019s safety profile, we identified a minimal epitope (S2) that was the target for anti-SpyCEP Abs that could protect IL-8 from SpyCEP-mediated proteolysis. Abs from healthy humans and from mice experimentally infected with GAS also recognized S2, albeit at low titers. Native SpyCEP may be poorly immunogenic (cryptic or subdominant), and it would be to the organism\u2019s advantage if the host did not induce a strong Ab response against it. However, S2 conjugated to diphtheria toxoid is highly immunogenic and induces Abs that recognize and neutralize SpyCEP. Hence, we describe a two-component peptide vaccine that induces Abs (anti-S2) that protect IL-8 from proteolysis and other Abs (anti-J8) that cause strain-independent killing in the presence of neutrophils. We show that either component alone is ineffectual in preventing skin infection and bacteremia due to CovR\/S mutants but that the combination induces complete protection. This protection correlated with a significant influx of neutrophils to the infection site. The data strongly suggest that the lack of natural immunity to hypervirulent GAS strains in humans could be rectified by this combination vaccine.<\/jats:p>","DOI":"10.4049\/jimmunol.1501994","type":"journal-article","created":{"date-parts":[[2016,3,12]],"date-time":"2016-03-12T03:56:07Z","timestamp":1457754967000},"page":"3364-3374","source":"Crossref","is-referenced-by-count":47,"title":["Combinatorial Synthetic Peptide Vaccine Strategy Protects against Hypervirulent CovR\/S Mutant Streptococci"],"prefix":"10.1093","volume":"196","author":[{"given":"Manisha","family":"Pandey","sequence":"first","affiliation":[{"name":"Institute for Glycomics, Griffith University , Gold Coast Campus, Southport, Queensland 4222 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0177-3032","authenticated-orcid":false,"given":"Rasmus","family":"Mortensen","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease Immunology, Statens Serum Institut , 2300 Copenhagen ,","place":["Denmark"]},{"name":"Department of Immunology and Microbiology, University of Copenhagen , 2200 Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainslie","family":"Calcutt","sequence":"additional","affiliation":[{"name":"Institute for Glycomics, Griffith University , Gold Coast Campus, Southport, Queensland 4222 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Powell","sequence":"additional","affiliation":[{"name":"Institute for Glycomics, Griffith University , Gold Coast Campus, Southport, Queensland 4222 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R","family":"Batzloff","sequence":"additional","affiliation":[{"name":"Institute for Glycomics, Griffith University , Gold Coast Campus, Southport, Queensland 4222 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes","family":"Dietrich","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease Immunology, Statens Serum Institut , 2300 Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael F","family":"Good","sequence":"additional","affiliation":[{"name":"Institute for Glycomics, Griffith University , Gold Coast Campus, Southport, Queensland 4222 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,4,15]]},"reference":[{"key":"2025030702154401200_r1","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":"2025030702154401200_r2","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1128\/JCM.00422-08","article-title":"Epidemiology of severe Streptococcus pyogenes disease in Europe","volume":"46","author":"Lamagni","year":"2008","journal-title":"J. Clin. Microbiol."},{"key":"2025030702154401200_r3","doi-asserted-by":"crossref","first-page":"565","DOI":"10.5694\/j.1326-5377.2007.tb01054.x","article-title":"The epidemiology of invasive group A streptococcal disease in Victoria, Australia","volume":"186","author":"O\u2019Grady","year":"2007","journal-title":"Med. J. Aust."},{"key":"2025030702154401200_r4","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1086\/521264","article-title":"The epidemiology of invasive group A streptococcal infection and potential vaccine implications: United States, 2000\u20132004","volume":"45","author":"O\u2019Loughlin","year":"2007","journal-title":"Clin. Infect. Dis."},{"key":"2025030702154401200_r5","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1038\/nrmicro2648","article-title":"Molecular insight into invasive group A streptococcal disease","volume":"9","author":"Cole","year":"2011","journal-title":"Nat. Rev. Microbiol."},{"key":"2025030702154401200_r6","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1086\/603541","article-title":"Emerging role of the interleukin-8 cleaving enzyme SpyCEP in clinical Streptococcus pyogenes infection","volume":"200","author":"Turner","year":"2009","journal-title":"J. Infect. Dis."},{"key":"2025030702154401200_r7","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1128\/IAI.01458-13","article-title":"Neutrophils select hypervirulent CovRS mutants of M1T1 group A Streptococcus during subcutaneous infection of mice","volume":"82","author":"Li","year":"2014","journal-title":"Infect. Immun."},{"key":"2025030702154401200_r8","doi-asserted-by":"crossref","first-page":"e5","DOI":"10.1371\/journal.ppat.0020005","article-title":"Genome-wide analysis of group a streptococci reveals a mutation that modulates global phenotype and disease specificity","volume":"2","author":"Sumby","year":"2006","journal-title":"PLoS Pathog."},{"key":"2025030702154401200_r9","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.chom.2008.07.002","article-title":"The IL-8 protease SpyCEP\/ScpC of group A Streptococcus promotes resistance to neutrophil killing","volume":"4","author":"Zinkernagel","year":"2008","journal-title":"Cell Host Microbe"},{"key":"2025030702154401200_r10","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1242\/jcs.108.1.311","article-title":"Interleukin-8 induces motile behavior and loss of focal adhesions in primary fibroblasts","volume":"108","author":"Dunlevy","year":"1995","journal-title":"J. Cell Sci."},{"key":"2025030702154401200_r11","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1189\/jlb.0803370","article-title":"Neutrophil chemoattractant genes KC and MIP-2 are expressed in different cell populations at sites of surgical injury","volume":"75","author":"Armstrong","year":"2004","journal-title":"J. Leukoc. Biol."},{"key":"2025030702154401200_r12","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1093\/jhmas\/54.2.337","article-title":"Rheumatic fever and streptococcal infection: unraveling the mysteries of a dread disease","volume":"54","author":"Stollerman","year":"1999","journal-title":"J. Hist. Med. Allied Sci."},{"key":"2025030702154401200_r13","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1128\/CMR.13.3.470","article-title":"Pathogenesis of group A streptococcal infections","volume":"13","author":"Cunningham","year":"2000","journal-title":"Clin. Microbiol. Rev."},{"key":"2025030702154401200_r14","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.4161\/hv.25506","article-title":"Strategies in the development of vaccines to prevent infections with group A streptococcus","volume":"9","author":"Good","year":"2013","journal-title":"Hum. Vaccin. Immunother."},{"key":"2025030702154401200_r15","doi-asserted-by":"crossref","first-page":"5448","DOI":"10.4049\/jimmunol.175.8.5448","article-title":"T cell mimicry and epitope specificity of cross-reactive T cell clones from rheumatic heart disease","volume":"175","author":"Ellis","year":"2005","journal-title":"J. Immunol."},{"key":"2025030702154401200_r16","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1056\/NEJM196409242711301","article-title":"Presence of bound immunoglobulins and complement in myocardium in acute rheumatic fever","volume":"271","author":"Kaplan","year":"1964","journal-title":"N. Engl. J. Med."},{"key":"2025030702154401200_r17","first-page":"147","article-title":"Heart-reactive antibody associated with rheumatic fever: characterization and diagnostic significance","volume":"7","author":"Zabriski","year":"1970","journal-title":"Clin. Exp. Immunol."},{"key":"2025030702154401200_r18","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1080\/08916930500484674","article-title":"Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease","volume":"39","author":"Guilherme","year":"2006","journal-title":"Autoimmunity"},{"key":"2025030702154401200_r19","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1084\/jem.156.4.1165","article-title":"Protective antigenic determinant of streptococcal M protein shared with sarcolemmal membrane protein of human heart","volume":"156","author":"Dale","year":"1982","journal-title":"J. Exp. Med."},{"key":"2025030702154401200_r20","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1084\/jem.161.1.113","article-title":"Multiple, heart-cross-reactive epitopes of streptococcal M proteins","volume":"161","author":"Dale","year":"1985","journal-title":"J. Exp. Med."},{"key":"2025030702154401200_r21","doi-asserted-by":"crossref","first-page":"4089","DOI":"10.4049\/jimmunol.145.12.4089","article-title":"Identification of an epitope of type 1 streptococcal M protein that is shared with a 43-kDa protein of human myocardium and renal glomeruli","volume":"145","author":"Kraus","year":"1990","journal-title":"J. Immunol."},{"key":"2025030702154401200_r22","doi-asserted-by":"crossref","first-page":"888","DOI":"10.4049\/jimmunol.148.3.888","article-title":"Epitopes of group A streptococcal M protein that evoke cross-protective local immune responses","volume":"148","author":"Bronze","year":"1992","journal-title":"J. Immunol."},{"key":"2025030702154401200_r23","doi-asserted-by":"crossref","first-page":"966","DOI":"10.4049\/jimmunol.142.3.966","article-title":"Cellular and biochemical responses of human T lymphocytes stimulated with streptococcal M proteins","volume":"142","author":"Kotb","year":"1989","journal-title":"J. Immunol."},{"key":"2025030702154401200_r24","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/0006-291X(89)92793-9","article-title":"Serine and tyrosine phosphorylation of 28- and 35-kDa proteins of human T lymphocytes stimulated by streptococcal M protein","volume":"158","author":"Kotb","year":"1989","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2025030702154401200_r25","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.4049\/jimmunol.142.7.2475","article-title":"Tropomyosin shares immunologic epitopes with group A streptococcal M proteins","volume":"142","author":"Fenderson","year":"1989","journal-title":"J. Immunol."},{"key":"2025030702154401200_r26","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.4049\/jimmunol.143.8.2677","article-title":"Human and murine antibodies cross-reactive with streptococcal M protein and myosin recognize the sequence GLN-LYS-SER-LYS-GLN in M protein","volume":"143","author":"Cunningham","year":"1989","journal-title":"J. Immunol."},{"key":"2025030702154401200_r27","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1093\/infdis\/162.4.875","article-title":"A new heart-cross-reactive antigen in Streptococcus pyogenes is not M protein","volume":"162","author":"Barnett","year":"1990","journal-title":"J. Infect. Dis."},{"key":"2025030702154401200_r28","doi-asserted-by":"crossref","first-page":"3545","DOI":"10.1128\/iai.58.11.3545-3552.1990","article-title":"Immunological cross-reactivity between Streptococcus mutans and human heart tissue examined by cross-immunization experiments","volume":"58","author":"Wu","year":"1990","journal-title":"Infect. Immun."},{"key":"2025030702154401200_r29","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1128\/iai.62.6.2440-2449.1994","article-title":"Cloning and sequence analysis of a gene encoding a 67-kilodalton myosin-cross-reactive antigen of Streptococcus pyogenes reveals its similarity with class II major histocompatibility antigens","volume":"62","author":"Kil","year":"1994","journal-title":"Infect. Immun."},{"key":"2025030702154401200_r30","doi-asserted-by":"crossref","first-page":"5345","DOI":"10.1128\/IAI.69.9.5345-5351.2001","article-title":"T-cell reactivity against streptococcal antigens in the periphery mirrors reactivity of heart-infiltrating T lymphocytes in rheumatic heart disease patients","volume":"69","author":"Guilherme","year":"2001","journal-title":"Infect. Immun."},{"key":"2025030702154401200_r31","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1161\/01.CIR.92.3.415","article-title":"Human heart-infiltrating T-cell clones from rheumatic heart disease patients recognize both streptococcal and cardiac proteins","volume":"92","author":"Guilherme","year":"1995","journal-title":"Circulation"},{"key":"2025030702154401200_r32","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1172\/JCI112531","article-title":"Association of class II human histocompatibility leukocyte antigens with rheumatic fever","volume":"77","author":"Ayoub","year":"1986","journal-title":"J. Clin. Invest."},{"key":"2025030702154401200_r33","doi-asserted-by":"crossref","first-page":"R340","DOI":"10.1186\/ar1000","article-title":"HLA class II associations with rheumatic heart disease among clinically homogeneous patients in children in Latvia","volume":"5","author":"Stanevicha","year":"2003","journal-title":"Arthritis Res. Ther."},{"key":"2025030702154401200_r34","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s11908-012-0263-7","article-title":"Vaccination against rheumatic heart disease: a review of current research strategies and challenges","volume":"14","author":"Pandey","year":"2012","journal-title":"Curr. Infect. Dis. Rep."},{"key":"2025030702154401200_r35","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1586\/14760584.2015.1081817","article-title":"Strategic development of the conserved region of the M protein and other candidates as vaccines to prevent infection with group A streptococci","volume":"14","author":"Good","year":"2015","journal-title":"Expert Rev. Vaccines"},{"key":"2025030702154401200_r36","doi-asserted-by":"crossref","first-page":"5915","DOI":"10.4049\/jimmunol.1500157","article-title":"A synthetic M protein peptide synergizes with a CXC chemokine protease to induce vaccine-mediated protection against virulent streptococcal pyoderma and bacteremia","volume":"194","author":"Pandey","year":"2015","journal-title":"J. Immunol."},{"key":"2025030702154401200_r37","first-page":"72197","article-title":"70 FR 72197\u2013Revocation of status of specific products; group A Streptococcus","volume":"70","author":"Food and Drug Administration","year":"2005","journal-title":"Fed. Regist."},{"key":"2025030702154401200_r38","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1001\/jama.1969.03150190037007","article-title":"Rheumatic fever following streptococcal vaccination. Report of three cases","volume":"207","author":"Massell","year":"1969","journal-title":"JAMA"},{"key":"2025030702154401200_r39","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1086\/374800","article-title":"Protection against group A streptococcus by immunization with J8-diphtheria toxoid: contribution of J8- and diphtheria toxoid-specific antibodies to protection","volume":"187","author":"Batzloff","year":"2003","journal-title":"J. Infect. Dis."},{"key":"2025030702154401200_r40","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0022-1759(02)00137-0","article-title":"The SPOT-synthesis technique. Synthetic peptide arrays on membrane supports\u2014principles and applications","volume":"267","author":"Frank","year":"2002","journal-title":"J. Immunol. Methods"},{"key":"2025030702154401200_r41","doi-asserted-by":"crossref","first-page":"2692","DOI":"10.4049\/jimmunol.1202333","article-title":"Long-term antibody memory induced by synthetic peptide vaccination is protective against Streptococcus pyogenes infection and is independent of memory T cell help","volume":"190","author":"Pandey","year":"2013","journal-title":"J. Immunol."},{"key":"2025030702154401200_r42","doi-asserted-by":"crossref","first-page":"4923","DOI":"10.1016\/j.vaccine.2009.06.042","article-title":"Impact of immunization against SpyCEP during invasive disease with two streptococcal species: Streptococcus pyogenes and Streptococcus equi","volume":"27","author":"Turner","year":"2009","journal-title":"Vaccine"},{"key":"2025030702154401200_r43","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1086\/432485","article-title":"Specific C-terminal cleavage and inactivation of interleukin-8 by invasive disease isolates of Streptococcus pyogenes","volume":"192","author":"Edwards","year":"2005","journal-title":"J. Infect. Dis."},{"key":"2025030702154401200_r44","doi-asserted-by":"crossref","first-page":"13855","DOI":"10.1073\/pnas.202353699","article-title":"Virulence control in group A Streptococcus by a two-component gene regulatory system: global expression profiling and in vivo infection modeling","volume":"99","author":"Graham","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030702154401200_r45","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1128\/IAI.01514-08","article-title":"B- and T-cell responses in group a streptococcus M-protein- or peptide-induced experimental carditis","volume":"77","author":"Gorton","year":"2009","journal-title":"Infect. Immun."},{"key":"2025030702154401200_r46","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1093\/intimm\/9.11.1723","article-title":"Mapping the minimal murine T cell and B cell epitopes within a peptide vaccine candidate from the conserved region of the M protein of group A streptococcus","volume":"9","author":"Hayman","year":"1997","journal-title":"Int. Immunol."},{"key":"2025030702154401200_r47","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/nbt1179","article-title":"Characterization and identification of vaccine candidate proteins through analysis of the group A Streptococcus surface proteome","volume":"24","author":"Rodr\u00edguez-Ortega","year":"2006","journal-title":"Nat. Biotechnol."},{"key":"2025030702154401200_r48","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1128\/IAI.01354-07","article-title":"A chemokine-degrading extracellular protease made by group A Streptococcus alters pathogenesis by enhancing evasion of the innate immune response","volume":"76","author":"Sumby","year":"2008","journal-title":"Infect. Immun."},{"key":"2025030702154401200_r49","doi-asserted-by":"crossref","first-page":"4628","DOI":"10.1038\/sj.emboj.7601327","article-title":"A streptococcal protease that degrades CXC chemokines and impairs bacterial clearance from infected tissues","volume":"25","author":"Hidalgo-Grass","year":"2006","journal-title":"EMBO J."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/196\/8\/3364\/61505562\/1501994.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/196\/8\/3364\/61505562\/1501994.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T02:33:51Z","timestamp":1741314831000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/196\/8\/3364\/7961652"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4]]},"references-count":49,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2016,4,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1501994","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,4]]},"published":{"date-parts":[[2016,4]]}}}