{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:22:16Z","timestamp":1792624936384,"version":"4.5.0"},"reference-count":40,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T00:00:00Z","timestamp":1610668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>A Staphylococcus aureus four-antigen vaccine (SA4Ag) was designed for the prevention of invasive disease in surgical patients. The vaccine is composed of capsular polysaccharide type 5 and type 8 CRM197 conjugates, a clumping factor A mutant (Y338A-ClfA) and manganese transporter subunit C (MntC). S. aureus pathogenicity is characterized by an ability to rapidly adapt to the host environment during infection, which can progress from a local infection to sepsis and invasion of distant organs. To test the protective capacity of the SA4Ag vaccine against progressive disease stages of an invasive S. aureus infection, a deep tissue infection mouse model, a bacteremia mouse model, a pyelonephritis model, and a rat model of infectious endocarditis were utilized. SA4Ag vaccination significantly reduced the bacterial burden in deep tissue infection, in bacteremia, and in the pyelonephritis model. Complete prevention of infection was demonstrated in a clinically relevant endocarditis model. Unfortunately, these positive preclinical findings with SA4Ag did not prove the clinical utility of SA4Ag in the prevention of surgery-associated invasive S. aureus infection.<\/jats:p>","DOI":"10.3390\/microorganisms9010177","type":"journal-article","created":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T12:44:05Z","timestamp":1610714645000},"page":"177","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Performance of a Four-Antigen Staphylococcus aureus Vaccine in Preclinical Models of Invasive S. aureus Disease"],"prefix":"10.3390","volume":"9","author":[{"given":"Ingrid L.","family":"Scully","sequence":"first","affiliation":[{"name":"Pfizer Vaccine Research &amp; Development, Pearl River, NY 10965, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yekaterina","family":"Timofeyeva","sequence":"additional","affiliation":[{"name":"Pfizer Vaccine Research &amp; Development, Pearl River, NY 10965, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Illenberger","sequence":"additional","affiliation":[{"name":"Pfizer Vaccine Research &amp; Development, Pearl River, NY 10965, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peimin","family":"Lu","sequence":"additional","affiliation":[{"name":"Pfizer Vaccine Research &amp; Development, Pearl River, NY 10965, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Liberator","sequence":"additional","affiliation":[{"name":"Pfizer Vaccine Research &amp; Development, Pearl River, NY 10965, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin U.","family":"Jansen","sequence":"additional","affiliation":[{"name":"Pfizer Vaccine Research &amp; Development, Pearl River, NY 10965, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annaliesa S.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Pfizer Vaccine Research &amp; Development, Pearl River, NY 10965, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1128\/CMR.10.3.505","article-title":"Nasal carriage of Staphylococcus aureus: Epidemiology, underlying mechanisms, and associated risks","volume":"10","author":"Kluytmans","year":"1997","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1056\/NEJM199808203390806","article-title":"Staphylococcus aureus infections","volume":"339","author":"Lowy","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1086\/522186","article-title":"National trends in Staphylococcus aureus infection rates: Impact on economic burden and mortality over a 6-year period (1998\u20132003)","volume":"45","author":"Noskin","year":"2007","journal-title":"Clin. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.3201\/eid2111.150452","article-title":"USA300 Methicillin-Resistant Staphylococcus aureus, United States, 2000\u20132013","volume":"21","author":"Carrel","year":"2015","journal-title":"Emerg. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Malachowa, N., Whitney, A.R., Kobayashi, S.D., Sturdevant, D.E., Kennedy, A.D., Braughton, K.R., Shabb, D.W., Diep, B.A., Chambers, H.F., and Otto, M. (2011). Global changes in Staphylococcus aureus gene expression in human blood. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0018617"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1056\/NEJMoa0808939","article-title":"Preventing surgical-site infections in nasal carriers of Staphylococcus aureus","volume":"362","author":"Bode","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1086\/341025","article-title":"Surgical site infections in orthopedic surgery: The effect of mupirocin nasal ointment in a double-blind, randomized, placebo-controlled study","volume":"35","author":"Kalmeijer","year":"2002","journal-title":"Clin. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1086\/510392","article-title":"Randomized controlled trial of chlorhexidine gluconate for washing, intranasal mupirocin, and rifampin and doxycycline versus no treatment for the eradication of methicillin-resistant Staphylococcus aureus colonization","volume":"44","author":"Simor","year":"2007","journal-title":"Clin. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3880","DOI":"10.1128\/AAC.00846-07","article-title":"Mupirocin-resistant, methicillin-resistant Staphylococcus aureus strains in Canadian hospitals","volume":"51","author":"Simor","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1128\/CVI.00354-12","article-title":"A recombinant clumping factor A-containing vaccine induces functional antibodies to Staphylococcus aureus that are not observed after natural exposure","volume":"19","author":"Hawkins","year":"2012","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_11","first-page":"1688","article-title":"Staphylococcus aureus manganese transport protein C is a highly conserved cell surface protein that elicits protective immunity against S","volume":"205","author":"Anderson","year":"2012","journal-title":"aureus and Staphylococcus epidermidis. J. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3415","DOI":"10.1128\/IAI.00392-06","article-title":"Identification of Staphylococcus aureus proteins recognized by the antibody-mediated immune response to a biofilm infection","volume":"74","author":"Brady","year":"2006","journal-title":"Infect. Immun."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Handke, L.D., Hawkins, J.C., Miller, A.A., Jansen, K.U., and Anderson, A.S. (2013). Regulation of Staphylococcus aureus MntC Expression and Its Role in Response to Oxidative Stress. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0077874"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"480","DOI":"10.4161\/hv.23223","article-title":"Capsular polysaccharides are an important immune evasion mechanism for Staphylococcus aureus","volume":"9","author":"Nanra","year":"2012","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5183","DOI":"10.1128\/IAI.66.11.5183-5189.1998","article-title":"Staphylococcus aureus serotype 5 capsular polysaccharide is antiphagocytic and enhances bacterial virulence in a murine bacteremia model","volume":"66","author":"Thakker","year":"1998","journal-title":"Infect. Immun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1128\/iai.58.7.2367-2374.1990","article-title":"Synthesis and immunologic properties in mice of vaccines composed of Staphylococcus aureus type 5 and type 8 capsular polysaccharides conjugated to Pseudomonas aeruginosa exotoxin A","volume":"58","author":"Fattom","year":"1990","journal-title":"Infect Immun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1128\/IAI.74.4.2215-2223.2006","article-title":"A novel Staphylococcus aureus vaccine: Iron surface determinant B induces rapid antibody responses in rhesus macaques and specific increased survival in a murine S. aureus sepsis model","volume":"74","author":"Kuklin","year":"2006","journal-title":"Infect. Immun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"336","DOI":"10.4161\/hv.18946","article-title":"Immunization with Staphylococcus aureus iron regulated surface determinant B (IsdB) confers protection via Th17\/IL17 pathway in a murine sepsis model","volume":"8","author":"Joshi","year":"2012","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_19","first-page":"491","article-title":"Vaccines for Staphylococcus aureus and Target Populations","volume":"409","author":"Pozzi","year":"2017","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2723","DOI":"10.1016\/j.vaccine.2013.04.002","article-title":"Vaccine review: \u201cStaphyloccocus aureus vaccines: Problems and prospects\u201d","volume":"31","author":"Jansen","year":"2013","journal-title":"Vaccine"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5452","DOI":"10.1016\/j.vaccine.2015.08.029","article-title":"Demonstration of the preclinical correlate of protection for Staphylococcus aureus clumping factor A in a murine model of infection","volume":"33","author":"Scully","year":"2015","journal-title":"Vaccine"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/978-1-4939-3387-7_22","article-title":"Murine Models of Bacteremia and Surgical Wound Infection for the Evaluation of Staphylococcus aureus Vaccine Candidates","volume":"1403","author":"Wang","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1006\/mpat.1993.1073","article-title":"Immunization with fibronectin binding protein from Staphylococcus aureus protects against experimental endocarditis in rats","volume":"15","author":"Schennings","year":"1993","journal-title":"Microb. Pathog."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1097\/00005792-198305000-00004","article-title":"Staphylococcus aureus endocarditis: Clinical manifestations in addicts and nonaddicts","volume":"62","author":"Chambers","year":"1983","journal-title":"Medicine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3429","DOI":"10.1016\/j.jmb.2013.06.033","article-title":"Three-dimensional structure and biophysical characterization of Staphylococcus aureus cell surface antigen-manganese transporter MntC","volume":"425","author":"Gribenko","year":"2013","journal-title":"J. Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Gribenko, A.V., Parris, K., Mosyak, L., Lidia, M., Handke, L., Hawkins, J.C., Severina, E., Matsuka, Y.V., and Anderson, A.S. (2016). High Resolution Mapping of Bactericidal Monoclonal Antibody Binding Epitopes on Staphylococcus aureus Antigen MntC. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005908"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.vaccine.2016.11.010","article-title":"Safety, tolerability, and immunogenicity of a 4-antigen Staphylococcus aureus vaccine (SA4Ag): Results from a first-in-human randomised, placebo-controlled phase 1\/2 study","volume":"35","author":"Frenck","year":"2017","journal-title":"Vaccine"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e02232-15","DOI":"10.1128\/mBio.02232-15","article-title":"Preclinical efficacy of clumping factor A in prevention of Staphylococcus aureus infection","volume":"7","author":"Li","year":"2016","journal-title":"mBio"},{"key":"ref_29","first-page":"e113","article-title":"QS-21: A Potent Vaccine Adjuvant","volume":"3","author":"Zhu","year":"2016","journal-title":"Nat. Prod. Chem. Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bigaeva, E., Doorn, E., Liu, H., and Hak, E. (2016). Meta-Analysis on Randomized Controlled Trials of Vaccines with QS-21 or ISCOMATRIX Adjuvant: Safety and Tolerability. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0154757"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.1016\/j.vaccine.2015.02.024","article-title":"A randomized phase I study of the safety and immunogenicity of three ascending dose levels of a 3-antigen Staphylococcus aureus vaccine (SA3Ag) in healthy adults","volume":"33","author":"Nissen","year":"2015","journal-title":"Vaccine"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"632","DOI":"10.4161\/hv.34414","article-title":"Efficacy profile of a bivalent Staphylococcus aureus glycoconjugated vaccine in adults on hemodialysis: Phase III randomized study","volume":"11","author":"Fattom","year":"2015","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1001\/jama.2013.3010","article-title":"Effect of an investigational vaccine for preventing Staphylococcus aureus infections after cardiothoracic surgery: A randomized trial","volume":"309","author":"Fowler","year":"2013","journal-title":"JAMA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.micinf.2011.11.001","article-title":"A battle for iron: Host sequestration and Staphylococcus aureus acquisition","volume":"14","author":"Haley","year":"2012","journal-title":"Microbes Infect."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"16942","DOI":"10.1073\/pnas.0606863103","article-title":"Vaccine assembly from surface proteins of Staphylococcus aureus","volume":"103","author":"Bae","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3680","DOI":"10.1073\/pnas.1424924112","article-title":"Vaccine composition formulated with a novel TLR7-dependent adjuvant induces high and broad protection against Staphylococcus aureus","volume":"112","author":"Bagnoli","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3157","DOI":"10.1128\/IAI.00258-15","article-title":"Four-Component Staphylococcus aureus Vaccine 4C-Staph Enhances Fcgamma Receptor Expression in Neutrophils and Monocytes and Mitigates S. aureus Infection in Neutropenic Mice","volume":"83","author":"Torre","year":"2015","journal-title":"Infect. Immun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1080\/21645515.2015.1011021","article-title":"Safety and immunogenicity of an investigational 4-component Staphylococcus aureus vaccine with or without AS03 adjuvant: Results of a randomized phase I trial","volume":"11","author":"Levy","year":"2015","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_39","unstructured":"(2020, April 25). ClinicalTrials.gov, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02388165?term=NCT02388165&draw=2&rank=1."},{"key":"ref_40","unstructured":"(2020, April 25). Pfizer Inc. Available online: https:\/\/investors.pfizer.com\/investor-news\/press-release-details\/2018\/Independent-Data-Monitoring-Committee-Recommends-Discontinuation-of-the-Phase-2b-STRIVE-Clinical-Trial-of-Staphylococcus-aureus-Vaccine-Following-Planned-Interim-Analysis\/default.aspx."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/9\/1\/177\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:11:37Z","timestamp":1760159497000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/9\/1\/177"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,15]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["microorganisms9010177"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms9010177","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,15]]}}}