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The pore\u2010forming \u03b1\u2010toxin (Hla) is a key virulence determinant that drives disease severity. We identified two high\u2010affinity anti\u2010Hla monoclonal antibodies, Hm0399 and Hm0411, derived from the sera of volunteers vaccinated with the\n                    <jats:italic>S. aureus<\/jats:italic>\n                    vaccine rFSAV. Mechanistic analyses\u2014including toxin neutralization assays, structure solution, and effector\u2010function characterization\u2014revealed that although both antibodies recognize overlapping epitopes on Hla, they confer protection through distinct and complementary mechanisms. Hm0411 potently neutralizes Hla toxicity by blocking receptor engagement through a defined salt\u2010bridge network, whereas Hm0399 engages a hydrogen\u2010bond interface that enhances Fc\u2010mediated effector functions. A dual\u2010antibody cocktail comprising Hm0399 and Hm0411 (Hm3\u20104) demonstrated robust therapeutic efficacy in the USA300\n                    <jats:italic>S. aureus<\/jats:italic>\n                    sepsis model and pneumonia model. Notably, protection was not compromised by pre\u2010existing immune imprinting. Transcriptomic profiling indicated enhanced Fc\u03b3 receptor\u2013mediated phagocytosis and suppression of pro\u2010inflammatory Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling pathways. In addition, combining Hm3\u20104 with ultra\u2010low doses of vancomycin or linezolid synergistically improved therapeutic outcomes in experimental sepsis. Collectively, these findings establish a dual\u2010antibody strategy targeting Hla that integrates virulence neutralization with augmentation of host immune defense, providing a framework for next\u2010generation immunotherapies against invasive\n                    <jats:italic>S. aureus<\/jats:italic>\n                    infection.\n                  <\/jats:p>","DOI":"10.1002\/mco2.70830","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T06:51:59Z","timestamp":1783320719000},"source":"Crossref","is-referenced-by-count":0,"title":["A Synergistic Dual\u2010Antibody Cocktail Targeting \u03b1\u2010Toxin Protects Against Invasive\n                    <i>Staphylococcus aureus<\/i>\n                    Infection by Neutralizing Virulence and Enhancing Host Defense"],"prefix":"10.1002","volume":"7","author":[{"given":"Liqun","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Microbiology and Biochemical Pharmacy National Engineering Research Center of Immunological Products College of Pharmacy and Laboratory Medicine Third Military Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Biochemical Pharmacy National Engineering Research Center of Immunological Products College of Pharmacy and Laboratory Medicine Third Military Medical University  Chongqing China"},{"name":"Clinical Laboratory Department Army 954th Hospital General Hospital of Tibet Military Region  Tibet China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyin","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Biochemical Pharmacy National Engineering Research Center of Immunological Products College of Pharmacy and Laboratory Medicine Third Military Medical University  Chongqing 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Military Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Biochemical Pharmacy National Engineering Research Center of Immunological Products College of Pharmacy and Laboratory Medicine Third Military Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Biochemical Pharmacy National Engineering Research Center of Immunological Products College of Pharmacy and Laboratory Medicine Third Military Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanming","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Biochemical Pharmacy National Engineering Research Center of Immunological Products College of Pharmacy and Laboratory Medicine Third Military Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Biochemical Pharmacy National Engineering Research Center of Immunological Products College of Pharmacy and Laboratory Medicine Third Military Medical University  Chongqing China"},{"name":"State Key Laboratory of Trauma and Chemical Poisoning Third Military Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,5]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02724-0"},{"key":"e_1_2_12_3_1","unstructured":"2021 Antibacterial Agents in Clinical and Preclinical Development: An Overview and 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