{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T05:13:32Z","timestamp":1772255612755,"version":"3.50.1"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2023,1,1]],"date-time":"2023-01-01T00:00:00Z","timestamp":1672531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000052","name":"HHS | NIH | NIH Office of the Director","doi-asserted-by":"publisher","award":["K01OD026569"],"award-info":[{"award-number":["K01OD026569"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002590","name":"American Lung Association","doi-asserted-by":"publisher","award":["IA-835950"],"award-info":[{"award-number":["IA-835950"]}],"id":[{"id":"10.13039\/100002590","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["1R21AI151571-01A1"],"award-info":[{"award-number":["1R21AI151571-01A1"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Streptococcus pneumoniae persists as a leading cause of bacterial pneumonia despite the widespread use of polysaccharide-based vaccines. The limited serotype coverage of current vaccines has led to increased incidence of nonvaccine serotypes, as well as an increase in antibiotic resistance among these serotypes. Pneumococcal infection often follows a primary viral infection such as influenza virus, which hinders host defense and results in bacterial spread to the lungs. We previously isolated human monoclonal Abs (mAbs) against the conserved surface Ag pneumococcal histidine triad protein D (PhtD), and we demonstrated that mAbs to this Ag are protective against lethal pneumococcal challenge prophylactically and therapeutically. In this study, we elucidated the mechanism of protection of a protective anti-pneumococcal human mAb, PhtD3, which is mediated by the presence of complement and macrophages in a mouse model of pneumococcal infection. Treatment with mAb PhtD3 reduced blood and lung bacterial burden in mice, and mAb PhtD3 is able to bind to bacteria in the presence of the capsular polysaccharide, indicating exposure of surface PhtD on encapsulated bacteria. In a mouse model of secondary pneumococcal infection, protection mediated by mAb PhtD3 and another mAb targeting a different epitope, PhtD7, was reduced; however, robust protection was restored by combining mAb PhtD3 with mAb PhtD7, indicating a synergistic effect. Overall, these studies provide new insights into anti-pneumococcal mAb protection and demonstrate, to our knowledge, for the first time, that mAbs to pneumococcal surface proteins can protect against secondary pneumococcal infection in the mouse model.<\/jats:p>","DOI":"10.4049\/jimmunol.2200349","type":"journal-article","created":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T23:59:56Z","timestamp":1672703996000},"page":"50-60","source":"Crossref","is-referenced-by-count":8,"title":["Synergistic Protection against Secondary Pneumococcal Infection by Human Monoclonal Antibodies Targeting Distinct Epitopes"],"prefix":"10.1093","volume":"210","author":[{"given":"Aaron D","family":"Gingerich","sequence":"first","affiliation":[{"name":"Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia , Athens, GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3012-2431","authenticated-orcid":false,"given":"Fredejah","family":"Royer","sequence":"additional","affiliation":[{"name":"Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia , Athens, GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna L","family":"McCormick","sequence":"additional","affiliation":[{"name":"Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia , Athens, GA"},{"name":"Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia , Athens, GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3567-1157","authenticated-orcid":false,"given":"Anna","family":"Scasny","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Mississippi Medical Center , Jackson, MS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0573-5658","authenticated-orcid":false,"given":"Jorge E","family":"Vidal","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Mississippi Medical Center , Jackson, MS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4709-2478","authenticated-orcid":false,"given":"Jarrod J","family":"Mousa","sequence":"additional","affiliation":[{"name":"Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia , Athens, GA"},{"name":"Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia , Athens, GA"},{"name":"Department of Biochemistry and Molecular Biology, Franklin College of Arts and Sciences, University of Georgia , Athens, GA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,1,1]]},"reference":[{"key":"2025021007580514200_r1","article-title":"WHO publishes list of bacteria for which new antibiotics are urgently needed","author":"World Health Organization","year":"2017"},{"key":"2025021007580514200_r2","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1007\/s10096-019-03485-3","article-title":"Adult vaccination for pneumococcal disease: a comparison of the national guidelines in Europe","volume":"38","author":"Bonnave","year":"2019","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"2025021007580514200_r3","doi-asserted-by":"crossref","first-page":"e00937-20","DOI":"10.1128\/mBio.00937-20","article-title":"A new pneumococcal capsule type, 10D, is the 100th Serotype and has a large cps fragment from an oral streptococcus","volume":"11","author":"Ganaie","year":"2020","journal-title":"MBio"},{"key":"2025021007580514200_r4","doi-asserted-by":"crossref","first-page":"e01792","DOI":"10.1128\/mBio.01792-15","article-title":"Nonencapsulated Streptococcus pneumoniae: emergence and pathogenesis","volume":"7","author":"Keller","year":"2016","journal-title":"MBio"},{"key":"2025021007580514200_r5","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1128\/CMR.00058-15","article-title":"Biological and epidemiological features of antibiotic-resistant Streptococcus pneumoniae in pre- and post-conjugate vaccine eras: a United States perspective","volume":"29","author":"Kim","year":"2016","journal-title":"Clin. Microbiol. Rev."},{"key":"2025021007580514200_r6","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S1473-3099(14)70822-9","article-title":"Serotype-specific effectiveness and correlates of protection for the 13-valent pneumococcal conjugate vaccine: a postlicensure indirect cohort study","volume":"14","author":"Andrews","year":"2014","journal-title":"Lancet Infect. Dis."},{"key":"2025021007580514200_r7","doi-asserted-by":"crossref","first-page":"2399","DOI":"10.1016\/j.vaccine.2014.02.096","article-title":"Differences in serious clinical outcomes of infection caused by specific pneumococcal serotypes among adults","volume":"32","author":"Grabenstein","year":"2014","journal-title":"Vaccine"},{"key":"2025021007580514200_r8","doi-asserted-by":"crossref","first-page":"e0226353","DOI":"10.1371\/journal.pone.0226353","article-title":"The shifting epidemiology and serotype distribution of invasive pneumococcal disease in Ontario, Canada, 2007\u20132017","volume":"14","author":"Wijayasri","year":"2019","journal-title":"PLoS One"},{"key":"2025021007580514200_r9","doi-asserted-by":"crossref","first-page":"845","DOI":"10.3390\/genes10110845","article-title":"Evolution of Streptococcus pneumoniae serotype 3 in England and Wales: a major vaccine evader","volume":"10","author":"Groves","year":"2019","journal-title":"Genes (Basel)"},{"key":"2025021007580514200_r10","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.vaccine.2019.10.056","article-title":"Increase in Streptococcus pneumoniae serotype 3 associated parapneumonic pleural effusion\/empyema after the introduction of PCV13 in Germany","volume":"38","author":"Goettler","year":"2020","journal-title":"Vaccine"},{"key":"2025021007580514200_r11","doi-asserted-by":"crossref","first-page":"4653","DOI":"10.1128\/IAI.73.8.4653-4667.2005","article-title":"Illustration of pneumococcal polysaccharide capsule during adherence and invasion of epithelial cells","volume":"73","author":"Hammerschmidt","year":"2005","journal-title":"Infect. Immun."},{"key":"2025021007580514200_r12","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1128\/CVI.00591-15","article-title":"Capsular polysaccharide (CPS) release by serotype 3 pneumococcal strains reduces the protective effect of anti-type 3 CPS antibodies","volume":"23","author":"Choi","year":"2015","journal-title":"Clin. Vaccine Immunol."},{"key":"2025021007580514200_r13","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1093\/infdis\/jit190","article-title":"Bacterial complications of respiratory tract viral illness: a comprehensive evaluation","volume":"208","author":"Falsey","year":"2013","journal-title":"J. Infect. Dis."},{"key":"2025021007580514200_r14","first-page":"1071","article-title":"Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1)\u2014United States, May\u2013August 2009","volume":"58","author":"Centers for Disease Control and Prevention (CDC)","year":"2009","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"2025021007580514200_r15","doi-asserted-by":"crossref","first-page":"235","DOI":"10.5858\/134.2.235","article-title":"Pulmonary pathologic findings of fatal 2009 pandemic influenza A\/H1N1 viral infections","volume":"134","author":"Gill","year":"2010","journal-title":"Arch. Pathol. Lab. Med."},{"key":"2025021007580514200_r16","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1086\/591708","article-title":"Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness","volume":"198","author":"Morens","year":"2008","journal-title":"J. Infect. Dis."},{"key":"2025021007580514200_r17","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.chom.2014.06.005","article-title":"Influenza promotes pneumococcal growth during coinfection by providing host sialylated substrates as a nutrient source","volume":"16","author":"Siegel","year":"2014","journal-title":"Cell Host Microbe"},{"key":"2025021007580514200_r18","doi-asserted-by":"crossref","first-page":"2047","DOI":"10.4049\/jimmunol.1301152","article-title":"Immune dysfunction and bacterial coinfections following influenza","volume":"191","author":"Metzger","year":"2013","journal-title":"J. Immunol."},{"key":"2025021007580514200_r19","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1164\/arrd.1986.134.5.1040","article-title":"Adherence of type I Streptococcus pneumoniae to tracheal epithelium of mice infected with influenza A\/PR8 virus","volume":"134","author":"Plotkowski","year":"1986","journal-title":"Am. Rev. Respir. Dis."},{"key":"2025021007580514200_r20","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1165\/rcmb.2007-0417OC","article-title":"Influenza virus infection decreases tracheal mucociliary velocity and clearance of Streptococcus pneumoniae","volume":"42","author":"Pittet","year":"2010","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025021007580514200_r21","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.4049\/jimmunol.2000094","article-title":"Influenza Infection Induces alveolar macrophage dysfunction and thereby enables noninvasive Streptococcus pneumoniae to cause deadly pneumonia","volume":"205","author":"Verma","year":"2020","journal-title":"J. Immunol."},{"key":"2025021007580514200_r22","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.4049\/jimmunol.1300014","article-title":"Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections","volume":"191","author":"Ghoneim","year":"2013","journal-title":"J. Immunol."},{"key":"2025021007580514200_r23","doi-asserted-by":"crossref","first-page":"6707","DOI":"10.1128\/IAI.00789-06","article-title":"Both influenza-induced neutrophil dysfunction and neutrophil-independent mechanisms contribute to increased susceptibility to a secondary Streptococcus pneumoniae infection","volume":"74","author":"McNamee","year":"2006","journal-title":"Infect. Immun."},{"key":"2025021007580514200_r24","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1086\/421525","article-title":"Effect of antiviral treatment on the outcome of secondary bacterial pneumonia after influenza","volume":"190","author":"McCullers","year":"2004","journal-title":"J. Infect. Dis."},{"key":"2025021007580514200_r25","doi-asserted-by":"crossref","first-page":"824788","DOI":"10.3389\/fcimb.2022.824788","article-title":"Diverse mechanisms of protective anti-pneumococcal antibodies","volume":"12","author":"Gingerich","year":"2022","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"2025021007580514200_r26","doi-asserted-by":"crossref","first-page":"e00747-20","DOI":"10.1128\/IAI.00747-20","article-title":"Broadly reactive human monoclonal antibodies targeting the pneumococcal histidine triad protein protect against fatal pneumococcal infection","volume":"89","author":"Huang","year":"2021","journal-title":"Infect. Immun."},{"key":"2025021007580514200_r27","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1189\/jlb.0407247","article-title":"Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice","volume":"83","author":"Daley","year":"2008","journal-title":"J. Leukoc. Biol."},{"key":"2025021007580514200_r28","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1080\/21645515.2017.1403698","article-title":"Antibodies to PcpA and PhtD protect mice against Streptococcus pneumoniae by a macrophage- and complement-dependent mechanism","volume":"14","author":"Visan","year":"2018","journal-title":"Hum. Vaccin. Immunother."},{"key":"2025021007580514200_r29","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1084\/jem.20110159","article-title":"MHC class I-specific antibody binding to nonhematopoietic cells drives complement activation to induce transfusion-related acute lung injury in mice","volume":"208","author":"Strait","year":"2011","journal-title":"J. Exp. Med."},{"key":"2025021007580514200_r30","doi-asserted-by":"crossref","first-page":"e1008942","DOI":"10.1371\/journal.ppat.1008942","article-title":"Antibody recognition of the Pneumovirus fusion protein trimer interface","volume":"16","author":"Huang","year":"2020","journal-title":"PLoS Pathog."},{"key":"2025021007580514200_r31","doi-asserted-by":"crossref","first-page":"e00953-17","DOI":"10.1128\/AEM.00953-17","article-title":"Competitive dominance within biofilm consortia regulates the relative distribution of pneumococcal nasopharyngeal density","volume":"83","author":"Wu","year":"2017","journal-title":"Appl. Environ. Microbiol."},{"key":"2025021007580514200_r32","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1128\/IAI.69.2.949-958.2001","article-title":"Identification and characterization of a novel family of pneumococcal proteins that are protective against sepsis","volume":"69","author":"Adamou","year":"2001","journal-title":"Infect. Immun."},{"key":"2025021007580514200_r33","doi-asserted-by":"crossref","first-page":"e0080021","DOI":"10.1128\/mBio.00800-21","article-title":"A structural model for the ligand binding of pneumococcal serotype 3 capsular polysaccharide-specific protective antibodies","volume":"12","author":"Ozdilek","year":"2021","journal-title":"MBio"},{"key":"2025021007580514200_r34","doi-asserted-by":"crossref","first-page":"e00300-18","DOI":"10.1128\/IAI.00300-18","article-title":"A capsular polysaccharide-specific antibody alters Streptococcus pneumoniae gene expression during nasopharyngeal colonization of mice","volume":"86","author":"Doyle","year":"2018","journal-title":"Infect. Immun."},{"key":"2025021007580514200_r35","doi-asserted-by":"crossref","first-page":"e1009405","DOI":"10.1371\/journal.ppat.1009405","article-title":"Sequential targeting of interferon pathways for increased host resistance to bacterial superinfection during influenza","volume":"17","author":"Barman","year":"2021","journal-title":"PLoS Pathog."},{"key":"2025021007580514200_r36","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1016\/j.vaccine.2017.03.071","article-title":"Efficacy of a novel, protein-based pneumococcal vaccine against nasopharyngeal carriage of Streptococcus pneumoniae in infants: a phase 2, randomized, controlled, observer-blind study","volume":"35","author":"Odutola","year":"2017","journal-title":"Vaccine"},{"key":"2025021007580514200_r37","doi-asserted-by":"crossref","first-page":"7482","DOI":"10.1016\/j.vaccine.2019.09.076","article-title":"Efficacy, safety and immunogenicity of a pneumococcal protein-based vaccine co-administered with 13-valent pneumococcal conjugate vaccine against acute otitis media in young children: a phase IIb randomized study","volume":"37","author":"Hammitt","year":"2019","journal-title":"Vaccine"},{"key":"2025021007580514200_r38","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.4049\/jimmunol.0900688","article-title":"Human neutrophils kill Streptococcus pneumoniae via serine proteases","volume":"183","author":"Standish","year":"2009","journal-title":"J. Immunol."},{"key":"2025021007580514200_r39","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1007\/BF01487042","article-title":"The importance of neutrophils in resistance to pneumococcal pneumonia in adult and neonatal mice","volume":"20","author":"Garvy","year":"1996","journal-title":"Inflammation"},{"key":"2025021007580514200_r40","doi-asserted-by":"crossref","first-page":"7542","DOI":"10.1016\/j.vaccine.2010.08.061","article-title":"The efficacy of pneumococcal capsular polysaccharide-specific antibodies to serotype 3 Streptococcus pneumoniae requires macrophages","volume":"28","author":"Fabrizio","year":"2010","journal-title":"Vaccine"},{"key":"2025021007580514200_r41","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1111\/1348-0421.12965","article-title":"Secondary streptococcal infection following influenza","volume":"66","author":"Okahashi","year":"2022","journal-title":"Microbiol. Immunol."},{"key":"2025021007580514200_r42","doi-asserted-by":"crossref","first-page":"e1003238","DOI":"10.1371\/journal.ppat.1003238","article-title":"Kinetics of coinfection with influenza A virus and Streptococcus pneumoniae","volume":"9","author":"Smith","year":"2013","journal-title":"PLoS Pathog."},{"key":"2025021007580514200_r43","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1128\/iai.42.3.1102-1108.1983","article-title":"Tracheal function during influenza infections","volume":"42","author":"Nugent","year":"1983","journal-title":"Infect. Immun."},{"key":"2025021007580514200_r44","doi-asserted-by":"crossref","first-page":"5593","DOI":"10.1016\/j.cell.2021.09.035","article-title":"Pan-ebolavirus protective therapy by two multifunctional human antibodies","volume":"184","author":"Gilchuk","year":"2021","journal-title":"Cell"},{"key":"2025021007580514200_r45","doi-asserted-by":"crossref","first-page":"E82","DOI":"10.1073\/pnas.1718441115","article-title":"Synergistic anti-HCV broadly neutralizing human monoclonal antibodies with independent mechanisms","volume":"115","author":"Mankowski","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025021007580514200_r46","first-page":"188","article-title":"A combination of two human neutralizing antibodies prevents SARS-CoV-2 infection in cynomolgus macaques","volume":"3","author":"Cobb","year":"2022","journal-title":"Med (N Y)"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/210\/1\/50\/61539961\/ji2200349.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/210\/1\/50\/61539961\/ji2200349.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T02:58:34Z","timestamp":1739156314000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/210\/1\/50\/7921598"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,1]]},"references-count":46,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2023,1,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.2200349","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.04.20.488872","asserted-by":"object"}]},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,1]]},"published":{"date-parts":[[2023,1,1]]}}}