{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:37:01Z","timestamp":1790861821479,"version":"4.1.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005942","name":"Funda\u00e7\u00e3o Butantan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005942","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The zoonotic influenza viruses cause seasonal epidemics and occasional pandemics, posing a significant public health threat. Transmitted by influenza A and B viruses, they result in ~1 billion annual infections, 3\u20135 million severe cases, and 300,000\u2013500,000 deaths worldwide, with U.S. healthcare costs reaching $87.1 billion yearly. Understanding viral biology is crucial for developing effective treatment and prevention strategies. This review analyzes 27 clinical trials of anti-influenza monoclonal antibodies (mAbs) from ClinicalTrials.gov, assessing their therapeutic and prophylactic potential. Some mAbs target conserved viral regions (e.g., hemagglutinin stem, M2e protein) for broad-spectrum neutralization. MHAA4549A demonstrated a 97.5% reduction in viral load in H3N2 models and showed synergistic effects with oseltamivir in severe cases. However, despite preclinical promise, others, such as VIR-2482 (intramuscular) and MEDI8852, failed in Phase 2 trials. Safety profiles were generally favorable, with mild Emergent Adverse Events (EAEs) (headache, gastrointestinal disturbances). Key challenges include poor mucosal tissue penetration and variable clinical responses. While mAb-oseltamivir combinations accelerated recovery in hospitalized patients, larger cohorts lacked statistical significance. Viral evolution remains a significant hurdle, emphasizing the need to target conserved epitopes. Future strategies may optimize half-life (e.g., Fc modifications in VIR-2482), improve mucosal delivery, and integrate mAbs with vaccines\/antivirals. mAbs hold promise for high-risk groups and pandemics but require further engineering to enhance efficacy and overcome biological barriers. Refinements in administration and design could establish monoclonal antibodies (mAbs) as a key tool in the management of influenza.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1669073","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T05:28:59Z","timestamp":1760074139000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Monoclonal antibodies against influenza viruses: a clinical trials review"],"prefix":"10.3389","volume":"16","author":[{"given":"Kenneth Gabriel","family":"Mota","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Maria","family":"Moro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0002-y","article-title":"Influenza","volume":"4","author":"Krammer","year":"2018","journal-title":"Nat Ver. Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/irv.12470","article-title":"The hidden burden of influenza: A review of the extra-pulmonary complications of influenza infection","volume":"11","author":"Sellers","year":"2017","journal-title":"Influenza Other Resp Viruses"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.26990","article-title":"A brief review of influenza virus infection","volume":"93","author":"Javanian","year":"2021","journal-title":"J Med Virol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2007.10.040","article-title":"Complications of viral influenza","volume":"121","author":"Rothberg","year":"2008","journal-title":"Am J Med"},{"key":"B5","doi-asserted-by":"publisher","first-page":"44","DOI":"10.5409\/wjcp.v9.i3.44","article-title":"Influenza B infections in children: A review","volume":"9","author":"Bhat","year":"2020","journal-title":"World J Clin Pediatr"},{"key":"B6","doi-asserted-by":"publisher","first-page":"4554","DOI":"10.1038\/s41598-020-79590-7","article-title":"Next generation methodology for updating HA vaccines against emerging human seasonal influenza A(H3N2) viruses","volume":"11","author":"Allen","year":"2021","journal-title":"Sci Rep"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-021-00603-0","article-title":"The evolution and future of influenza pandemic preparedness","volume":"53","author":"Harrington","year":"2021","journal-title":"Exp Mol Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2013.03.021","article-title":"Broadly neutralizing antibodies against influenza viruses","volume":"98","author":"Laursen","year":"2013","journal-title":"Antiviral Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.01914","article-title":"Integrating influenza antigenic dynamics with molecular evolution","volume":"3","author":"Bedford","year":"2014","journal-title":"eLife"},{"key":"B10","unstructured":"Global Influenza Programme"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0056-x","article-title":"Next-generation influenza vaccines: opportunities and challenges","volume":"19","author":"Wei","year":"2020","journal-title":"Nat Rev Drug Discov"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/irv.13276","article-title":"Recent advances, approaches and challenges in the development of universal influenza vaccines. Influenza and other respir","volume":"18","author":"Lim","year":"2024","journal-title":"Viruses"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2022.101207","article-title":"Broad neutralizing antibody-based strategies to tackle influenza","volume":"53","author":"Sun","year":"2022","journal-title":"Curr Opin Virology"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiu539","article-title":"Efficacy and safety of treatment with an anti-M2e monoclonal antibody in experimental human influenza","volume":"211","author":"Ramos","year":"2015","journal-title":"J Infect Dis"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0003942","article-title":"Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human igM+ Memory B cells","volume":"3","author":"Throsby","year":"2008","journal-title":"PLoS One"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa1725","article-title":"Safety and efficacy of CR6261 in an influenza A H1N1 healthy human challenge model","volume":"73","author":"Han","year":"2021","journal-title":"Clin Infect Dis"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1126\/science.1204839","article-title":"A highly conserved neutralizing epitope on group 2 influenza A viruses","volume":"333","author":"Ekiert","year":"2011","journal-title":"J Sci"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.2147\/VAAT.S13306","article-title":"Antibody targeting of TSG101 on influenza-infected cells","volume":"2010","author":"Bonavia","year":"2010","journal-title":"Virus Adaptation Treat"},{"key":"B19","unstructured":"Phase I Human Safety Studies of FGI-101-1A6 to Combat HINI Influenza Virus\n          \n          \n            \n              Diaz\n              L\n            \n          \n          \n          2013"},{"key":"B20","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.chom.2013.06.004","article-title":"An in vivo human-plasmablast enrichment technique allows rapid identification of therapeutic influenza A antibodies","volume":"14","author":"Nakamura","year":"2013","journal-title":"CHM"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00607-16","article-title":"Two phase 1, randomized, double-blind, placebo-controlled, single-ascending-dose studies to investigate the safety, tolerability, and pharmacokinetics of an anti-influenza A virus monoclonal antibody, MHAA4549A, in healthy volunteers","volume":"60","author":"Lim","year":"2016","journal-title":"Antimicrob Agents. Chemother"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01154-17","article-title":"Phase 2 randomized trial of the safety and efficacy of MHAA4549A, a broadly neutralizing monoclonal antibody, in a human influenza A virus challenge model","volume":"61","author":"McBride","year":"2017","journal-title":"Antimicrob Agents. Chemother"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00352-20","article-title":"A phase 2 randomized, double-blind, placebo-controlled trial of MHAA4549A, a monoclonal antibody, plus oseltamivir in patients hospitalized with severe influenza A virus infection","volume":"64","author":"Lim","year":"2020","journal-title":"Antimicrob Agents. Chemother"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofab630","article-title":"A phase 2 randomized, double-blind, placebo-controlled trial of the monoclonal antibody MHAA4549A in patients with acute uncomplicated influenza A infection","volume":"9","author":"Lim","year":"2022","journal-title":"OFID"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00279-17","article-title":"A phase 1, randomized, double-blind, placebo-controlled, single-ascending-dose study to investigate the safety, tolerability, and pharmacokinetics of an anti-influenza B virus monoclonal antibody, MHAB5553A, in healthy volunteers","volume":"61","author":"Lim","year":"2017","journal-title":"Antimicrob Agents. Chemother"},{"key":"B26","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1016\/j.cell.2016.05.073","article-title":"Structure and function analysis of an antibody recognizing all influenza A subtypes","volume":"166","author":"Kallewaard","year":"2016","journal-title":"Cell"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jix292","article-title":"The hemagglutinin A stem antibody MEDI8852 prevents and controls disease and limits transmission of pandemic influenza viruses","volume":"216","author":"Paules","year":"2017","journal-title":"J Infect Dis"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.biologicals.2017.08.007","article-title":"A phase 1 study to evaluate the safety and pharmacokinetics of MEDI8852, an anti-influenza A monoclonal antibody, in healthy adult volunteers","volume":"50","author":"Mallory","year":"2017","journal-title":"Biologicals"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00694-18","article-title":"Evaluation of MEDI8852, an anti-influenza A monoclonal antibody, in treating acute uncomplicated influenza","volume":"62","author":"Ali","year":"2018","journal-title":"Antimicrob Agents. Chemother"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01273-23","article-title":"A phase 1 study in healthy volunteers to investigate the safety, tolerability, and pharmacokinetics of VIR-2482: a monoclonal antibody for the prevention of severe influenza A illness","volume":"68","author":"Plotnik","year":"2024","journal-title":"Antimicrob Agents. Chemother"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciae368","article-title":"A randomized, placebo-controlled trial to evaluate the safety and efficacy of VIR-2482 in healthy adults for prevention of influenza A illness (PENINSULA)","volume":"79","author":"Tan","year":"2024","journal-title":"Clin Infect Dis"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2015.03.019","article-title":"Amino acid interaction networks provide a new lens for therapeutic antibody discovery and anti-viral drug optimization","volume":"11","author":"Viswanathan","year":"2015","journal-title":"COVIRO"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1502374112","article-title":"A broadly neutralizing human monoclonal antibody is effective against H7N9","volume":"112","author":"Tharakaraman","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02457-15","article-title":"The hemagglutinin stem-binding monoclonal antibody VIS410 controls influenza virus-induced acute respiratory distress syndrome","volume":"60","author":"Baranovich","year":"2016","journal-title":"Antimicrob Agents. Chemother"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2016.02.021","article-title":"Safety and upper respiratory pharmacokinetics of the hemagglutinin stalk-binding antibody VIS410 support treatment and prophylaxis based on population modeling of seasonal influenza A outbreaks","volume":"5","author":"Wollacott","year":"2016","journal-title":"EBioMedicine"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2020.104763","article-title":"Clinical and virological responses to a broad-spectrum human monoclonal antibody in an influenza virus challenge study","volume":"184","author":"Sloan","year":"2020","journal-title":"Antiviral Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2018.12.051","article-title":"Safety and efficacy of monoclonal antibody VIS410 in adults with uncomplicated influenza A infection: Results from a randomized, double-blind, phase-2, placebo-controlled study","volume":"40","author":"Hershberger","year":"2019","journal-title":"EBioMedicine"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0236172","article-title":"Broader neutralization of CT-P27 against influenza A subtypes by combining two human monoclonal antibodies","volume":"15","author":"Yi","year":"2020","journal-title":"PLoS One"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/v13061011","article-title":"Animal models for influenza research: strengths and weaknesses","volume":"13","author":"Nguyen","year":"2021","journal-title":"Viruses"},{"key":"B40","doi-asserted-by":"crossref","first-page":"2890","DOI":"10.1007\/978-1-0716-4326-6_3","article-title":"Animal models in influenza research","volume-title":"Influenza Virus. Methods in Molecular Biology","author":"Zhou","year":"2025"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2024.2392651","article-title":"Fully human monoclonal antibodies against Ebola virus possess complete protection in a hamster model","volume":"13","author":"Li","year":"2024","journal-title":"Emerging Microbes Infections"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/antib11010017","article-title":"Immune- and non-immune-mediated adverse effects of monoclonal antibody therapy: A survey of 110 approved a ntibodies","volume":"11","author":"Baldo","year":"2022","journal-title":"Antibodies"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06136-y","article-title":"A pan-influenza antibody inhibiting neuraminidase via receptor mimicry","volume":"618","author":"Momont","year":"2023","journal-title":"Nat"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-025-01955-3","article-title":"Drug\u2013Fc conjugate CD388 targets influenza virus neuraminidase and is broadly protective in mice","volume":"10","author":"D\u00f6hrmann","year":"2025","journal-title":"Nat Microbiol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1669073\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T05:29:00Z","timestamp":1760074140000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1669073\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,10]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2025.1669073"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1669073","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,10]]},"article-number":"1669073"}}