{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T00:16:56Z","timestamp":1793060216851,"version":"4.5.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Shigellosis significantly impacts global health, particularly affecting vulnerable populations in low- and middle-income countries, with over 270 million annual infections. It also causes morbidity in specific high-risk groups in high-income countries. Antibiotic treatment is increasingly compromised by multidrug-resistant strains, highlighting the urgent need for a <jats:italic>Shigella<\/jats:italic> vaccine. We developed a four-component O-antigen-based vaccine candidate targeting <jats:italic>Shigella sonnei<\/jats:italic> and <jats:italic>Shigella flexneri<\/jats:italic> 1b, 2a, and 3a serotypes, named altSonflex1-2-3, to provide broad protection against most globally prevalent <jats:italic>Shigella<\/jats:italic> strains. Here, we characterized the O-antigen structural features of a panel of <jats:italic>S. flexneri<\/jats:italic> drug-resistant clinical isolates and verified that they did not significantly differ from the O-antigen in the vaccine. Preclinical sera elicited by altSonflex1-2\u20133 were bactericidal against most strains, confirming the ability of anti-O-antigen antibodies to recognize and kill <jats:italic>in vitro<\/jats:italic> different clinical isolates. Importantly, our results suggest that altSonflex1-2\u20133 could offer protection against antimicrobial-resistant <jats:italic>Shigella<\/jats:italic> strains, addressing a critical public health issue.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1652460","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T05:33:39Z","timestamp":1756964019000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Antibodies elicited by altSonflex1-2-3 GMMA vaccine are bactericidal against a panel of drug-resistant Shigella clinical isolates"],"prefix":"10.3389","volume":"16","author":[{"given":"Elena","family":"Boero","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Di Benedetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Vezzani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renzo","family":"Alfini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter-Jan","family":"Ceyssens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giannoula S.","family":"Tansarli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferric C.","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Fontana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Carrara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Mancini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miren","family":"Iturriza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Sala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Giannelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Micoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0009826","article-title":"Rationalizing the design of a broad coverage Shigella vaccine based on evaluation of immunological cross-reactivity among S. flexneri serotypes","volume":"15","author":"Citiulo","year":"2021","journal-title":"PloS Negl Trop Dis"},{"key":"B2","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1038\/s41541-023-00725-8","article-title":"A next-generation GMMA-based vaccine candidate to fight shigellosis","volume":"8","author":"Rossi","year":"2023","journal-title":"NPJ Vaccines"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252011123","article-title":"High-throughput luminescence-based serum bactericidal assay optimization and characterization to assess human sera functionality against multiple shigella flexneri serotypes","volume":"25","author":"Caradonna","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(18)30362-1","article-title":"Estimates of the global, regional, and national morbidity, mortality, and aetiologies of diarrhoea in 195 countries: a systematic analysis for the Global Burden of Disease Study 2016","volume":"18","year":"2018","journal-title":"Lancet Infect Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(18)30475-4","article-title":"Morbidity and mortality due to shigella and enterotoxigenic Escherichia coli diarrhoea: the Global Burden of Disease Study 1990-2016","volume":"18","author":"Khalil","year":"2018","journal-title":"Lancet Infect Dis"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30925-9","article-title":"Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019","volume":"396","year":"2020","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0011475","article-title":"Shigella and childhood stunting: Evidence, gaps, and future research directions","volume":"17","author":"Bagamian","year":"2023","journal-title":"PloS Negl Trop Dis"},{"key":"B8","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.ijid.2023.01.034","article-title":"Consequences of Shigella infection in young children: a systematic review","volume":"129","author":"Libby","year":"2023","journal-title":"Int J Infect diseases: IJID: Off Publ Int Soc Infect Dis"},{"key":"B9","article-title":"Shigellosis","volume-title":"ECDC","year":"2024"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)33296-8","article-title":"Shigellosis","volume":"391","author":"Kotloff","year":"2018","journal-title":"Lancet"},{"key":"B11","article-title":"Guidelines for the control of shigellosis, including epidemics due to Shigella dysenteriae type 1","year":"2005"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-023-00906-1","article-title":"Antimicrobial-resistant Shigella: where do we go next","volume":"21","author":"Baker","year":"2023","journal-title":"Nat Rev Microbiol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1983","DOI":"10.1038\/s41467-023-37672-w","article-title":"The evolution and international spread of extensively drug resistant Shigella sonnei","volume":"14","author":"Mason","year":"2023","journal-title":"Nat Commun"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(22)00879-9","article-title":"Genomic reconstruction and directed interventions in a multidrug-resistant Shigellosis outbreak in Seattle, WA, USA: a genomic surveillance study","volume":"23","author":"Tansarli","year":"2023","journal-title":"Lancet Infect Dis"},{"key":"B15","article-title":"WHO bacterial priority pathogens list, 2024","year":"2024"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1721095115","article-title":"Impact of existing vaccines in reducing antibiotic resistance: Primary and secondary effects","volume":"115","author":"Klugman","year":"2018","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4465","article-title":"The role of vaccines in preventing bacterial antimicrobial resistance","volume":"24","author":"Jansen","year":"2018","journal-title":"Nat Med"},{"key":"B18","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/s41579-020-00506-3","article-title":"The role of vaccines in combatting antimicrobial resistance","volume":"19","author":"Micoli","year":"2021","journal-title":"Nat Rev Microbiol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines10091376","article-title":"The shigella vaccines pipeline","volume":"10","author":"MacLennan","year":"2022","journal-title":"Vaccines (Basel)"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2022.10.011","article-title":"Threshold protective levels of serum IgG to Shigella lipopolysaccharide: re-analysis of Shigella vaccine trials data","volume":"29","author":"Cohen","year":"2023","journal-title":"Clin Microbiol Infect"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2019.1606971","article-title":"Serum IgG antibodies to Shigella lipopolysaccharide antigens - a correlate of protection against shigellosis","volume":"15","author":"Cohen","year":"2019","journal-title":"Hum Vaccin Immunother"},{"key":"B22","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s41541-024-00822-2","article-title":"Putative correlates of protection against shigellosis assessing immunomarkers across responses to S. sonnei investigational vaccine","volume":"9","author":"Conti","year":"2024","journal-title":"NPJ Vaccines"},{"key":"B23","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s13099-015-0061-5","article-title":"Draft genomes of Shigella strains used by the STOPENTERICS consortium","volume":"7","author":"Rossi","year":"2015","journal-title":"Gut Pathog"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-695X.2012.01000.x","article-title":"Shigella flexneri O-antigens revisited: final elucidation of the O-acetylation profiles and a survey of the O-antigen structure diversity","volume":"66","author":"Perepelov","year":"2012","journal-title":"FEMS Immunol Med Microbiol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/0264-410x(96)00006-0","article-title":"Cross-reactivity of Shigella flexneri serotype 2a O antigen antibodies following immunization or infection","volume":"14","author":"Van De Verg","year":"1996","journal-title":"Vaccine"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiae273","article-title":"Safety and immunogenicity of a 4-component GMMA-based Shigella vaccine in healthy European adults: Stage 1 of a randomized, controlled phase I\/II clinical trial","volume":"230","author":"Leroux-Roels","year":"2024","journal-title":"J Infect Dis"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciu468","article-title":"Shigella isolates from the global enteric multicenter study inform vaccine development","volume":"59","author":"Livio","year":"2014","journal-title":"Clin Infect diseases: an Off Publ Infect Dis Soc America"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00412-16","article-title":"Functional and antigen-specific serum antibody levels as correlates of protection against shigellosis in a controlled human challenge study","volume":"24","author":"Shimanovich","year":"2017","journal-title":"Clin Vaccine Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1303641110","article-title":"Intracellular Shigella remodels its LPS to dampen the innate immune recognition and evade inflammasome activation","volume":"110","author":"Paciello","year":"2013","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B30","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1080\/21645515.2019.1640427","article-title":"Functional antibodies as immunological endpoints to evaluate protective immunity against Shigella","volume":"16","author":"Ndungo","year":"2020","journal-title":"Hum Vaccin Immunother"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/166.1.158","article-title":"Age-specific prevalence of serum antibodies to the invasion plasmid and lipopolysaccharide antigens of shigella species in Chilean and north american populations","volume":"166","author":"Van De Verg","year":"1992","journal-title":"J Infect Dis"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-3083.2002.01079.x","article-title":"Delayed and reduced adaptive humoral immune responses in children with shigellosis compared with in adults","volume":"55","author":"Raqib","year":"2002","journal-title":"Scandinavian J Immunol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/s41541-022-00497-7","article-title":"Rapid generation of Shigella flexneri GMMA displaying natural or new and cross-reactive O-Antigens","volume":"7","author":"Gasperini","year":"2022","journal-title":"NPJ Vaccines"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines8020160","article-title":"GMMA and Glycoconjugate Approaches Compared in Mice for the Development of a Vaccine against Shigella flexneri Serotype 6","volume":"8","author":"Raso","year":"2020","journal-title":"Vaccines (Basel)"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3390\/biology13040256","article-title":"Development and application of a high-throughput method for the purification and analysis of surface carbohydrates from klebsiella pneumoniae","volume":"13","author":"Nonne","year":"2024","journal-title":"Biol (Basel)"},{"key":"B36","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1007\/978-1-0716-0795-4_14","article-title":"O-antigen extraction, purification, and chemical conjugation to a carrier protein","volume":"2183","author":"Micoli","year":"2021","journal-title":"Methods Mol Biol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-1900-1_14","article-title":"Methods for assessment of OMV\/GMMA quality and stability","volume":"2414","author":"Micoli","year":"2022","journal-title":"Methods Mol Biol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1272","DOI":"10.3390\/vaccines12111272","article-title":"Design of a glycoconjugate vaccine against salmonella paratyphi A","volume":"12","author":"Alfini","year":"2024","journal-title":"Vaccines"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/ht9020014","article-title":"Intra-laboratory evaluation of luminescence based high-throughput serum bactericidal assay (L-SBA) to determine bactericidal activity of human sera against shigella","volume":"9","author":"Rossi","year":"2020","journal-title":"High Throughput"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3390\/biotech11030029","article-title":"Setup and Characterization of a High-Throughput Luminescence-Based Serum Bactericidal Assay (L-SBA) to Determine Functionality of Human Sera against Shigella flexneri","volume":"11","author":"Mancini","year":"2022","journal-title":"BioTech (Basel)"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2021.101076","article-title":"Efficacy, safety, and immunogenicity of the Shigella sonnei 1790GAHB GMMA candidate vaccine: Results from a phase 2b randomized, placebo-controlled challenge study in adults","volume":"39","author":"Frenck","year":"2021","journal-title":"EClinicalMedicine"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1652460\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T05:33:40Z","timestamp":1756964020000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1652460\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,4]]},"references-count":41,"alternative-id":["10.3389\/fimmu.2025.1652460"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1652460","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,4]]},"article-number":"1652460"}}