{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T02:12:41Z","timestamp":1772071961360,"version":"3.50.1"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T00:00:00Z","timestamp":1662681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p><jats:italic>Shigella<\/jats:italic> is associated with a significant burden of disease worldwide among individuals of all ages and is the major cause of moderate and severe diarrhea in children under five years of age in low- and middle-income countries. Several candidate vaccines against <jats:italic>Shigella<\/jats:italic> species are currently under clinical development. The investigational 1790GAHB vaccine against <jats:italic>Shigella sonnei<\/jats:italic> is based on GMMA (Generalized Modules for Membrane Antigens) technology. The vaccine was well tolerated and induced high antibody levels in early-phase clinical trials in both <jats:italic>Shigella<\/jats:italic>-endemic and non-endemic settings. The present analysis assessed the bactericidal activity of antibodies induced by 1790GAHB in healthy Kenyan adults during a phase 2a, controlled, randomized study (NCT02676895). Participants received two doses of 1790GAHB 4 weeks apart containing either 1.5\/25 \u00b5g or 6\/100 \u00b5g O antigen\/protein, or active comparator vaccines (Control). Serum bactericidal activity (SBA) against <jats:italic>S. sonnei<\/jats:italic> was assessed at pre-vaccination (D1), 28 days post-first dose (D29) and 28 days post-second dose (D57), using a luminescence-based assay. Most participants had SBA titers above the lower limit of quantification of the assay at D1. SBA geometric mean titers increased 3.4-fold in the 1.5\/25 \u00b5g group and 6.3-fold in the 6\/100 \u00b5g group by D29 and were maintained at D57. There was no increase in SBA geometric mean titers in the Control group. A strong correlation was observed between SBA titers and anti-<jats:italic>S. sonnei<\/jats:italic> lipopolysaccharide serum immunoglobulin G antibody concentrations (Pearson correlation coefficient = 0.918), indicating that SBA can effectively complement enzyme-linked immunosorbent assay data by indicating the functionality of 1790GAHB-induced antibodies.<\/jats:p>","DOI":"10.3389\/fimmu.2022.971866","type":"journal-article","created":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T13:05:18Z","timestamp":1663247118000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Complement-mediated serum bactericidal activity of antibodies elicited by the Shigella sonnei GMMA vaccine in adults from a shigellosis-endemic country: Exploratory analysis of a Phase 2a randomized study"],"prefix":"10.3389","volume":"13","author":[{"given":"Melissa C.","family":"Kapulu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Usman","family":"Nakakana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella S.","family":"Scir\u00e9","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleanna","family":"Sarakinou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentino","family":"Conti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omar","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Acquaviva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Necchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina W.","family":"Obiero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura B.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip","family":"Bejon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Njuguna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Micoli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Audino","family":"Podda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,9]]},"reference":[{"key":"B1","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":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(18)32203-7","article-title":"Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: A systematic analysis for the global burden of disease study 2017","volume":"392","year":"2018","journal-title":"Lancet"},{"key":"B3","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":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(13)60844-2","article-title":"Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the global enteric multicenter study, GEMS): A prospective, case-control study","volume":"382","author":"Kotloff","year":"2013","journal-title":"Lancet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(15)00151-5","article-title":"Pathogen-specific burdens of community diarrhoea in developing countries: A multisite birth cohort study (MAL-ED)","volume":"3","author":"Platts-Mills","year":"2015","journal-title":"Lancet Glob Health"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2005.02.002","article-title":"The epidemiology of travel-associated shigellosis-regional risks, seasonality and serogroups","volume":"51","author":"Ekdahl","year":"2005","journal-title":"J Infect"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/jtm\/tay049","article-title":"Is a Shigella vaccine needed for travellers and the military","volume":"25","author":"Riddle","year":"2018","journal-title":"J Travel Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/s2214-109x(19)30541-8","article-title":"Diarrhoeal disease and subsequent risk of death in infants and children residing in low-income and middle-income countries: Analysis of the GEMS case-control study and 12-month GEMS-1A follow-on study","volume":"8","author":"Levine","year":"2020","journal-title":"Lancet Glob Health"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(16)31529-x","article-title":"Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: A reanalysis of the GEMS case-control study","volume":"388","author":"Liu","year":"2016","journal-title":"Lancet"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jiph.2017.09.025","article-title":"Emergence of antibiotic resistant Shigella species: A matter of concern","volume":"11","author":"Puzari","year":"2018","journal-title":"J Infect Public Health"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.13189\/iid.2017.050101","article-title":"Emergence of extensively drug-resistant Shigella sonnei in Bangladesh","volume":"5","author":"Rahman","year":"2017","journal-title":"Immunol Infect Dis"},{"key":"B12","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1586\/14787210.2015.983902","article-title":"Treatment of drug-resistant Shigella infections","volume":"13","author":"Klontz","year":"2015","journal-title":"Expert Rev Anti Infect Ther"},{"key":"B13","unstructured":"Antibiotic resistance threats in the United States2019"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/s1473-3099(17)30753-3","article-title":"Discovery, research, and development of new antibiotics: The WHO priority list of antibiotic-resistant bacteria and tuberculosis","volume":"18","author":"Tacconelli","year":"2018","journal-title":"Lancet Infect Dis"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2017.00064","article-title":"How do the virulence factors of Shigella work together to cause disease","volume":"7","author":"Mattock","year":"2017","journal-title":"Front Cell Infect Mi"},{"key":"B16","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":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2016.02.075","article-title":"Status of vaccine research and development for Shigella","volume":"34","author":"Mani","year":"2016","journal-title":"Vaccine"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30488-6","article-title":"Safety and immunogenicity of a synthetic carbohydrate conjugate vaccine against Shigella flexneri 2a in healthy adult volunteers: a phase 1, dose-escalating, single-blind, randomised, placebo-controlled study","volume":"21","author":"Cohen","year":"2021","journal-title":"Lancet Infect Dis"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2018.06.063","article-title":"A phase I trial to evaluate the safety and immunogenicity of WRSs2 and WRSs3; two live oral candidate vaccines against Shigella sonnei","volume":"36","author":"Frenck","year":"2018","journal-title":"Vaccine"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1128\/cvi.00224-16","article-title":"Safety and immunogenicity of a candidate bioconjugate vaccine against Shigella flexneri 2a administered to healthy adults: A single-blind, randomized phase I study","volume":"23","author":"Riddle","year":"2016","journal-title":"Clin Vaccine Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1021\/acs.bioconjchem.5b00617","article-title":"A synthetic carbohydrate conjugate vaccine candidate against shigellosis: Improved bioconjugation and impact of alum on immunogenicity","volume":"27","author":"van der Put","year":"2016","journal-title":"Bioconjug Chem"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103310","article-title":"Human challenge study with a Shigella bioconjugate vaccine: Analyses of clinical efficacy and correlate of protection","volume":"66","author":"Talaat","year":"2021","journal-title":"EBioMedicine"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00583-17","article-title":"Assembly, biochemical characterization, immunogenicity, adjuvanticity, and efficacy of Shigella artificial invaplex","volume":"3","author":"Turbyfill","year":"2018","journal-title":"mSphere"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines10020328","article-title":"Towards a four-component GMMA-based vaccine against Shigella","volume":"10","author":"Micoli","year":"2022","journal-title":"Vaccines (Basel)"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2017.07.013","article-title":"Safety profile and immunologic responses of a novel vaccine against Shigella sonnei administered intramuscularly, intradermally and intranasally: Results from two parallel randomized phase 1 clinical studies in healthy adult volunteers in Europe","volume":"22","author":"Launay","year":"2017","journal-title":"EBioMedicine"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00335","article-title":"Booster vaccination with GVGH Shigella sonnei 1790GAHB GMMA vaccine compared to single vaccination in unvaccinated healthy European adults: Results from a phase 1 clinical trial","volume":"10","author":"Launay","year":"2019","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01884","article-title":"A phase 2a randomized study to evaluate the safety and immunogenicity of the 1790GAHB generalized modules for membrane antigen vaccine against Shigella sonnei administered intramuscularly to adults from a shigellosis-endemic country","volume":"8","author":"Obiero","year":"2017","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1038\/s41598-020-80421-y","article-title":"Dissecting the contribution of O-antigen and proteins to the immunogenicity of Shigella sonnei generalized modules for membrane antigens (GMMA)","volume":"11","author":"Mancini","year":"2021","journal-title":"Sci Rep"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.715393","article-title":"GMMA-based vaccines: The known and the unknown","volume":"12","author":"Mancini","year":"2021","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2020.101433","article-title":"Outer membrane vesicle vaccines","volume":"50","author":"Micoli","year":"2020","journal-title":"Semin Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3329\/jhpn.v29i5.8896","article-title":"Differential host immune responses to epidemic and endemic strains of Shigella dysenteriae type I","volume":"29","author":"Sayem","year":"2011","journal-title":"J Health Popul Nutr"},{"key":"B32","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1093\/ajcn.81.2.495","article-title":"Effects of zinc supplementation as adjunct therapy on the systemic immune responses in shigellosis","volume":"81","author":"Rahman","year":"2005","journal-title":"Am J Clin Nutr"},{"key":"B33","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":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.671325","article-title":"Antibodies elicited by the Shigella sonnei GMMA vaccine in adults trigger complement-mediated serum bactericidal activity: Results from a phase 1 dose escalation trial followed by a booster extension","volume":"12","author":"Micoli","year":"2021","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"e0134478","DOI":"10.1371\/journal.pone.0134478","article-title":"Production of a shigella sonnei vaccine based on generalized modules for membrane antigens (GMMA), 1790GAHB","volume":"10","author":"Gerke","year":"2015","journal-title":"PloS One"},{"key":"B36","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1007\/s12033-014-9804-7","article-title":"Comparison of colorimetric assays with quantitative amino acid analysis for protein quantification of generalized modules for membrane antigens (GMMA)","volume":"57","author":"Rossi","year":"2015","journal-title":"Mol Biotechnol"},{"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","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":"B39","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"},{"key":"B40","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":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103308","article-title":"Immune response characterization in a human challenge study with a Shigella flexneri 2a bioconjugate vaccine","volume":"66","author":"Clarkson","year":"2021","journal-title":"EBioMedicine"},{"key":"B42","doi-asserted-by":"publisher","first-page":"S829","DOI":"10.1093\/infdis\/jiab395","article-title":"Functional antibodies and innate immune responses to WRSS1, a live oral Shigella sonnei vaccine candidate, in Bangladeshi adults and children","volume":"224","author":"Sarker","year":"2021","journal-title":"J Infect Dis"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2019.11.067","article-title":"The use and abuse of a 4-fold increase in antibody response to assess immunogenicity in early stage vaccine clinical trials","volume":"38","author":"Saul","year":"2020","journal-title":"Vaccine"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00520","article-title":"IgG subclasses and allotypes: From structure to effector functions","volume":"5","author":"Vidarsson","year":"2014","journal-title":"Front Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830210103","article-title":"Human IgG subclass pattern of inducing complement-mediated cytolysis depends on antigen concentration and to a lesser extent on epitope patchiness, antibody affinity and complement concentration","volume":"21","author":"Michaelsen","year":"1991","journal-title":"Eur J Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.971866\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T10:02:19Z","timestamp":1663668139000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.971866\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,9]]},"references-count":45,"alternative-id":["10.3389\/fimmu.2022.971866"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.971866","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,9]]},"article-number":"971866"}}