{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T03:49:13Z","timestamp":1784260153898,"version":"3.55.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T00:00:00Z","timestamp":1749081600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Shigellosis is among the top causes of bacterial diarrhea with significantly high morbidity and mortality for children under five years of age in low- and middle-income countries. Unfortunately, there are currently no licensed vaccines to prevent shigellosis. Our laboratory has developed the protein-based subunit vaccine candidate L-DBF by fusing the type III secretion system proteins IpaB and IpaD with the mucosal adjuvant LTA1, the active moiety of the heat-labile toxin from enterotoxigenic <jats:italic>Escherichia coli<\/jats:italic>. L-DBF delivered intranasally has been shown to protect against multiple serotypes of <jats:italic>Shigella<\/jats:italic> using the lethal pulmonary mice model. In recent work, we showed that even following prior infection with two sublethal doses of <jats:italic>S. flexneri<\/jats:italic> 2a in adult mice, L-DBF effectively cross-protects mice from a potentially lethal challenge with <jats:italic>S. sonnei<\/jats:italic> in addition to <jats:italic>S. flexneri<\/jats:italic>. We therefore wanted to know whether a prior sublethal infection by <jats:italic>S. flexneri<\/jats:italic> or <jats:italic>S. sonnei<\/jats:italic> would impact the protective immune response elicited by L-DBF against heterologous lethal infections in an aged mouse model. Elderly mice were subjected to a single sublethal dose of <jats:italic>S. flexneri<\/jats:italic> or <jats:italic>S. sonnei<\/jats:italic> prior to vaccination with L-DBF. We found that pre-exposed mice receiving L-DBF developed heterologous cross-protection against both <jats:italic>S. flexneri<\/jats:italic> and <jats:italic>S. sonnei<\/jats:italic> lethal challenge doses. This contrasts with unvaccinated mice that succumbed to the lethal challenge, despite a single homologous or heterologous pre-exposure to <jats:italic>Shigella<\/jats:italic> spp. Thus, L-DBF is a strong candidate for a protective shigellosis vaccine in all age groups to protect against commonly encountered <jats:italic>Shigella<\/jats:italic> serotypes in both na\u00efve hosts and those pre-exposed with homologous or heterologous <jats:italic>Shigella<\/jats:italic> serotypes.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1586537","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T05:29:54Z","timestamp":1749101394000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The fusion subunit vaccine L-DBF protects aged mice against heterologous lethal Shigella challenge after prior exposure"],"prefix":"10.3389","volume":"16","author":[{"given":"Md Shafiullah","family":"Parvej","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ti","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhrid","family":"Maiti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zackary K.","family":"Dietz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debaki R.","family":"Howlader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mst Nusrat","family":"Zahan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa","family":"Cato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satabdi","family":"Biswas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William D.","family":"Picking","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy L.","family":"Picking","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,5]]},"reference":[{"key":"B1","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\u20132016","volume":"18","author":"Khalil","year":"2018","journal-title":"Lancet Infect Diseases"},{"key":"B2","doi-asserted-by":"publisher","first-page":"4649","DOI":"10.3390\/ijms24054649","article-title":"Toward a shigella vaccine: opportunities and challenges to fight an antimicrobial-resistant pathogen","volume":"24","author":"Raso","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B3","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":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s12223-020-00773-w","article-title":"Shigella flexneri: an emerging pathogen","volume":"65","author":"Nisa","year":"2020","journal-title":"Folia Microbiologica"},{"key":"B5","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/s00203-020-02034-3","article-title":"Shigella sonnei: virulence and antibiotic resistance","volume":"203","author":"Shad","year":"2021","journal-title":"Arch Microbiology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0003708","article-title":"The rising dominance of shigella sonnei: an intercontinental shift in the etiology of bacillary dysentery","volume":"9","author":"Thompson","year":"2015","journal-title":"PloS Neglected Trop Diseases"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082601","article-title":"Changing Trends in the Prevalence of Shigella Species: Emergence of Multi-Drug Resistant Shigella sonnei Biotype g in Bangladesh","volume":"8","author":"Ud-Din","year":"2013","journal-title":"PloS One"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/jobm.201900075","article-title":"Effect of the bacterial growth phase and coculture conditions on the interaction of Acanthamoeba castellanii with Shigella dysenteriae, Shigella flexneri, and Shigella sonnei","volume":"59","author":"Zarei","year":"2019","journal-title":"J Basic Microbiol"},{"key":"B9","article-title":"WHO updates list of drug-resistant bacteria most threatening to human health","year":"2024"},{"key":"B10","doi-asserted-by":"publisher","first-page":"817","DOI":"10.3390\/antibiotics12050817","article-title":"Prevalence of antibiotic-resistant shigella spp. in Bangladesh: A systematic review and meta-analysis of 44,519 samples","volume":"12","author":"Ahmed","year":"2023","journal-title":"Antibiotics (Basel)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3201\/eid2806.220131","article-title":"Antimicrobial-resistant shigella spp. in San Diego, California, USA, 2017-2020","volume":"28","author":"Gaufin","year":"2022","journal-title":"Emerg Infect Dis"},{"key":"B12","doi-asserted-by":"publisher","first-page":"451","DOI":"10.3390\/microorganisms9020451","article-title":"The shigella type III secretion system: an overview from top to bottom","volume":"9","author":"Muthuramalingam","year":"2021","journal-title":"Microorganisms"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.06174-11","article-title":"Broadly protective shigella vaccine based on type III secretion apparatus proteins","volume":"80","author":"Martinez-Becerra","year":"2012","journal-title":"Infection Immunity"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00859-13","article-title":"Characterization of a novel fusion protein from IpaB and IpaD of shigella spp. and its potential as a pan-shigella Vaccine","volume":"81","author":"Martinez-Becerra","year":"2013","journal-title":"Infection Immunity"},{"key":"B15","doi-asserted-by":"publisher","first-page":"15128","DOI":"10.1038\/s41598-019-51356-w","article-title":"LTA1 is a safe, intranasal enterotoxin-based adjuvant that improves vaccine protection against influenza in young, old and B-cell-depleted (\u03bcMT) mice","volume":"9","author":"Valli","year":"2019","journal-title":"Sci Rep"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fitd.2021.729731","article-title":"L-DBF elicits cross protection against different serotypes of shigella spp","volume":"2","author":"Lu","year":"2021","journal-title":"Front Trop Dis"},{"key":"B17","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1007\/s11908-018-0634-9","article-title":"Travel and the spread of drug-resistant bacteria","volume":"20","author":"Schwartz","year":"2018","journal-title":"Curr Infect Dis Rep"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.00062-23","article-title":"The L-DBF vaccine cross protects mice against different Shigella serotypes after prior exposure to the pathogen","volume":"11","author":"Lu","year":"2023","journal-title":"Microbiol Spectrum"},{"key":"B19","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","author":"Troeger","year":"2018","journal-title":"Lancet Infect Diseases"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15585\/mmwr.ss7003a1","article-title":"Surveillance of vaccination coverage among adult populations -United States, 2018","volume":"70","author":"Lu","year":"2021","journal-title":"MMWR Surveill Summ"},{"key":"B21","volume-title":"World population ageing 1950\u20132050","year":"2002"},{"key":"B22","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.smim.2018.10.010","article-title":"Vaccination in the elderly: The challenge of immune changes with aging","volume":"40","author":"Ciabattini","year":"2018","journal-title":"Semin Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2014.06.006","article-title":"Immunosenescence and vaccine failure in the elderly: strategies for improving response","volume":"162","author":"Boraschi","year":"2014","journal-title":"Immunol Lett"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2005.04.019","article-title":"The unmet need in the elderly: designing new influenza vaccines for older adults","author":"McElhaney","year":"2005","journal-title":"Vaccine"},{"key":"B25","doi-asserted-by":"publisher","first-page":"6597","DOI":"10.1038\/s41467-023-42021-y","article-title":"A spatial sequencing atlas of age-induced changes in the lung during influenza infection","volume":"14","author":"Kasmani","year":"2023","journal-title":"Nat Commun"},{"key":"B26","doi-asserted-by":"publisher","first-page":"2836","DOI":"10.1016\/j.immuni.2023.10.013","article-title":"Single-cell atlas of healthy human blood unveils age-related loss of NKG2C(+)GZMB(-)CD8(+) memory T cells and accumulation of type 2 memory T cells","volume":"56","author":"Terekhova","year":"2023","journal-title":"Immunity"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.733566","article-title":"The dynamics of B cell aging in health and disease","volume":"12","author":"de Mol J","year":"2021","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms12040775","article-title":"The impact of immune system aging on infectious diseases","volume":"12","author":"Quiros-Roldan","year":"2024","journal-title":"Microorganisms"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.5.2775-2786.2003","article-title":"Complete genome sequence and comparative genomics of shigella flexneri serotype 2a strain 2457T","volume":"71","author":"Wei","year":"2003","journal-title":"Infection Immunity"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2369","article-title":"Shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from Europe","volume":"44","author":"Holt","year":"2012","journal-title":"Nat Genet"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1017\/S0950268812001677","article-title":"The Shigella human challenge model","volume":"141","author":"Porter","year":"2013","journal-title":"Epidemiol Infect"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2015.1046660","article-title":"Impact of formulation and particle size on stability and immunogenicity of oil-in-water emulsion adjuvants","volume":"11","author":"Iyer","year":"2015","journal-title":"Hum Vaccines Immunotherapeutics"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.4155\/tde-2016-0068","article-title":"Intranasal delivery of nanoparticle-based vaccines","volume":"8","author":"Marasini","year":"2017","journal-title":"Ther Deliv"},{"key":"B34","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/s41467-019-14230-x","article-title":"Oil-in-water emulsion adjuvants for pediatric influenza vaccines: a systematic review and meta-analysis","volume":"11","author":"Lin","year":"2020","journal-title":"Nat Communications"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1372349","article-title":"Development of a nano-emulsion based multivalent protein subunit vaccine against Pseudomonas aeruginosa","volume":"15","author":"Howlader","year":"2024","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1128\/iai.63.5.1947-1954.1995","article-title":"Antibody and cytokine responses in a mouse pulmonary model of Shigella flexneri serotype 2a infection","volume":"63","author":"Van De Verg","year":"1995","journal-title":"Infection Immunity"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2004.06.021","article-title":"High-throughput imaging of bacterial colonies grown on filter plates with application to serum bactericidal assays","volume":"292","author":"Liu","year":"2004","journal-title":"J Immunol Methods"},{"key":"B38","doi-asserted-by":"publisher","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":"B39","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.66.4.1342-1348.1998","article-title":"An essential role for gamma interferon in innate resistance to Shigella flexneri infection","volume":"66","author":"Way","year":"1998","journal-title":"Infect Immun"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002809","article-title":"IFN\u03b3 Inhibits the Cytosolic Replication of Shigella flexneri via the Cytoplasmic RNA Sensor RIG-I","volume":"8","author":"Jehl","year":"2012","journal-title":"PloS Pathogens"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2019\/1356540","article-title":"Intracellular pathogens: host immunity and microbial persistence strategies","volume":"2019","author":"Thakur","year":"2019","journal-title":"J Immunol Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1093\/femspd\/ftw111","article-title":"Cytokines IL-17 and IL-22 in the host response to infection","volume":"74","author":"Valeri","year":"2016","journal-title":"Pathog Dis"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1053\/j.gastro.2019.08.021","article-title":"Antigen-specific mucosal immunity regulates development of intestinal bacteria-mediated diseases","volume":"157","author":"Fujimoto","year":"2019","journal-title":"Gastroenterology"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-024-00874-4","article-title":"Insights into vaccines for elderly individuals: from the impacts of immunosenescence to delivery strategies","volume":"9","author":"Hou","year":"2024","journal-title":"NPJ Vaccines"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2011.41","article-title":"Secretory IgA\u2019s complex roles in immunity and mucosal homeostasis in the gut","volume":"4","author":"Mantis","year":"2011","journal-title":"Mucosal Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2011.06.001","article-title":"Shigella are versatile mucosal pathogens that circumvent the host innate immune system","volume":"23","author":"Ashida MO","year":"2011","journal-title":"Curr Opin Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2011.03.005","article-title":"Impaired in vivo CD4+ T cell expansion and differentiation in aged mice is not solely due to T cell defects: Decreased stimulation by aged dendritic cells","volume":"132","author":"Pereira","year":"2011","journal-title":"Mech Ageing Dev"},{"key":"B48","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1111\/j.1600-065X.1997.tb01027.x","article-title":"Age-related changes in antibody repertoire: contribution from T cells","volume":"160","author":"Song","year":"1997","journal-title":"Immunological Rev"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2019.01.035","article-title":"The total IgM, IgA and IgG antibody responses to pneumococcal polysaccharide vaccination (Pneumovax\u00ae23) in a healthy adult population and patients diagnosed with primary immunodeficiencies","volume":"37","author":"Parker","year":"2019","journal-title":"Vaccine"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glv085","article-title":"Salivary functional antibody secretion is reduced in older adults: A potential mechanism of increased susceptibility to bacterial infection in the elderly","volume":"70","author":"Heaney","year":"2015","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02654-19","article-title":"Shigella sonnei O-antigen inhibits internalization, vacuole escape, and inflammasome activation","volume":"10","author":"Watson","year":"2019","journal-title":"mBio"},{"key":"B52","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1016\/j.chom.2017.05.004","article-title":"Shigella sonnei encodes a functional T6SS used for interbacterial competition and niche occupancy","volume":"21","author":"Anderson","year":"2017","journal-title":"Cell Host Microbe"},{"key":"B53","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":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.06.003","article-title":"Why aging T cells fail: implications for vaccination","volume":"24","author":"Haynes","year":"2006","journal-title":"Immunity"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1662","article-title":"Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road","volume":"5","author":"Levine","year":"2007","journal-title":"Nat Rev Microbiology"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004099","article-title":"Unexpected role for IL-17 in protective immunity against hypervirulent Mycobacterium tuberculosis HN878 infection","volume":"10","author":"Gopal","year":"2014","journal-title":"PloS Pathog"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/ni1449","article-title":"IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge","volume":"8","author":"Khader","year":"2007","journal-title":"Nat Immunol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1007\/s40475-014-0019-6","article-title":"Shigella: A highly virulent and elusive pathogen","volume":"1","author":"Zaidi","year":"2014","journal-title":"Curr Trop Med Rep"},{"key":"B59","doi-asserted-by":"publisher","first-page":"102554","DOI":"10.1016\/j.tmaid.2023.102554","article-title":"Shigellosis in Southeast Asia: A systematic review and meta-analysis","volume":"52","author":"Muzembo","year":"2023","journal-title":"Travel Med Infect Disease"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1586537\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T05:29:55Z","timestamp":1749101395000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1586537\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,5]]},"references-count":59,"alternative-id":["10.3389\/fimmu.2025.1586537"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1586537","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,5]]},"article-number":"1586537"}}