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To develop a cross-protective vaccine against heterogeneous\n                      <jats:italic toggle=\"yes\">Shigella<\/jats:italic>\n                      species and serotypes, we attempted to apply an epitope- and structure-based vaccinology platform, multiepitope fusion antigen, to construct an optimal polyvalent chimeric immunogen with functional epitopes from the key\n                      <jats:italic toggle=\"yes\">Shigella<\/jats:italic>\n                      virulence determinants. With\n                      <jats:italic toggle=\"yes\">Shigella<\/jats:italic>\n                      invasion plasmid antigens B and D functional epitopes identified in recent studies, in this study, we focused on\n                      <jats:italic toggle=\"yes\">Shigella<\/jats:italic>\n                      intracellular spread protein A (IcsA; also known as virulence gene G, VirG), a multifunctional virulence factor that plays roles in bacterial adherence, invasion, and particularly intracellular and intercellular spread. We\n                      <jats:italic toggle=\"yes\">in silico<\/jats:italic>\n                      predicted continuous B-cell immunodominant epitopes from the IcsA functional passenger domain, and we fused each epitope to a non-homologous carrier protein,\n                      <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                      adhesin CS4 subunit CsaB, for epitope fusions. We then immunized mice with each epitope fusion and examined antibody functions against\n                      <jats:italic toggle=\"yes\">Shigella<\/jats:italic>\n                      bacterial invasion and adherence. Eleven IcsA B-cell epitopes were identified and fused to CsaB. Mice intramuscularly immunized with each epitope fusion developed IgG responses. Mouse serum antibodies significantly reduced\n                      <jats:italic toggle=\"yes\">Shigella sonnei<\/jats:italic>\n                      or\n                      <jats:italic toggle=\"yes\">Shigella flexneri<\/jats:italic>\n                      2a bacterial invasion or adherence\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      , particularly from the fusion with epitope #2 (\n                      <jats:sub>122<\/jats:sub>\n                      GDNNDGNSCGGNG\n                      <jats:sub>134<\/jats:sub>\n                      ), #3 (\n                      <jats:sub>156<\/jats:sub>\n                      GGSGADHNGDGGE\n                      <jats:sub>168<\/jats:sub>\n                      ), #7 (\n                      <jats:sub>309<\/jats:sub>\n                      YIISGKEDDGTQNV\n                      <jats:sub>325<\/jats:sub>\n                      ), #9 (\n                      <jats:sub>485<\/jats:sub>\n                      WNDTDGDSHG\n                      <jats:sub>494<\/jats:sub>\n                      ), or #10 (\n                      <jats:sub>507<\/jats:sub>\n                      TILADNLSHHNIN\n                      <jats:sub>523<\/jats:sub>\n                      ). These IcsA epitopes are more effective in inducing functional antibodies, suggesting their antigenic utility in constructing an optimal polyvalent\n                      <jats:italic toggle=\"yes\">Shigella<\/jats:italic>\n                      immunogen and developing a cross-protective vaccine, and perhaps in better understanding their role in IcsA biogenesis.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        An effective\n                        <jats:italic toggle=\"yes\">Shigella<\/jats:italic>\n                        vaccine is urgently needed to reduce\n                        <jats:italic toggle=\"yes\">Shigella<\/jats:italic>\n                        -associated diarrhea and dysentery.\n                        <jats:italic toggle=\"yes\">Shigella<\/jats:italic>\n                        IcsA (or VirG) plays a crucial role in\n                        <jats:italic toggle=\"yes\">Shigella<\/jats:italic>\n                        bacterial pathogenesis and is conserved across\n                        <jats:italic toggle=\"yes\">Shigella<\/jats:italic>\n                        species and serotypes, thus making IcsA an excellent antigen target in\n                        <jats:italic toggle=\"yes\">Shigella<\/jats:italic>\n                        vaccine development. Identification of the functional epitopes of the IcsA passenger domain from this study enables us to construct an optimal epitope- and structure-based polyvalent immunogen for a cross-protective multivalent\n                        <jats:italic toggle=\"yes\">Shigella<\/jats:italic>\n                        vaccine. Unlike the lipopolysaccharide-based whole-cell or subunit vaccine candidates that are serotype-specific, a multivalent vaccine carrying functional epitopes of conserved virulence determinants would be cross-protective against the heterogeneous\n                        <jats:italic toggle=\"yes\">Shigella<\/jats:italic>\n                        species and serotypes, effectively preventing shigellosis and dysentery. Data from this study may also provide insightful information for a better understanding of IcsA biogenesis.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/aem.01175-25","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T13:00:11Z","timestamp":1755867611000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["Characterization of\n                    <i>Shigella<\/i>\n                    virulence factor intracellular spread A (IcsA, or VirG) functional epitopes against\n                    <i>S. flexneri<\/i>\n                    2a and\n                    <i>S. sonnei<\/i>\n                    invasion and adherence"],"prefix":"10.1128","volume":"91","author":[{"given":"Aashwina","family":"Madhwal","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/047426m28","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathobiology, University of Illinois at Urbana-Champaign","place":["Urbana, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai Simha Reddy","family":"Vakamalla","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/047426m28","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathobiology, University of Illinois at Urbana-Champaign","place":["Urbana, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/047426m28","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathobiology, University of Illinois at Urbana-Champaign","place":["Urbana, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3723-2257","authenticated-orcid":true,"given":"Weiping","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/047426m28","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathobiology, University of Illinois at Urbana-Champaign","place":["Urbana, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)60844-2"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1662"},{"key":"e_1_3_3_4_2","volume-title":"Bacterial diarrhea","author":"Akhondi H","year":"2025","unstructured":"Akhondi H, Goldin J, Simonsen KA. 2025. 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