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This study evaluated the MPXV immunogenic antigens and the impact of vaccinia virus (VACV) vaccination and MPXV infection on cross-reactive antibody responses to conserved proteins from representative MPXV strains that reflected the evolutionary trajectory.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Phylogenetic analyses were first conducted to reveal the evolutionary trajectory of MPXV from 1970 to 2024. A total of 84 serum samples were collected: 42 from VACV-vaccinated individuals, 12 from MPXV-infected participants in the early stage, 13 from the late stage, and 17 from naive individuals. Demographic data, MPXV and HIV status, as well as other clinical information were collected using standardized forms. Immunogenicity, cross-reactive antibody responses, and amino acid similarity to 15 MPXV surface proteins were assessed using enzyme-linked immunosorbent assays, VACV neutralization tests, and sequence alignment. Data analysis methods included analysis of variance, Mann\u2013Whitney U test, binary logistic regression, Pearson correlation, and linear regression, with a significance threshold of\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.05.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The 186 complete genome sequences were classified into different clades and lineages, ranging from clade Ia to clade IIb C.1.1. Individuals infected with MPXV demonstrated strong antibody responses to antigens A35R, B6R, H3L, and E8L. VACV-vaccinated individuals exhibited broader cross-reactivity, particularly against A21L (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0003), A28L (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0028), A29L (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0324), G2R (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0003), and H2R (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0008), compared to MPXV-infected individuals. Pearson correlation analysis revealed significant associations (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0049) between antibody responses and the amino acid sequence similarity with other orthopoxviruses. Furthermore, MPXV-infected individuals exhibited greater neutralizing activity against VACV than those VACV-vaccinated individuals (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.0001), while the vaccinated group retained cross-protective immunity even decades post-vaccination.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>A35R, B6R, H3L, and E8L are the main immunogenic antigens of MPXV. VACV-vaccination triggers a cross-reactive antibody response to MPXV surface proteins. Our findings suggest the need for targeted vaccines and antibody treatments for MPXV, as well as the reintroduction of smallpox vaccinations with booster doses for high-risk groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s40249-025-01280-1","type":"journal-article","created":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T21:34:41Z","timestamp":1740432881000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Immunogenicity of monkeypox virus surface proteins and cross-reactive antibody responses in vaccinated and infected individuals: implications for vaccine and therapeutic development"],"prefix":"10.1186","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5136-8126","authenticated-orcid":false,"given":"Jing","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changyi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiling","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaifeng","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjie","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiliang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanliang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,25]]},"reference":[{"issue":"10","key":"1280_CR1","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1038\/s41577-022-00775-4","volume":"22","author":"FM Lum","year":"2022","unstructured":"Lum FM, Torres-Ruesta A, Tay MZ, Lin RTP, Lye DC, R\u00e9nia L, et al. 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Vaccine. 2013;31(42):4706\u20139.","journal-title":"Vaccine"}],"container-title":["Infectious Diseases of Poverty"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40249-025-01280-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40249-025-01280-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40249-025-01280-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T21:35:08Z","timestamp":1740432908000},"score":1,"resource":{"primary":{"URL":"https:\/\/idpjournal.biomedcentral.com\/articles\/10.1186\/s40249-025-01280-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,25]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1280"],"URL":"https:\/\/doi.org\/10.1186\/s40249-025-01280-1","relation":{},"ISSN":["2049-9957"],"issn-type":[{"value":"2049-9957","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,25]]},"assertion":[{"value":"23 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 January 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 February 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All sample collection work involved and all procedures involving human participants in this study was approved by the Ethics Committee of Nanjing Hospital affiliated to Nanjing University of Chinese Medicine (the Second Hospital of Nanjing) (2023-LS-ky046) and Nanjing Hospital of Chinese Medicine (KY2024035) affiliated to Nanjing University of Chinese Medicine, and was conducted in accordance with the guidelines of the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Hongjie Yu is an editorial board member of the journal\n                      Infectious Diseases of Poverty\n                      . He was not involved in the peer-review or handling of the manuscript. The authors have no other competing interests to disclose.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12"}}