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The limited durability of memory responses, particularly from mRNA vaccines, remains a major challenge for achieving long-term protection. Developing vaccines that induce more sustained immunity would lessen the need for frequent revaccination, improving global vaccination logistics, especially in resource-limited settings. DNA-launched self-amplifying RNA replicons (DREP) and modified vaccinia virus Ankara (MVA) vectors are promising vaccine platforms capable of inducing potent humoral and cellular immunity. In this study, we evaluated SARS-CoV-2-specific immune responses in C57BL\/6 mice following homologous and heterologous prime\/boost regimens combining DREP- and MVA-based vaccines expressing the spike (S) protein from either the ancestral Wuhan strain or the Omicron XBB.1.5 variant. Homologous (DREP\/DREP, MVA\/MVA) and heterologous (DREP\/MVA) regimens were followed for six months. MVA-S(3P)-based boosters elicited robust and durable anti-S IgG antibodies cross-recognizing multiple variants, with minimal decay over time. Neutralization mapped to the booster antigen: MVA-S(3P\n                    <jats:sub>Wuhan<\/jats:sub>\n                    ) induced neutralization of the ancestral strain, while MVA-S(3P\n                    <jats:sub>XBB.1.5<\/jats:sub>\n                    ) selectively neutralized Omicron subvariants, maintaining high titers for at least six months. MVA-S(3P) boosters also enhanced antibody Fc-effector functions, memory B cells, and T follicular helper responses. Early after boosting, heterologous DREP\/MVA regimens induced stronger CD4\u207a and CD8\u207a T-cell responses, while at six months all MVA-S(3P)-boosted groups maintained superior, long-lived cellular immunity. Collectively, MVA-S(3P)-based boosters improved the magnitude, breadth, and durability of humoral and cellular responses, supporting their strategic use in homologous and heterologous DREP\/MVA vaccination regimens against SARS-CoV-2 and emerging variants.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-46699-0","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T17:36:13Z","timestamp":1775756173000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Homologous MVA and heterologous DREP\/MVA vaccine regimens induce robust and durable immune responses against SARS-CoV-2"],"prefix":"10.1038","volume":"16","author":[{"given":"Patricia","family":"P\u00e9rez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Esteso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda A.","family":"Noriega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Perez","family":"Vidakovics","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Liljestr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald M.","family":"McInerney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariano","family":"Esteban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Garc\u00eda-Arriaza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"issue":"3","key":"46699_CR1","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/j.immuni.2024.01.017","volume":"57","author":"K Srivastava","year":"2024","unstructured":"Srivastava, K. et al. 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