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To establish such a vaccine, we generated two multivalent vesicular stomatitis virus (VSV)-based vaccine candidates that simultaneously target H5N1 hemagglutinin (H5\n                      <jats:sub>05<\/jats:sub>\n                      or H5\n                      <jats:sub>22<\/jats:sub>\n                      ) and the ectodomain of matrix protein 2 (M2e) and characterized their ability to induce protective immune responses. Our results revealed that vaccine immunization induced high humoral immune responses against both the HPAI hemagglutinin (HA) protein and the M2 protein in mice. Intriguingly, vaccine-immunized mouse sera exhibited highly efficient neutralizing activity against the corresponding H5 pseudovirus and mediated potent and broad antibody-dependent cellular cytotoxicity (ADCC) activity against M2e derived from human and avian influenza H5, H1, H3, and H7 viruses. Furthermore, both intranasal (IN) and intramuscular immunization (IM) of V-EtM2e\/H5\n                      <jats:sub>22<\/jats:sub>\n                      provided efficient protection against HPAI H5N1 virus challenge in mice, with a 100% survival rate and a nondetectable viral load in several tissues. Notably, noninvasive mucosal IN delivery achieved protection equal to that of IM delivery at a 100-fold lower immunizing dose. These findings provide strong evidence for the effectiveness of a multivalent VSV-based vaccine against human (avian) influenza A viruses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>Avian influenza, especially highly pathogenic avian influenza (HPAI) viruses, can cause a highly contagious airborne disease that poses a significant public health threat. The development of a multivalent vaccine is very important to control these viral infections. In this study, we have developed a multivalent vaccine that simultaneously targets two critical HPAI H5N1 surface viral proteins and fully protects against highly pathogenic H5N1 infection in a mouse model. This study provides convincing evidence for the effectiveness of a multivalent vaccine against highly pathogenic influenza A viruses.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00097-26","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T13:00:40Z","timestamp":1781614840000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["A VSV-vector vaccine simultaneously targeting H5N1 hemagglutinin and matrix protein 2 induces robust neutralizing and ADCC antibody responses and provides full protection against lethal H5N1 infection in a mouse model"],"prefix":"10.1128","volume":"100","author":[{"given":"Zhujun","family":"Ao","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02gfys938","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Human Retrovirology, University of Manitoba","place":["Winnipeg, 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