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Here, two mRNA constructs encoding different versions of the low\u2010calcium response virulence (LcrV) protective antigen, an essential virulence factor of\n                    <jats:italic>Y. pestis<\/jats:italic>\n                    , are designed and evaluated. Next, the immunogenicity and protective efficacy both independently and in combination is assessed with the previously reported F1\u2010encoding mRNA construct in the well\u2010established mouse model of pneumonic plague. The findings reveal that human Fc\u2010conjugated F1 + LcrV combination mRNA vaccination resulted in significant immune activation and substantial protection against intranasal\n                    <jats:italic>Y. pestis<\/jats:italic>\n                    challenge. Notably, the combined vaccine demonstrates protective efficacy against two highly virulent wild\u2010type\n                    <jats:italic>Y. pestis<\/jats:italic>\n                    strains representing distinct biovars and an atypical, unencapsulated strain. This study represents the first comprehensive evaluation of mRNA constructs encoding innovatively designed versions of LcrV and F1 for pneumonic plague prevention, addressing critical gaps in current vaccination approaches. This study establishes the mRNA\u2010lipid nanoparticle (LNP)\u00a0platform as a promising tool for addressing bacterial pathogens, including those resistant to antibiotics. By broadening its applicability to diverse threats, this technology represents an innovative approach to tackling some of the most pressing challenges in global health.\n                  <\/jats:p>","DOI":"10.1002\/advs.202501286","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T16:48:26Z","timestamp":1745599706000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Novel Bivalent mRNA\u2010LNP Vaccine for Highly Effective Protection against Pneumonic Plague"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0710-5481","authenticated-orcid":false,"given":"Uri","family":"Elia","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics Israel Institute for Biological Research  Ness\u2010Ziona 76100 Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinon","family":"Levy","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics Israel Institute for Biological Research  Ness\u2010Ziona 76100 Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hila","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics Israel Institute for Biological Research  Ness\u2010Ziona 76100 Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2750-5394","authenticated-orcid":false,"given":"Ayelet","family":"Zauberman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics Israel Institute for Biological Research  Ness\u2010Ziona 76100 Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Gur","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics Israel Institute for Biological Research  Ness\u2010Ziona 76100 Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8596-6247","authenticated-orcid":false,"given":"Inbal","family":"Hazan\u2010Halevy","sequence":"additional","affiliation":[{"name":"Laboratory of Precision NanoMedicine Shmunis School for Biomedicine and Cancer Research George S. Wise Faculty of Life Sciences Tel Aviv University  Tel Aviv 69978 Israel"},{"name":"Center for Nanoscience and Nanotechnology Tel Aviv University  Tel Aviv 69978 Israel"},{"name":"Department of Materials Sciences and Engineering Iby and Aladar Fleischman Faculty of Engineering Tel Aviv University  Tel Aviv 69978 Israel"},{"name":"Cancer Biology Research Center Tel Aviv University  Tel Aviv 69978 Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moshe","family":"Aftalion","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics Israel Institute for Biological Research  Ness\u2010Ziona 76100 Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shani","family":"Benarroch","sequence":"additional","affiliation":[{"name":"Laboratory of Precision NanoMedicine Shmunis School for Biomedicine and Cancer Research George S. Wise Faculty of Life Sciences Tel Aviv University  Tel Aviv 69978 Israel"},{"name":"Center for Nanoscience and Nanotechnology Tel Aviv University  Tel Aviv 69978 Israel"},{"name":"Department of Materials Sciences and Engineering Iby and Aladar Fleischman Faculty of Engineering Tel Aviv University  Tel Aviv 69978 Israel"},{"name":"Cancer Biology Research Center Tel Aviv University  Tel Aviv 69978 Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3435-8599","authenticated-orcid":false,"given":"Erez","family":"Bar\u2010Haim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics Israel Institute for Biological Research  Ness\u2010Ziona 76100 Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1520-4175","authenticated-orcid":false,"given":"Orit","family":"Redy\u2010Keisar","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry Israel Institute for Biological Research  Ness\u2010Ziona 76100 Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4374-9981","authenticated-orcid":false,"given":"Ofer","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics Israel Institute for Biological Research  Ness\u2010Ziona 76100 Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8238-0673","authenticated-orcid":false,"given":"Dan","family":"Peer","sequence":"additional","affiliation":[{"name":"Laboratory of Precision NanoMedicine Shmunis School for Biomedicine and Cancer Research George S. 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