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Outer membrane vesicles (OMVs) isolated from YptbS46 harboring an <jats:italic>lcrV<\/jats:italic> expression plasmid, pSMV13, are designated OMV<jats:sub>46<\/jats:sub>\u2010LcrV, which contained MPLA and high amounts of LcrV (Low Calcium response V) and displayed low activation of Toll\u2010like receptor 4 (TLR4). Intramuscular prime\u2010boost immunization with 30\u00a0\u00b5g of of OMV<jats:sub>46<\/jats:sub>\u2010LcrV exhibited substantially reduced reactogenicity than the parent OMV<jats:sub>44<\/jats:sub>\u2010LcrV and conferred complete protection to mice against a high\u2010dose of respiratory <jats:italic>Y. pestis<\/jats:italic> challenge. OMV<jats:sub>46<\/jats:sub>\u2010LcrV immunization induced robust adaptive responses in both lung mucosal and systemic compartments and orchestrated innate immunity in the lung, which are correlated with rapid bacterial clearance and unremarkable lung damage during <jats:italic>Y. pestis<\/jats:italic> challenge. Additionally, OMV<jats:sub>46<\/jats:sub>\u2010LcrV immunization conferred long\u2010term protection. Moreover, immunization with reduced doses of OMV<jats:sub>46<\/jats:sub>\u2010LcrV exhibited further lower reactogenicity and still provided great protection against pneumonic plague. The studies strongly demonstrate the feasibility of OMV<jats:sub>46<\/jats:sub>\u2010LcrV as a new type of plague vaccine candidate.<\/jats:p>","DOI":"10.1002\/smll.202307066","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T23:22:24Z","timestamp":1701127344000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Pneumonic Plague Protection Induced by a Monophosphoryl Lipid A Decorated <i>Yersinia<\/i> Outer\u2010Membrane\u2010Vesicle Vaccine"],"prefix":"10.1002","volume":"20","author":[{"given":"Saugata","family":"Majumder","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbial Disease Albany Medical College  Albany NY 12208 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreya","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Disease Albany Medical College  Albany NY 12208 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Disease Albany Medical College  Albany NY 12208 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Disease Albany Medical College  Albany NY 12208 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazel","family":"Dellario","sequence":"additional","affiliation":[{"name":"Wadsworth Center New York State Department of Health  Albany NY 12237 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixin","family":"Sui","sequence":"additional","affiliation":[{"name":"Wadsworth Center New York State Department of Health  Albany NY 12237 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqiang","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Duke University Medical Center  Durham NC 27710 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0071-6987","authenticated-orcid":false,"given":"Wei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Disease Albany Medical College  Albany NY 12208 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,11,27]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00044-19"},{"key":"e_1_2_9_2_1","volume-title":"Plague in the 21st Century: Global Public Health Challenges and Goals","author":"Hinnebusch B. 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