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Enhanced mucosal immunity may be required to block infection and onward transmission. Intranasal administration of current vaccines has proven inconsistent\n                    <jats:sup>3\u20137<\/jats:sup>\n                    , suggesting that alternative immunization strategies may be required. Here we show that intratracheal boosting with a bivalent Ad26-based SARS-CoV-2 vaccine results in substantial induction of mucosal humoral and cellular immunity and near-complete protection against SARS-CoV-2 BQ.1.1 challenge. A total of 40 previously immunized rhesus macaques were boosted with a bivalent Ad26 vaccine by the intramuscular, intranasal and intratracheal routes, or with a bivalent mRNA vaccine by the intranasal route. Ad26 boosting by the intratracheal route led to a substantial expansion of mucosal neutralizing antibodies, IgG and IgA binding antibodies, and CD8\n                    <jats:sup>+<\/jats:sup>\n                    and CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell responses, which exceeded those induced by Ad26 boosting by the intramuscular and intranasal routes. Intratracheal Ad26 boosting also led to robust upregulation of cytokine, natural killer, and T and B cell pathways in the lungs. After challenge with a high dose of SARS-CoV-2 BQ.1.1, intratracheal Ad26 boosting provided near-complete protection, whereas the other boosting strategies proved less effective. Protective efficacy correlated best with mucosal humoral and cellular immune responses. These data demonstrate that these immunization strategies induce robust mucosal immunity, suggesting the feasibility of developing vaccines that block respiratory viral infections.\n                  <\/jats:p>","DOI":"10.1038\/s41586-023-06951-3","type":"journal-article","created":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T12:02:21Z","timestamp":1702555341000},"page":"385-391","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":111,"title":["Mucosal boosting enhances vaccine protection against SARS-CoV-2 in macaques"],"prefix":"10.1038","volume":"626","author":[{"given":"Katherine","family":"McMahan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9821-1492","authenticated-orcid":false,"given":"Frank","family":"Wegmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malika","family":"Aid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Sciacca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2100-8461","authenticated-orcid":false,"given":"Nicole P.","family":"Hachmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6641-0342","authenticated-orcid":false,"given":"Catherine","family":"Jacob-Dolan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Powers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5654-1744","authenticated-orcid":false,"given":"David","family":"Hope","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6924-5346","authenticated-orcid":false,"given":"Cindy","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0505-6051","authenticated-orcid":false,"given":"Juliana","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1800-1784","authenticated-orcid":false,"given":"Tetyana","family":"Murdza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0899-2548","authenticated-orcid":false,"given":"Camille R.","family":"Mazurek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1307-2508","authenticated-orcid":false,"given":"Amelia","family":"Hoyt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4700-8224","authenticated-orcid":false,"given":"Adrianus C. 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EBioMedicine 85, 104298 (2022).","journal-title":"EBioMedicine"},{"key":"6951_CR4","doi-asserted-by":"publisher","first-page":"936","DOI":"10.1002\/eji.202249823","volume":"52","author":"M Cokaric Brdovcak","year":"2022","unstructured":"Cokaric Brdovcak, M. et al. ChAdOx1-S adenoviral vector vaccine applied intranasally elicits superior mucosal immunity compared to the intramuscular route of vaccination. Eur. J. Immunol. 52, 936\u2013945 (2022).","journal-title":"Eur. J. Immunol."},{"key":"6951_CR5","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18077-5","volume":"11","author":"L Feng","year":"2020","unstructured":"Feng, L. et al. An adenovirus-vectored COVID-19 vaccine confers protection from SARS-COV-2 challenge in rhesus macaques. Nat. Commun. 11, 4207 (2020).","journal-title":"Nat. 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Early estimates of bivalent mRNA vaccine effectiveness in preventing COVID-19-associated emergency department or urgent care encounters and hospitalizations among immunocompetent adults\u2014VISION Network, nine states, September\u2013November 2022. MMWR Morb. Mortal. Wkly Rep. 71, 1616\u20131624 (2022).","journal-title":"MMWR Morb. Mortal. Wkly Rep."},{"key":"6951_CR9","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.15585\/mmwr.mm715152e2","volume":"71","author":"D Surie","year":"2022","unstructured":"Surie, D. et al. Early estimates of bivalent mRNA vaccine effectiveness in preventing COVID-19-associated hospitalization among immunocompetent adults aged \u226565 years\u2014IVY Network, 18 states, September 8\u2013November 30, 2022. MMWR Morb. Mortal. Wkly Rep. 71, 1625\u20131630 (2022).","journal-title":"MMWR Morb. Mortal. 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A research and development (R&D) roadmap for broadly protective coronavirus vaccines: a pandemic preparedness strategy. Vaccine 41, 2101\u20132112 (2023).","journal-title":"Vaccine"},{"key":"6951_CR13","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1056\/NEJMp2307867","volume":"389","author":"X Becerra","year":"2023","unstructured":"Becerra, X. & Jha, A. Project NextGen\u2014defeating SARS-CoV-2 and preparing for the next pandemic. N. Engl. J. Med. 389, 773\u2013775 (2023).","journal-title":"N. Engl. J. Med."},{"key":"6951_CR14","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.1056\/NEJMoa2101544","volume":"384","author":"J Sadoff","year":"2021","unstructured":"Sadoff, J. et al. Safety and efficacy of single-dose Ad26.COV2.S vaccine against COVID-19. N. Engl. J. Med. 384, 2187\u20132201 (2021).","journal-title":"N. Engl. J. 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