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Current influenza vaccines elicit an immune response that primarily targets the head domain of the viral glycoprotein hemagglutinin (HA). Influenza viruses, however, readily evade this response by acquiring mutations in the head domain. While vaccines that target the more conserved HA stalk may circumvent this problem, low levels of antistalk antibodies are elicited by vaccination, possibly due to the poor accessibility of the stalk domain to B cell receptors. In this work, it is demonstrated that nanoparticles presenting HA in an inverted orientation generate tenfold higher antistalk antibody titers after a prime immunization and fivefold higher antistalk titers after a boost than nanoparticles displaying HA in its regular orientation. Moreover, nanoparticles presenting HA in an inverted orientation elicit a broader antistalk response that reduces mouse weight loss and improves survival after challenge to a greater extent than nanoparticles displaying HA in a regular orientation. Refocusing the antibody response toward conserved epitopes by controlling antigen orientation may enable the design of broadly protective nanovaccines targeting influenza viruses and other pathogens with pandemic potential.<\/jats:p>","DOI":"10.1002\/adhm.202202729","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T12:59:25Z","timestamp":1674478765000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Nanovaccines Displaying the Influenza Virus Hemagglutinin in an Inverted Orientation Elicit an Enhanced Stalk\u2010Directed Antibody Response"],"prefix":"10.1002","volume":"12","author":[{"given":"Steven J.","family":"Frey","sequence":"first","affiliation":[{"name":"School of Chemical &amp; Biomolecular Engineering Georgia Institute of Technology  Atlanta GA 30332 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Manuel","family":"Carre\u00f1o","sequence":"additional","affiliation":[{"name":"Department of Microbiology Icahn School of Medicine at Mount Sinai  New York NY 10029 USA"},{"name":"Center for Vaccine Research and Pandemic Preparedness (C\u2010VaRPP) Icahn School of Medicine at Mount Sinai  New York NY 10029 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominika","family":"Bielak","sequence":"additional","affiliation":[{"name":"Department of Microbiology Icahn School of Medicine at Mount Sinai  New York NY 10029 USA"},{"name":"Center for Vaccine Research and Pandemic Preparedness (C\u2010VaRPP) Icahn School of Medicine at Mount Sinai  New York NY 10029 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ammar","family":"Arsiwala","sequence":"additional","affiliation":[{"name":"School of Chemical &amp; Biomolecular Engineering Georgia Institute of Technology  Atlanta GA 30332 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara G.","family":"Altomare","sequence":"additional","affiliation":[{"name":"Department of Microbiology Icahn School of Medicine at Mount Sinai  New York NY 10029 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad","family":"Varner","sequence":"additional","affiliation":[{"name":"School of Chemical &amp; Biomolecular Engineering Georgia Institute of Technology  Atlanta GA 30332 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Rosen\u2010Cheriyan","sequence":"additional","affiliation":[{"name":"School of Chemical &amp; Biomolecular Engineering Georgia Institute of Technology  Atlanta GA 30332 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goran","family":"Bajic","sequence":"additional","affiliation":[{"name":"Department of Microbiology Icahn School of Medicine at Mount Sinai  New York NY 10029 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Krammer","sequence":"additional","affiliation":[{"name":"Department of Microbiology Icahn School of Medicine at Mount Sinai  New York NY 10029 USA"},{"name":"Center for Vaccine Research and Pandemic Preparedness (C\u2010VaRPP) Icahn School of Medicine at Mount Sinai  New York NY 10029 USA"},{"name":"Department of Pathology Molecular and Cell Based Medicine Icahn School of Medicine at Mount Sinai  New York NY 10029 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3084-4098","authenticated-orcid":false,"given":"Ravi S.","family":"Kane","sequence":"additional","affiliation":[{"name":"School of Chemical &amp; Biomolecular Engineering Georgia Institute of Technology  Atlanta GA 30332 USA"},{"name":"Wallace H. 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