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As a result, vaccine efficacy can vary widely from one year to the next, and the wild-type antigens in the seasonal vaccine need to be updated frequently to stay current with the ever-changing viral landscape. To address this, 5 computationally optimized broadly reactive antigens (COBRAs) were designed from influenza A(H3N2) viruses that circulated during 2018 to 2022. These novel vaccine antigens incorporate important immunological epitopes from recently circulating viruses into one vaccine antigen providing the immune system with a variety of targets to elicit protective immune responses against. These computationally optimized H3 hemagglutinin vaccine antigens were first tested in immunologically na\u00efve mice, in which they elicited antibodies with protective hemagglutination inhibition titers and neutralization activity against A(H3N2) vaccine strains from the last decade. Immune responses elicited by these vaccines were further enhanced in cohorts of mice and ferrets that were previously exposed to historical seasonal influenza viruses. In these animals, the COBRA HA antigens recalled epitopes recognized by influenza hemagglutinin\u2013specific memory cells leading to stronger humoral immune responses. Incorporating these antigens into seasonal vaccines could improve protective efficacy in vaccinated individuals and reduce the need to reformulate vaccines annually.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf092","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T23:56:36Z","timestamp":1747871796000},"page":"1698-1713","source":"Crossref","is-referenced-by-count":8,"title":["H3 hemagglutinin proteins optimized for 2018 to 2022 elicit neutralizing antibodies across panels of modern influenza A(H3N2) viruses"],"prefix":"10.1093","volume":"214","author":[{"given":"James D","family":"Allen","sequence":"first","affiliation":[{"name":"Florida Research and Innovation Center, Cleveland Clinic , Port Saint Lucie, FL,","place":["United States"]},{"name":"Department of Infection Biology, Lerner Research Institute, Cleveland Clinic , Cleveland, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica M","family":"Medina","sequence":"additional","affiliation":[{"name":"Florida Research and Innovation Center, Cleveland Clinic , Port Saint Lucie, FL,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew H","family":"Thomas","sequence":"additional","affiliation":[{"name":"Florida Research and Innovation Center, Cleveland Clinic , Port Saint Lucie, FL,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Lynch","sequence":"additional","affiliation":[{"name":"Florida Research and Innovation Center, Cleveland Clinic , Port Saint Lucie, FL,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron","family":"Nelson","sequence":"additional","affiliation":[{"name":"Florida Research and Innovation Center, Cleveland Clinic , Port Saint Lucie, FL,","place":["United 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