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To combat these ACE2\u2010utilizing merbecoviruses, we developed virus\u2010like particle (VLP) vaccines displaying their receptor\u2010binding domain and subdomain 1 (RBD\u2010SD1) antigens fused to SpyTags. These antigens were then conjugated to SpyCatcher\u2010mi3 nanoparticles. Immunization of mice with each RBD\u2010SD1\u2010mi3 vaccine produced robust IgG responses against homologous antigens and measurable but reduced binding to heterologous RBD\u2010SD1 proteins. Antigenic cartography showed that antigenic relationships broadly reflected sequence identity with HKU5 positioned between NeoCoV and HKU5\u2010CoV\u20102. Despite HKU5 and HKU5\u2010CoV\u20102 sharing the greatest genetic similarity, cross\u2010reactive titers between these two groups were not substantially higher than those observed with NeoCoV. In a surrogate virus neutralization test (sVNT), sera from mice vaccinated with NeoCoV RBD\u2010SD1\u2010mi3 or HKU5\u2010CoV\u20102 RBD\u2010SD1\u2010mi3 showed strong inhibition of receptor binding by their respective Fc\u2010fused RBD\u2010SD1 proteins. Sera from mice vaccinated with HKU5 RBD\u2010SD1\u2010mi3 exhibited some cross\u2010inhibition activity against both NeoCoV and HKU5\u2010CoV\u20102 Fc\u2010fused RBD\u2010SD1. Together, these findings show that the RBD\u2010SD1\u2010displaying nanoparticle vaccine can elicit cross\u2010reactive antibodies against ACE2\u2010binding merbecoviruses and that antigenic relationships are shaped by more than sequence similarity.<\/jats:p>","DOI":"10.1002\/bit.70356","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:34:32Z","timestamp":1787164472000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Characterization of Immune Responses to RBD\u2010SD1 Nanoparticle Vaccines Derived From ACE2\u2010Capable HKU5\u2010CoV\u20102, NeoCoV, and HKU5 Merbecoviruses"],"prefix":"10.1002","author":[{"given":"Peter J.","family":"Halfmann","sequence":"first","affiliation":[{"name":"Department of Pathobiological Sciences, School of Veterinary Medicine, Influenza Research Institute University of Wisconsin Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Soo","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Chemical &amp; Biomolecular Engineering Georgia Institute of Technology Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Augustine","family":"Duffy","sequence":"additional","affiliation":[{"name":"School of Chemical &amp; Biomolecular Engineering Georgia Institute of Technology Atlanta Georgia USA"},{"name":"Parker H. 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