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U.S.A."],"published-print":{"date-parts":[[2024,11,19]]},"abstract":"<jats:p>Mumps virus (MuV) is a highly contagious paramyxovirus that is endemic in most regions of the world and continues to cause outbreaks even in highly immunized populations. Outbreaks of mumps in countries with high measles, mumps, and rubella vaccination coverage have been attributed to waning immunity and antigenic differences between the Jeryl Lynn vaccine strain (genotype A) and circulating wild-type viruses. To obtain a subunit vaccine, we used structure-based design to engineer the mumps fusion (F) glycoprotein stabilized in its prefusion conformation (Pre-F) as well as a chimeric immunogen comprising Pre-F linked to mumps hemagglutinin neuraminidase (HN); in mice, both Pre-F antigen and the chimeric antigen elicited potent cross-reactive plaque reducing neutralizing titers to genotypes A, G, and H mumps. A crystal structure of mumps Pre-F at 2.16 \u00c5 resolution validated the stabilization strategy, while a post-fusion form of F was engineered as a comparator. Monoclonal antibodies to mumps Pre-F and HN were isolated from immunized mice; 7 of 14 Pre-F-specific antibodies and 9 of 15 HN-specific antibodies were capable of neutralizing genotype G MuV with a range of potencies. Additionally, 7 of 14 Pre-F-specific antibodies neutralized genotype A mumps. Structural and binding analyses of Pre-F-specific antibodies revealed binding to four discrete neutralizing antigenic sites and binding analyses of HN-specific antibodies revealed binding to five discrete neutralizing antigenic sites. Overall, the PreF and the chimeric Pre-F\/HN immunogens are promising candidates to boost MMR-elicited immunity to mumps or as a next-generation vaccine.<\/jats:p>","DOI":"10.1073\/pnas.2404053121","type":"journal-article","created":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T15:03:13Z","timestamp":1731337393000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":12,"title":["Structure-based design of glycoprotein subunit vaccines for mumps"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5578-4728","authenticated-orcid":false,"given":"Rebecca J.","family":"Loomis","sequence":"first","affiliation":[{"name":"Vaccine Research Center, NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Ting","family":"Lai","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5525-5252","authenticated-orcid":false,"given":"Sun B.","family":"Sowers","sequence":"additional","affiliation":[{"name":"Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Fisher","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1957-3268","authenticated-orcid":false,"given":"Alexandrine","family":"Derrien-Colemyn","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1038-7328","authenticated-orcid":false,"given":"David R.","family":"Ambrozak","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaroslav","family":"Tsybovsky","sequence":"additional","affiliation":[{"name":"Electron Microscopy Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD 21701"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen N.","family":"Crooke","sequence":"additional","affiliation":[{"name":"Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0324-6916","authenticated-orcid":false,"given":"Donald R.","family":"Latner","sequence":"additional","affiliation":[{"name":"Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8544-6447","authenticated-orcid":false,"given":"Wing-Pui","family":"Kong","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0007-7169","authenticated-orcid":false,"given":"Tracy J.","family":"Ruckwardt","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4950-7016","authenticated-orcid":false,"given":"Stanley A.","family":"Plotkin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pennsylvania, Doylestown, PA 18902"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter D.","family":"Kwong","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Mascola","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8112-0853","authenticated-orcid":false,"given":"Barney S.","family":"Graham","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4047-8151","authenticated-orcid":false,"given":"Carole J.","family":"Hickman","sequence":"additional","affiliation":[{"name":"Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume B. 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