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This report presents the first investigation of RhCMV\/SIV vaccines in RhCMV-seronegative macaques lacking anti-vector immunity. Fifty percent of rhesus macaques (RM) vaccinated with a combined RhCMV-Gag, -Env, and -Retanef (RTN) vaccine controlled pathogenic SIV challenge despite high peak viremia. However, kinetics of viral load control by vaccinated RM were considerably delayed compared to previous reports. Impact of a TLR5 agonist (flagellin; FliC) on vaccine efficacy and immunogenicity was also examined. An altered vaccine regimen containing an SIV Gag-FliC fusion antigen instead of Gag was significantly less immunogenic and resulted in reduced protection. Notably, RhCMV-Gag and RhCMV-Env vaccines elicited anti-Gag and anti-Env antibodies in RhCMV-seronegative RM, an unexpected contrast to vaccination of RhCMV-seropositive RM. These findings confirm that RhCMV-vectored SIV vaccines significantly protect against SIV pathogenesis. However, pre-existing vector immunity and a pro-inflammatory vaccine adjuvant may influence RhCMV\/SIV vaccine immunogenicity and efficacy. Future investigation of the impact of pre-existing anti-vector immune responses on protective immunity conferred by this vaccine platform is warranted.<\/jats:p>","DOI":"10.1038\/s41598-020-71075-x","type":"journal-article","created":{"date-parts":[[2020,8,20]],"date-time":"2020-08-20T10:07:20Z","timestamp":1597918040000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["RhCMV serostatus and vaccine adjuvant impact immunogenicity of RhCMV\/SIV vaccines"],"prefix":"10.1038","volume":"10","author":[{"given":"W. L. 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The potential individual and institutional conflicts of interest have been reviewed and managed by University of California Davis. Authors J.D.D., H.T.K., L.D.C., K.M., X.S., G.D.T., and B.L.S. declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"14056"}}