Journal of virology 2017 07 26() pii 10.1128/JVI.00560-17
Human respiratory syncytial virus (RSV) is the leading cause of pediatric bronchiolitis and hospitalizations. RSV can also cause severe complications in elderly and immunocompromised individuals. There is no licensed vaccine. We previously generated a PIV5-vectored vaccine candidate expressing the RSV fusion protein (F) that was immunogenic and protective in mice. In this work, our goal was to improve the original vaccine candidate by modifying the PIV5 vector or by modifying the RSV-F antigen. We previously demonstrated that inserting a foreign gene at the PIV5 SH-HN junction or deleting PIV5 SH increased vaccine efficacy. Additionally, other groups have demonstrated that antibodies against the pre-fusion conformation of the RSV-F have more potent neutralizing activity than antibodies against the post-fusion conformation. Therefore, to improve on our previously developed vaccine candidate, we inserted RSV-F at the PIV5 SH-HN gene junction or used RSV-F to replace PIV5 SH. We also engineered PIV5 to express a pre-fusion stabilized F mutant. The candidates were tested in BALB/c mice via the intranasal route and induced both humoral and cell-mediated immunity. They also protected against RSV infection in the mouse lung. When administered intranasally or subcutaneously in cotton rats, the candidates were highly immunogenic and reduced RSV loads in both the upper and lower respiratory tracts. PIV5-RSV-F was equally protective when administered intranasally or subcutaneously. In all cases, the pre-fusion F mutant did not induce higher neutralizing antibody titers than wild-type F. These results show that antibodies against both pre- and post-fusion F are important for neutralizing RSV, and should be considered when designing a vectored RSV vaccine. The findings also that indicate PIV5-RSV-F may be administered subcutaneously, which is the preferred route for vaccinating infants who may develop nasal congestion as a result of intranasal vaccination.IMPORTANCE Despite decades of research, human respiratory syncytial virus (RSV) is still a major health concern for which there is no vaccine. A parainfluenza virus 5-vectored vaccine expressing the native RSV fusion protein (RSV-F) has previously been shown to confer robust immunity against RSV infection in mice, cotton rats, and nonhuman primates. To improve our previous vaccine candidate, we have developed four new candidates that incorporate modifications to the PIV5 backbone, replace native RSV-F with a pre-fusion stabilized RSV-F mutant, or combine both RSV-F and PIV5 backbone modifications. In this work, we characterize the new vaccine candidates and test their efficacies in both murine and cotton rat models of RSV infection. Most importantly, we have found that PIV5-based RSV vaccine candidates were efficacious in preventing lower respiratory infection as well as in reducing nasal viral load when administrated via the subcutaneous route.