DISCUSSION
RSV infection, RSV, RSV LRTD, RSV disease, infection, ADNKA
RSV INFECTION, INFECTION
RSV vaccine development has been hindered by an incomplete understanding of the crucial aspects of the immune response required for protection from RSV infection and the lack of a universally agreed-upon correlate of protection in the RSV-experienced population. Additionally, infection with RSV does not confer long-lasting immunity, and waning or impaired immunity with age is thought to contribute to the RSV disease burden in older adults (In this study, all active vaccination regimens that were tested, including Ad26.RSV.preF, RSV preF protein, and the Ad26.RSV.preF/RSV preF protein combination vaccine, induced robust RSV preF-specific IgG1, IgA1, Fc receptor binding, and Fc-effector function responses; IgG1, IgA1, and Fc receptor binding were maintained up to 6 months for Ad26.RSV.preF alone and the Ad26.RSV.preF/RSV preF protein combination vaccine. The Ad26.RSV.preF/RSV preF protein combination vaccine induced substantially greater IgA1, ADNP, and ADNKA responses compared with Ad26.RSV.preF alone, suggesting important contributions to these responses by RSV preF protein. Interestingly, some RSV preF-specific Fc-effector functions (i.e., ADCD, ADNP, and ADNKA) that were not substantially present at baseline, and thus not induced or retained from prior natural infection, were induced following vaccination with the Ad26.RSV.preF/RSV preF protein combination vaccine, suggesting a Importantly, robust neutralizing antibody responses and RSV-specific IgG antibody responses may be insufficient to provide complete protection from RSV infection, as evidenced by the failure of several RSV F-specific vaccine candidates, suggesting that a more polyfunctional immune response may be necessary for protection (Recent work has demonstrated a correlation between increased mucosal IgA titers and protection from RSV infection (Data from the multivariate immune profiling analysis suggest that the addition of RSV preF protein to Ad26.RSV.preF improves the overall Fc-effector function response, in terms of both magnitude and polyfunctionality. The Ad26.RSV.preF/RSV preF protein combination vaccine is differentiated from RSV preF protein alone by its more robust RSV preF-specific IgA1 and IgM responses and the One important limitation of this study was the small sample size. Because this was an exploratory analysis of vaccine-induced immune responses, large numbers of samples were not specifically reserved for this analysis, and the number of available samples was limited. Given that limitation, no analysis to determine immune correlates of protection was possible; further studies profiling vaccine-induced protective immune responses for the Ad26.RSV.preF/RSV preF protein vaccine are ongoing.Importantly, the Ad26.RSV.preF/RSV preF protein combination vaccine evaluated in this study demonstrated 80.0% vaccine efficacy for prevention of RSV LRTD in a phase 2b clinical trial among adults aged ≥65 years (These results demonstrate the breadth of the immune responses induced by the Ad26.RSV.preF/RSV preF protein vaccine.