The Impact of Systemic Immunosuppression on RSV Antibody Generation and Effector Functions After Vaccination

PROJECT SUMMARY Immunosuppressed persons (ISPs) have a nearly 40% risk of hospitalization if infected with respiratory syncytial virus (RSV). Recently, novel RSV vaccines based on the prefusion F protein of the virus were found to be effective at reducing RSV disease, but these were not tested in high-risk ISPs. Owing to immunosuppression, ISPs often develop attenuated antibody responses to vaccines and require either additional doses or different formulations to achieve protective levels of antibodies. Antibodies against prefusion F are associated with protection from RSV disease and thought to be central to the protection afforded by RSV vaccines. Our preliminary data indicate that, among ISPs, the antibody response to RSV vaccines is heterogeneous, with many ISPs demonstrating minimal or no response. However, the nature of this decreased response (i.e. unrecognized antibody epitopes and impact on neutralizing and non-neutralizing functions) remains unknown. Furthermore, the influence of specific immunosuppressive medications and the type of vaccine received (adjuvanted vs. unadjuvanted) is undetermined. To protect this high-risk group from this common and often devastating infection, a comprehensive understanding of the antibody response to these vaccines by ISPs is necessary and will improve vaccine recommendations, design, and medication management. The proposed research will address these uncertainties by systematically studying the antibody response to novel RSV vaccines in a national observational cohort of ISPs, comparing the responses to those of healthy participants (HPs). This national cohort of highly engaged ISPs was critical in our previous successful efforts to define the effects of immunosuppression on SARS-CoV-2 vaccination, and we will leverage this opportunity to discern the impact of immunosuppression on antibody responses to RSV vaccines. We will accomplish this by quantifying the prefusion F and neutralizing antibody response longitudinally in these groups and determining the impact of vaccine type (adjuvanted vs. unadjuvanted), type of immunosuppressive medication, and demographic factors (Aim 1). Additionally, we will study the entire viral antibody epitope landscape before and after vaccination using innovative DNA barcoded-protein technology to identify key gaps in epitope recognition, measure the impact of pre-existing immunity on vaccine responses, and correlate specific epitope responses with antibody function (Aim 2). Finally, the researchers will measure the effect of immunosuppression and vaccine adjuvant on antibody subtype, subclass, and non-neutralizing functions using a systems serology approach (Aim 3). The investigators' established productive collaborative relationships, extensive experience studying antibody responses in high-risk and/or immunosuppressed populations, and this cohort of ISPs provide the ideal circumstances to provide critical knowledge that promises to be directly applicable to improving RSV vaccine responses in this high-risk group and inform future vaccine design for immunosuppressed persons.