Real-World Effectiveness of Perinatal RSV Immunoprophylaxis - PROJECT SUMMARY Respiratory syncytial virus (RSV) is a significant source of morbidity and mortality in the pediatric population. It is estimated that every year, over 100,000 children under 5 years of age die from RSV, half of whom are infants <6 months of age. The burden that RSV exerts on healthcare systems cannot be overstated. In the United States, RSV is associated with 1.5 million annual medical encounters in children less than five years and is the leading cause of hospitalization among infants under one year of age. The pending introduction of new immunoprophylactic agents offers unique opportunities to confront the challenge of RSV in infants. Two products whose approval is imminent include a vaccine that is administered to pregnant women to protect their newborns and a long-acting monoclonal antibody (mAb) that is deployed like a vaccine and routinely given to all newborns. As is the case with any new vaccine, it will be important to conduct studies during the early phases of implementing these new immunization strategies to answer many unanswered questions surrounding their risks and benefits in real-world settings. To address this critical need, we propose a large- scale case-control study that integrates data from different modalities (e.g., clinical, demographic, virologic, immunologic) to evaluate the effectiveness of perinatal RSV immunoprophylaxis. Cases and controls will be identified using active surveillance in both inpatient and outpatient clinical sites of the Yale New Haven Health System, the largest and most comprehensive healthcare system in Connecticut, with 8 large hospitals and close to 4 million outpatient encounters every year. We will enroll patients seeking health care for acute respiratory illness and confirm RSV infection using approved molecular assays. We will use data-gathering protocols that are both exhaustive and identical for both cases and controls and collect data from multiple sources, including health records, interviews, immunization registries, and population-based surveys. We will generate estimates of effectiveness for each type of immunization used, disaggregated by time from immunization, disease severity, and sociodemographic characteristics (Aim 1). We will also perform genetic characterization of all the study's RSV cases, monitor the virus's genetic diversity over time, and quantify the relative effectiveness of immunoprophylaxis against various viral lineages (Aim 2). Finally, we will collect acute and convalescent blood from a subset of infants and employ a single-cell and multi-omics approach to study the dynamics of the innate and adaptive immune responses during RSV infection and explore the molecular mechanisms that contribute to immunoprophylaxis failure (Aim 3). The results from this project will be critical as it will allow policymakers to determine whether these products are sufficiently beneficial to warrant continual inclusion in the immunization program. Further, if our results show that immunization confers considerable protection, these data can be a potent incentive to increase the strength of recommendations by healthcare providers and boost acceptance by patients.
