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.