Globally, respiratory syncytial virus (RSV) is the major respiratory viral pathogen of infants and young children. RSV infection in children under 5 years results in 33.1 million cases of lower respiratory tract infections, 2.5-4.1 million hospitalizations, and approximately 60,000-200,000 deaths per year. RSV also contributes significantly to illness and death in the immunocompromised, those with co-morbidities and the elderly. Until recently, there were no approved vaccines or anti-viral drugs for RSV. However, in 2023, FDA approved a maternal RSVpreF vaccine, and a long-acting monoclonal antibody called nirsevimab to protect infants against severe RSV infection. Additionally, three RSVpreF vaccines were approved for the prevention of severe RSV infection in older adults. Furthermore, during the COVID-19 pandemic, there was a total absence of RSV circulation, followed by re-emergence that was out-of-season, and caused significantly higher number of cases and hospitalizations. The introduction of vaccines and monoclonal antibodies along with the altered epidemiology of RSV are likely to impact the molecular evolutionary trajectory of RSV. Therefore, it is vital to monitor the molecular evolutionary trajectory of RSV and define critical regulators that influence susceptibility to infection, disease severity and response to interventions in physiologically relevant organoid models.
In the RSV component of GCID we will:
Aim1:
Determine the geo-temporal genomic changes in RSV and elucidate the contributions of the microbiome, virome, and host transcriptome on the severity of RSV infections in children.
Aim 2:
Cultivate RSV isolates in pediatric nasal organoids from healthy and diseased states and determine virus strain- and host-specific differences in susceptibility and transcriptional responses.
Impact of our studies:
- We will generate full-length RSV genome collections from children across the US from seven sites of New Vaccine Surveillance Network representing 7 major metropolitan cities.
- We will analyze for genomic changes at major temporal events: pre-pandemic, pandemic, post-pandemic, and with the introduction of therapeutic interventions.
- We will determine how microbiome, host transcriptome, and viral transcriptome interact to affect viral evolution and disease severity in children.
- We will investigate the pathogenesis of viral variants in physiologically relevant pediatric human nose organoids (HNOs) from both healthy and diseased states in order to define viral fitness, identify host mediators of susceptibility and discover diagnostic biomarkers of mucosal disease.