Pre-Existing Upregulation of Interferon Pathways in the Nasopharynx Impacts Viral Shedding Following Live Attenuated Influenza Vaccine Challenge in Children

Abstract

Rationale: In children lacking adaptive immunity to influenza, upper respiratory tract innate immune responses may be important and explain variability in viral shedding and disease outcome. Objectives: We used live attenuated influenza vaccine (LAIV) as a surrogate challenge model in children to identify pre-infection mucosal transcriptomic signatures associated with subsequent viral shedding. We also determined whether asymptomatic respiratory viral infection impact these signatures. Methods: Children aged 24-59 months (n=82) were given one dose of trivalent LAIV during a prospective, observational, phase 4 study in The Gambia (NCT02972957). Nasopharyngeal swabs were used to determine gene expression and asymptomatic respiratory viral infection prior to challenge, and LAIV viral loads at day 2 and 7. Gene set enrichment analysis was used to identify transcriptomic signatures representing gene pathways and cell types at baseline associated with subsequent LAIV viral load. Main Results: In children seronegative for each influenza strain, upregulation of interferon signaling pathways prior to LAIV receipt was significantly associated with lower strain-specific viral loads at day 2 and 7. Asymptomatic respiratory viruses were detected in 42% of children. Several interferon-stimulated genes were differentially expressed in children with asymptomatic respiratory viral infection and negatively correlated with LAIV viral loads. Upregulation of genes enriched in macrophages, neutrophils and eosinophils was also associated with lower viral loads, and found more commonly in children with asymptomatic non-influenza viral infections. Conclusions: Variability in mucosal interferon gene expression prior to infection in children may impact the course of subsequent influenza infections. This variability may be due to frequent asymptomatic respiratory viral infections, demonstrating the potential importance of virus-virus interactions in the upper respiratory tract in determining the outcome of respiratory viral infections in children.