A Systems Analysis Approach to Define the Protective Host Immune Responses of Children with Mild Respiratory Syncytial Virus Infection

Almost all children are infected with RSV by 2 yrs of age, yet <3% are hospitalized. The immune response of children with mild RSV infection who do not develop severe disease is not fully understood. Characterization of such response may have implications for vaccine development. We sought to define the transcriptomic and cellular immune profiles associated with mild RSV disease in children. We enrolled 190 previously healthy children <2 yrs of age: 125 with RSV infection treated as outpatients (OP; mild disease; n = 41) or inpatients (IP; severe disease; n = 84), and age-matched healthy controls (HC; n = 65). Nasopharyngeal RSV loads, blood RNA transcriptome and WBC immunophenotyping were analyzed according to disease severity. OP were older (7.6 m) than IP (2.6 m; P < 0.01). Median duration of symptoms at enrollment in both groups was 4 days, yet RSV loads were higher in OP vs. IP (5.5 log10 and 4.9 log10 copies/mL respectively; P = 0.05). To control for differences in age, transcriptional signatures were derived in an age-matched discovery cohort (OP n = 24; IP n = 24; HC n = 24) and subsequently validated in an independent validation cohort (n = 55). Compared with IP, the OP signature was characterized by greater activation of interferon (IFN) and plasma cell genes, less suppression of T-cell, and cytotoxic/NK cell genes and less activation of inflammation and neutrophil genes (P < 0.01; Fig 1). Overall, plasma cell genes positively correlated with number of plasmablasts, plasma cells, and T follicular helper cells (r=0.6; P < .01), while IFN gene expression inversely correlated with T-cells, DC and B cells numbers (r=-0.4 P < .05). Neutrophil numbers correlated with neutrophil (r=0.5; P < =.02) and inflammation gene expression (r=0.8; P < 0.001). Last, monocyte numbers were higher in IP and OP vs. HC (P < 0.01) however; HLA-DR low monocytes were increased only in IP. Children with mild disease demonstrated a distinct cellular and transcriptional immune response to RSV. Despite that RSV loads were higher in these children, IFN expression and monocyte activation were increased and T and NK cell genes less suppressed, suggesting that robust immune responses are associated with improved clinical outcomes in children with RSV infection. O. Ramilo, Abbvie: Board Member, Consulting fee; Regeneron: Board Member, Consulting fee; Janssen: Board Member and Investigator, Consulting fee and Research grant; NIH: Grant Investigator, Research grant; A. Mejias, Janssen: Investigator and Scientific Advisor, Consulting fee and Research support; Abbvie: Consultant and Scientific Advisor, Speaker honorarium; Novartis: CME lecture, Speaker honorarium; NIH: Investigator, Research grant