Inhibition of STAT6 during vaccination with formalin‐inactivated RSV prevents induction of Th2‐cell‐biased airway disease

The pattern of immune response to a vaccine antigen can influence both efficacy and adverse events. Th2‐cell‐deviated responses have been implicated in both human and murine susceptibility to enhanced disease following formalin‐inactivated (FI) vaccines for measles and RSV. In this study, we used the Th2‐cell‐deviated murine model of FI‐RSV vaccination to test the ability of a dominant negative, cell‐penetrating peptide inhibitor of STAT6 (STAT6 inhibitory peptide (IP)) to modulate the vaccine‐induced predisposition to exaggerated inflammation during later RSV infection. Intranasal delivery of STAT6‐IP in BALB/c mice at the time of distal intramuscular FI‐RSV vaccination (Early Intervention) markedly decreased vaccine‐enhanced, Th2‐cell‐dependent pathology upon subsequent RSV challenge. Administration of the STAT6‐IP at the time of RSV challenge (Late Intervention) had no effect. Following RSV challenge, the STAT6‐IP‐treated mice in the Early Intervention group had lower airway eosinophils, increased lung IFN‐γ levels, as well as increased IFN‐γ‐secreting CD4+ and CD8+ cells in the lungs. Our findings demonstrate the feasibility of targeting intracellular signaling pathways as a new way to modulate vaccine‐induced responses.