title: Inhibition of STAT6 during vaccination with formalin-inactivated RSV prevents induction of Th2-cell-biased airway disease.
abstract: 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.
authors.affiliation: Research Institute of the McGill University Health Centre, Montreal General Hospital, Montreal, QC, Canada.
authors.forename: Bharat T
authors.initials: BT
authors.lastname: Srinivasa
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Fixman
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Ward
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D004804:Eosinophils / Q000276:immunology; D005557:Formaldehyde; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008168:Lung / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000517:prevention & control*; D022261:Respiratory Syncytial Virus Vaccines / Q000276:immunology / Q000494:pharmacology*; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D015164:Vaccines, Inactivated / Q000276:immunology / Q000494:pharmacology
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; D022261:Respiratory Syncytial Virus Vaccines; D050800:STAT6 Transcription Factor; D015164:Vaccines, Inactivated; D005557:Formaldehyde; D007371:Interferon-gamma
keywords: Formalin-inactivated RSV vaccine; Respiratory syncytial virus; STAT6; STAT6-inhibitory peptide; Vaccine-enhanced disease