IL-17 & neutrophils in the RSV vaccine enhanced disease

ACOSTA PL; HIJANO DR; LAWRENCE A; NEWCOMB D; PEEBLES RS; PRINCE G; POLACK FP

Bariloche

Simposio; RSV Symposium; 2016

Background: Approximately 50% of infants are infected by respiratory syncytial virus (RSV) during their first year of life. There is still no vaccine licensed against the virus. A major obstacle to vaccine development has been the enhanced respiratory disease (ERD) that affected children immunized with a formalin-inactivated vaccine against RSV (FIRSV) in the 1960s. Pathogenesis of ERD was always associated with a polarization Th-2 of the immune response. Our data suggest that ERD was due to a polarization to Th-17 instead of Th-2.Methods: FIRSV (1x105 pfu), RSV A2 (1x105 pfu) or PBS (placebo) vaccine immunizations were performed footpad. We challenged mice 60 days later with RSV A2 (1x106 pfu) IN. Histopathology, cell differentials, cytokine responses, transcription factors and airway hyperreactivity (AHR) were performed. Lung sections of toddlers who died of ERD in 1967 were stained for histopathology.Results: 1)FIRSV enhanced IL-17 production in regional lymph nodes after immunization compared to the response elicited by RSV. 2) Large number of neutrophils were found in BAL of mice vaccinated with FIRSV after RSV challenge. 3) Th-1 immune response is suppressed and Th-2 response is enhanced. 4) Th-17 immune response is enhanced in the lungs of mice with ERD. 5) ROR-γt (Th17 master transcription factor) levels are increased in the lungs of mice with ERD. 6) AHR & bronchiopneumonia are significantly decreased in mice treated with anti-IL-17 antibody. 7) AHR & bronchiopneumonia are significantly decreased in mice treated with anti-Ly66 antibody. 8) IL-17 positive cells and neutrophils are abundant in the lungs of toddlers killed by ERD in 1967.Conclusions: IL-17A and neutrophils play a key role in enhanced RSV disease.