RSV vaccine-enhanced disease

Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in children worldwide. About one-third of children infected by RSV will experience bronchiolitis or pneumonia and 0.5%-2% will require hospitalization. Currently there is no licensed RSV vaccine due to difficulties in creating a vaccine that is immunogenic, low pathogenicity, and does not induce vaccine-enhanced disease following RSV infection. Formalin-inactivated RSV (FI-RSV) was administered during a vaccine trial in the early 1960’s. Upon natural RSV infection, the majority of the children that received the FI-RSV vaccine experienced increased morbidity and mortality. Histological analysis of lung tissue revealed pulmonary eosinophilia, neutrophilia, and monocytic infiltrate. The Th2-mediated pulmonary eosinophilia has long been thought to be the major contributor to vaccine-enhanced disease.

Mice immunized with FI-RSV reveal cellular infiltrate and enhanced disease following RSV infection, mimicking the response observed in the FI-RSV vaccinated children. As noted before, vaccine-enhanced disease is generally thought to be attributed to the increased pulmonary eosinophilia. However, RSV challenge of FI-RSV vaccinated mice deficient in eosinophils (dblGATA-1 KO), reveals no difference in disease (i.e. increased weight loss and decreased lung function) compared to WT controls. This suggests that eosinophils are not necessary for vaccine-enhanced disease. Interestingly, antibody-mediated depletion of CD4 T cells prior to RSV challenge results in ablation of vaccine-enhanced disease symptoms. The mechanism(s) that mediate vaccine-enhanced disease remain unclear. Therefore, our laboratory plans to investigate how and by what mechanisms the CD4 T cell response mediates vaccine-enhanced disease.

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