Determining the role of TH1 cells in mediating RSV vaccine-enhanced disease
RSV is the leading cause of lower respiratory tract infection and hospitalization in young children under 5 years old, and accounts for an estimated 100,000 hospitalizations and 1,000 deaths per year in the U.S. alone. In the 1960’s, a series of RSV vaccine trials were conducted using formalin-inactivated RSV. Vaccinated children experienced high morbidity and mortality following natural RSV infection, and histological analysis of lung tissue displayed pulmonary eosinophilia. This TH2-induced pulmonary eosinophilia is generally thought to be the major contributor to the vaccine-enhanced disease seen in these vaccinated children.
Our laboratory mimics the vaccine-enhanced disease observed in the children from the 1960’s vaccine trial by priming mice with a recombinant vaccinia virus (vacv), which expresses the RSV attachment protein (G). Following RSV infection, vacvG primed mice display increased weight loss, decreased lung function and pulmonary eosinophilia. As noted before, vaccine-enhanced disease is generally thought to be attributed to the TH2-induced pulmonary eosinophilia. However, priming of mice using a recombinant vacv expressing the RSV fusion (F) protein induces a strong TH1 response after challenge with RSV, and no TH2 response. These mice exhibit no pulmonary eosinophilia, but still display vaccine-enhanced disease (i.e. increased weight loss and decreased lung function), thus suggesting that vaccine-enhanced disease does not absolutely require a TH2 response. Further supporting this hypothesis, our laboratory has shown that STAT6 KO mice, which display diminished TH2 responses, do not develop pulmonary eosinophilia, but still exhibit vaccine-enhanced disease. In contrast, STAT4 KO mice, which display diminished TH1 responses, have pulmonary eosinophilia, but fail to develop vaccine-enhanced disease. The mechanism in which TH1-mediated immune response causes vaccine-enhanced disease is unclear. Therefore, through the use of STAT4 KO mice our laboratory plans to investigate the role of RSV-specific TH1 responses in mediating the development of vaccine-enhanced disease.
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