Structure-guided engineering to increase respiratory syncytial virus G protein immunogenicity

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PROJECT SUMMARY Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract disease in young children worldwide and is also a major cause of morbidity and some mortality in the elderly and immunocompromised. No approved RSV vaccine exists. Our goal is to utilize a structure-guided design approach to rationally engineer RSV G protein immunogens that induce robust and protective immunity against RSV. RSV G protein is one of two major immunogenic proteins on the RSV surface and has key roles in virus attachment to airway epithelial cells and virus modulation of innate immune defenses. RSV G protein is the target of neutralizing and protective antibodies. The G protein as a vaccine immunogen has been hampered by poor immunogenicity and by a paucity of structural information on its epitopes. In this proposal, we will test our central hypothesis that engineered multimeric RSV G immunogens that display protective conformational epitopes will elicit robust and protective RSV immunity. We will use an integrated approach to pursue four specific aims: (1) Use structural studies to define conserved RSV G protein epitopes recognized by protective antibodies, (2) Use structure-guided design to engineer multimeric RSV G protein immunogens, (3) Evaluate engineered RSV G protein immunogens for improved immunogenicity, and (4) Use a comprehensive immune analysis to evaluate RSV G protein CCD immunogens for balanced cytokine responses and protective antibodies made in response to vaccination. The proposed research will generate RSV G vaccine immunogens as candidates with demonstrated efficacy in preventing RSV infection and disease pathogenesis.