Immune Response and Vaccine Efficacy in a Rodent Model

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The long term objective of this research is to produce an effective vaccine against respiratory syncytial virus (RSV), human parainfluenza virus-type 1 (hPIV-1) and human parainfluenza virus-type 3 (hPIV-3). Sendai virus (mouse PIV-1) has proven effective as a vaccine for hPIV-1 in non-human primate studies, and developments in reverse genetic engineering now permit additional genes to be inserted as passengers in the Sendal virus genome. The recombinant Sendal viruses (rSV) that incorporate passenger genes for membrane proteins of other respiratory viral pathogens may thus provide protective immunity both to hPIV-1 and to the other viruses. To provide a foundation for the confident formulation of vaccines to be tested in primates and humans, this section proposes an extensive course of experimentation to establish safety and efficacy in a laboratory rodent model, the cotton rat (Sigmodon hispidus), in which human respiratory viruses grow well after intranasal inoculation. Initial Specific Aims in this project involve testing and comparing individual strains of rSV that carry genes for the attachment and fusion proteins of RSV or hPIV-3. Experiments are designed to assess the vigor of the humoral and cellular immune responses generated by rSV inoculations, and to evaluate associated protective immunity and immunopathological reactions. Our last Aim is to test increasingly complex combinations of rSV strains, with the final objective of formulating an optimized rSV cocktail that will function safely and effectively to provide protection from RSV, hPIV-1 and hPIV-3. Studies proposed in this Project (Project 2) will be highly interactive with Projects 1 and 3. Products and concepts from Project 1 will support each of the Specific Aims, which will, in turn, support the non-human primate and clinical studies in Project 3. Ultimately, we propose that the research from this interactive Program Project will yield a safe, effective and affordable respiratory virus vaccine for children.