RSV-INDUCED PATTERNS OF CYTOKINE EXPRESSION AND DISEASE

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Respiratory syncytial virus (RSV) is an important cause of respiratory disease that has received high priority for vaccine development. Previous vaccine candidates have failed in clinical trials, and formalin- inactivated alum-precipitated whole virus preparation was associated with vaccine-enhanced illness. RSV subunit vaccines are in preclinical development and early phase I trials in RSV-seropositive infants have begun. We have described a BALB/c mouse model for the study of RSV immunopathogenesis, and have recently obtained evidence that priming with inactivated RSV antigen induces a type 2T helper lymphocyte (Th2) pattern of cytokine mRNA expression (dominant IL-4 expression), whereas priming with live RSV induces a Th1-like response (dominant IFN-gamma expression) in mice following RSV challenge. Finding that initial antigen priming can result in selective induction of immune responses following subsequent nasal challenge, suggests a new and testable hypothesis for the pathogenesis of RSV-vaccine enhance illness. There is evidence in other animal model systems that selective activation of Th subsets can be induced by immunization or infection and can influence disease outcome. It has recently been shown that Th immunization or infection and can influence disease outcome. It has recently been shown that Th lymphocyte subpopulations with distinct patterns of cytokine secretion can also be found in man. We therefore propose to utilize the mouse model of RSV to determine the mechanism by which immunization selectively activate T cell populations and patterns of cytokine expression. We will identify the phenotype of cells that produce the cytokine mRNA in lung. We will also define the correlation between formulation, route, dose, and timing of priming immunization and the pattern of cytokine mRNA expression in lung and expression of disease. This work will add to our general understanding of the immunologic determinants of RSV vaccine- enhanced disease can be identified will advance vaccine development for RSV and other surface-restricted viruses.