INDUCTION OF MUCOSAL IMMUNITY BY PARENTERAL INOCULATION

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As a pediatrician with a background in public health, my interest in vaccine development has been longstanding. While working in Dr. Paul Offit's laboratory at The Children's Hospital of Philadelphia, I have found the close relationship between the basic science of host-pathogen interactions and the application of newly-acquired knowledge to develop candidate vaccines to be very exciting. I am pursuing the Mentored Clinical Scientist Development Award (K08) to further my research and analytic skills in the areas of mucosal immunology and vaccinology. The PSA allows for acquisition of these skills through a program composed of coursework in immunology and virology and a progressive research program as outlined below. Parenteral immunization has for decades been used to stimulate protection from a variety of infections whose site of replication is limited solely to mucosal surfaces (e.g., influenza and pertussis). Although many recent efforts have focused on mucosal immunization to induce immunity from mucosal pathogens, the successful development of such vaccines has been slow. Additionally, several observations suggest that the development of new and the optimization of existing parenteral vaccines may have been prematurely abandoned. Intramuscular (IM) inoculation of mice with the intestinal pathogen, rotavirus, induces production of virus-specific IgA and IgG by intestinal lymphocytes. The capacity of parenteral immunization to induce a mucosal immune response obviates several issues which have impeded the development of orally-administered vaccines. These observations will be extended by addressing the following questions: 1) What are the relative capacities of oral or IM inoculation to induce virus-specific humoral and cellular immune responses among intestinal lymphocytes? To what extent is induction of these responses dependent upon the nature of the virus (e.g., infectious vs. noninfectious)? 2) What are the relative capacities of IM or oral inoculation of rotavirus to protect against rotavirus challenge? 3) By what mechanism or mechanisms does IM inoculation induce an immune response at the intestinal surface? 4) Are the viral proteins recognized by virus-specific humoral and cellular immune responses altered following IM as compared with oral inoculation?