Rotavirus is the leading cause of severe gastroenteritis in young children worldwide. A vaccine to prevent a rotavirus infection would prevent over 500,000 deaths/year in developing countries and save the United States over $1 billion a year in health care costs, but recently, the only licensed vaccine was withdrawn due to associated side effects. Protection from rotavirus infection and resulting disease is dependent on the initiation and maintenance of an immunological response. The goal of this application is to understand and compare the difference in protective immunological responses induced by a live rotavirus infection and by a non-replicating subunit vaccine (VLPs). The immunological response to both live rotavirus infection and a VLP vaccine will be differentiated by many factors including the time of response, the type of cells that control the response, and establishment of immunological memory. In mice, rotavirus infection and VLP vaccination can induce sterilizing immunity. The exact mechanisms through which rotavirus and VLPs induce sterilizing immunity in the mouse have not been elicited. I hypothesize that (i) clearance of and sterilizing immunity established by a primary rotavirus infection occurs predominately as a result of T cell independent B lymphocyte activation, and (ii) VLP vaccination will cause sterilizing immunity through T cell dependent B lymphocyte activation. To test this hypothesis, flow cytometry will be used to identify, quantitate, and functionally characterize activated lymphocyte subsets during clearance of a primary rotavirus infection, after vaccination with VLPs, and after a rotavirus challenge of previously infected or VLP vaccinated mice. These will be the first studies to systematically identify and compare subsets of activated lymphocytes between a live infected and VLP vaccinated animal and correlating these responses with protection from infection. Understanding the mechanisms of how rotavirus and vaccination with VLPs activate the immune system to induce sterilizing immunity will aid in better vaccine design and may identify benchmarks for testing potential vaccine effectiveness in humans.
