In 1967, the formalin-inactivated vaccine against respiratory syncytial virus (RSV) primed infants and children to develop an enhanced form of lower respiratory tract disease upon exposure to RSV in the community. Thirty-seven years later, the mechanism of illness of this enhanced disease remains unclear. Furthermore, why inactivated vaccines against this virus elicit non-protective antibody is not understood. No vaccine against RSV has been licensed since. We use a novel mouse model of enhanced disease to address these questions. We hypothesize that affinity maturation of RSV-specific B cells is required for development of a protective antibody response against RSV. We further hypothesize that immunization of RSV- naive mice with nonreplicating RSV vaccines activates B cells that do not undergo affinity maturation and therefore elicits a non-protective RSV-specific antibody response. This non-protective response results in immune complex formation and deposition in the lungs and enhanced disease. We propose the following Specific Aims: 1) Determine whether the method of RSV inactivation is important for vaccine-enhanced disease. 2) Determine the role of RSV F and G protective antigens in vaccine-enhanced disease. 3) Determine whether vaccine-enhanced disease is associated with the lack of affinity maturation of the B cell response to FIRSV, and therefore can be prevented by promoting affinity maturation of the B cell response to FIRSV.
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