Vaccine-enhanced respiratory syncytial virus disease

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DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is the leading cause of respiratory infections in infants and young children worldwide. In the 1960s, a formalin-inactivated RSV vaccine (FIRSV) was developed and administered to infants and children in the U.S. Subsequent exposure of vaccinated children to RSV during community outbreaks resulted in increased morbidity and mortality in vaccine recipients who contracted RSV. The mechanism of illness was never clarified and there is still no licensed vaccine against RSV. Recently, we established a mouse model of enhanced RSV disease that uses bronchoconstriction and pneumonia, characteristic and serious manifestations of RSV disease and vaccine-enhanced RSV disease in infants and children, as primary correlates of disease enhancement to compare degrees of illness elicited by typical and vaccine enhanced disease. Using this model and post-mortem lung sections from affected children we showed that deposition of immune complexes that fix complement in the lungs play a crucial role in the pathogenesis of enhanced RSV disease. However, whether development of pathologic antibodies leading to immune-complex disease is caused by formalin disruption of RSV critical protective epitopes during inactivation or promoted by an RSV-specific and problem associated with lack of affinity maturation of the B cell response to FIRSV is unknown. Furthermore, it is unclear if either or both RSV protective antigens (fusion (F) and attachment (G) proteins) can be used safely in subunit vaccines or whether disease-enhancement can be avoided using a different method of RSV inactivation or a subunit vaccine. We propose to examine vaccine-enhanced RSV disease and further develop a safe model for vaccine testing. 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.