Immunopathogenesis of vaccine-enhanced RSV disease

Abstract

Inducing a strong immune response is an essential aim of vaccination. Although immune responses to virus infections are usually protective, they can also be harmful. The best-documented examples of an immune response increasing disease severity are with dengue, measles and respiratory syncytial virus infections. In the 1960s, administration of formalin-inactivated, tissue culture grown RSV (FI-RSV) was found to induce strong ELISA binding but poor virus-neutralising antibody. Infants given this ‘lot 100’ vaccine appeared to exhibit an increased rate of RSV infection during subsequent natural RSV outbreaks. Although it has not been possible to exactly delineate the cause of disease enhancement in man, animal models strongly suggest that it was due to strong (and perhaps unbalanced) T cell priming rather than infection-enhancing or sensitising antibody. In animal models, enhanced disease can result from over-exuberant T cell priming which recruits an abundant inflammatory infiltrate in the lung (the nature of which depends on the patterns of cytokines and chemokines produced). Formalin-treated RSV vaccination has been linked specifically to the induction of Th2 cells, which make IL-4 and IL-5 and induce a strong pulmonary eosinophilic response. The vaccine dosing regime and the interval between vaccination and challenge can be critical to the induction of protection or pathology. Defining the correlates of protection and disease enhancement in man is critical to the rational development of effective and protective vaccines against RSV.