Enhancing protective immunity against RSV by inhibitors of sphingolipid synthesis

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PROJECT SUMMARY Infections with respiratory syncytial virus (RSV) are a considerable global health threat with high morbidity and mortality in populations at risk, especially young children. Despite decades of intense efforts, a safe and effective vaccine against RSV is not available. The development of an active immunization strategy has been hampered by the risk for severe lung disease. Severe RSV lung disease first occurred in small children who had been vaccinated with a formalin- inactivated vaccine upon infection with RSV. Lessons learned from studying severe RSV disease, and responses to RSV antigens point to the need for a successful vaccine to induce robust Th1-biased immune response and potent neutralizing antibodies. We found that simultaneous inhibition of sphingolipid de novo synthesis and mucosal administration RSV induces a robust, Th1 biased and protective immune responses. We hypothesize that inhibitors of serine-palmitoyl CoA transferase (SPT), the rate-limiting step of sphingolipid synthesis, can function as potent adjuvants to enhance and favorably shape the immunogenicity of an RSV vaccine. Further, the mechanism of this novel adjuvant strategy might differ substantially from the pro-inflammatory and TLR-activating properties of other adjuvants. The aims of this exploratory proposal are two-fold: First, to confirm the adjuvant effect of SPT-inhibitors for a variety or biological relevant variables and targets for a RSV vaccine, most importantly the capacity to enhance Th1 immunity and to lower the risk for vaccine-enhanced disease. Second, to elucidate the innate immune mechanisms that trigger the increased adaptive immune responses. Given the early stage of this project, we will focus mostly on lung dendritic cells and potential alterations in immune cell trafficking induced by changes in pulmonary mucosal sphingolipid synthesis. These results could then inform further detailed immune characterization of other potentially affected cells, such as T follicular helper and regulatory cells and further development of SPT-inhibitors as potential adjuvants for vaccines against other respiratory pathogens.