SPARCL · Dissecting early Skin-based immune responses to PARasites in ControLled human infection studies to design novel vaccines

Parasitic diseases cause considerable morbidity and mortality in poverty-stricken areas, affecting hundreds of millions of lives globally. Vaccines are urgently needed to alleviate disease and lift the economic consequences. Plasmodium falciparum malaria, Schistosoma mansoni and Necator americanus hookworms are together responsible for the greatest burden of disease. Vaccination with attenuated parasites is an efficacious strategy in inducing immunity to parasites in animal models. Recently, we have translated attenuated parasite vaccination to humans in proof-of-concept clinical trials in which we protected subsets of individuals from challenge. This unique preliminary data indicates a role for the skin as a prime immunological organ. Based on these findings, I propose to create a next generation highly immunogenic, adjuvanted whole parasite vaccines, ready for pre-clinical testing. We will build on our previous experience with chemical tools to load whole parasites with adjuvants. To measure the potency of the new vaccines, we aim to measure early skin-based humoral and cellular immune markers which correlate with protection in our samples from prior and novel controlled human infection models. We will assess the functionality of antibodies by adapting our current molecular imaging tools to quantitatively analyze movement kinematics of parasites in representative 3D environments resembling the human skin. Cellular correlates of protection in skin will be mapped using imaging mass cytometry on freshly obtained skin biopsies from experimentally infected volunteers. Through combined, parallel analysis of circulating immune markers by high-dimensional flow cytometry, we aim to take a comprehensive approach including local and circulating markers to identify protective immune responses. This high-risk high-gain proposal is aimed to break the impasse in the field of parasite vaccine development and open a novel out-of-the-box avenue to fill the vaccine pipeline.