REVERSE · Reversing vaccine hypo-responsiveness

Prevention of infectious diseases through vaccination is one of the greatest achievements of medicine, yet there is growing realisation that vaccine immunogenicity and efficacy varies greatly across populations in high- versus low/middle- income countries (LMIC) and in urban- versus rural areas within one country. For example, whereas vaccination of volunteers in Europe with attenuated malaria vaccine can result in 100% protection, the efficacy drops to only 29% when tested in Africa, where it is needed most. Other vaccines, such as rotavirus, BCG, yellow fever and Ebola show similar trends in either immunogenicity or efficacy. It is my ambition to take on the challenge of understanding the mechanisms underlying vaccine hypo-responsiveness across populations and find ways to REVERSE it.I hypothesize that the variation in the immunological network, shaped by exposure to microorganisms and parasites, as well as by cellular metabolic state of populations residing in distinct environmental conditions, underlies vaccine hypo-responsiveness and can be REVERSEd by immunological and metabolic interventions. To address this, I will compare unique cohorts from LMIC and Europe, using single cell technologies to understand the immunological and metabolic networks that govern innate and adaptive immune responses. Not only blood but also secondary lymphoid organs will be studied to gain critical information on key cell-cell interactions within germinal centers, and how they are influenced by cells beyond B and T cells, discovering key pathways underlying hypo-responsiveness. I will take advantage of increasing availability of clinically approved modulatory compounds to target these pathways to improve vaccine responses in our in vitro models. I will also perform a proof of concept clinical trial to establish a pipeline for translating the fundamental insights gained, to human testing, and pave the way to new horizons for vaccines to show their full potential worldwide.