The Mevalonate Pathway Is A Druggable Target For Vaccine Adjuvant Discovery

An adjuvant is an ingredient of a vaccine to modify the immune response by giving a higher amount of antibodies,faster responses and a longer-lasting protection.Adjuvants have proven to be a key component in modern vaccine development,especially anti-tumor vaccine.There is an urgent need for improved vaccine adjuvants for cancer immunotherapies.However,there are just five FDA-approved adjuvants:aluminum salts(‘alum'),MF-59,AS03,AS04,and Cp G.The shortage of new powerful and safe adjuvants has been an important factor restricting the development of modern vaccines.This paucity of new adjuvants arises in large part from our limited understanding of adjuvant mechanisms of action,and a consequent lack of druggable targets.The mevalonate(MEV)pathway is a core metabolic pathway which plays an important role in multiple cellular processes including cholesterol biosynthesis and protein post-translational prenylation.Mevalonate kinase(MVK),an essential enzyme in the mevalonate pathway,catalyzes the phosphorylation of mevalonate.Patients carrying loss-of-function mutations of MVK develop immune-stimulatory phenotypes,such as periodic fever,increased inflammatory cytokine production,and elevated serum immunoglobulin levels.These autoinflammatory phenotypes suggest that the mevalonate pathway regulates the inflammatory responses.In this work,we tested lipophilic statins and bisphosphonates that target three distinct MEV pathway enzymes and characterized their wide applicability and high potency as therapeutic and prophylactic vaccine adjuvants.The adjuvanticity associated with the MEV pathway inhibition covers multiple arms of immunity,including cytolytic and Th1 T cell responses,and are therefore highly robust in viral and cancer vaccinations.As demonstrated in multiple mouse cancer models,the mevalonate pathway inhibitors are robust for cancer vaccinations and synergize with immune checkpoint antibodies.The adjuvanticity associated with MVA pathway inhibition could induce strong immune responses and is thus suitable for influenza vaccines and cancer immunotherapies.Because these inhibitor's targets are clear,it is thus helpful to the mechanism study.These inhibitors function independently of conventional ‘‘danger sensing''.Instead,they inhibit the geranylgeranylation of some small GTPases in antigen-presenting cells,resulting in arrested endosomal maturation,prolonged antigen retention,enhanced antigen presentation and T cell activation.These findings offer new insights of MEV pathway by linking this core biochemical process and the population-based statin use to a new approach in vaccine development,with rationally designed chemistry aiming at cellular targets other than danger sensing.This work revealed a new mechanism of natural adaptive immune activation,and will be important in new adjuvant finding,adjuvant mechanism investigation and caner immunotherapy.