Project Summary/Abstract Plasmodium vivax is the second leading cause of malaria and the most prevalent cause of malaria outside of Africa. The estimated cost of the global burden of vivax malaria is $1.4 - $4 billion per year and more people live at risk worldwide from P. vivax than P. falciparum. It is endemic mostly in poor countries where access to affordable health care is lacking, which leads to lost adult productivity. Relapse infections from P. vivax poses a special challenge to malaria elimination and eradication because of its ability to repeatedly restart blood-stage infections from hypnozoites – the dormant parasite that can persist in human livers from weeks to years after the sporozoite infection. Exacerbating the problem, P. vivax transmission occurs prior to onset of clinical signs and treatment options to clear relapsing parasites in the dormant liver stage are limited. The goal of this U01 project is to accelerate vivax malaria vaccine development by validation of an optimal combination of P. vivax target antigens in pre-erythrocytic stages. Our vaccine strategy seeks to validate candidate antigens that together can effectively inhibit sporozoite infection and block liver stage development, including blood stage breakthrough infection. Our strategy exploits our new in vitro functional assay for experimental studies of liver stage development of P. vivax. We will pursue a structural vaccinology approach, using broadly neutralizing binding inhibitory antisera and monoclonal antibodies to identify and characterize the highest value immunogens and vaccine delivery method to design a multivalent vaccine to prevent and eliminate vivax malaria.