The goal of our proposal is to develop new approaches for the prevention and treatment of human malaria caused by the parasite Plasmodium vivax (P. vivax). This type of malaria, known as vivax malaria, is the most widely distributed type of malaria with 3.3 billion people at risk and at least 15 million clinical cases worldwide each year. As the most common form of malaria outside sub-Saharan Africa, it can cause severe illness and death across a large segment of the world's population. Most individuals exposed to P. vivax through repeated infection gain partial immunity over time. The immunity is mediated, in part, by acquired antibodies (Abs) to essential parasite proteins that can block the parasite invasion into liver and red blood cells thereby preventing infection and if infected reduce the risk of disease. This proposal aims to isolate human monoclonal antibodies (mAbs) from individuals with immunity to vivax malaria that recognize a few key molecules known to be essential for invasion of liver and red blood cells. Once isolated these mAbs will be evaluated as to whether they block parasite invasion of liver and red cells in vitro, and in vivo using murine models and genetically modified parasites. Monoclonal Abs with potent blocking activity will be further characterized as to exactly how and where they interact with parasite proteins and whether individuals in diverse populations also have the same or similar antibodies. This information can be used to help to design a vaccine against vivax malaria. These mAbs can also be used for treatment of severely ill patients, or for prevention of vivax malaria over time, since a single injection of modified mAbs can last for weeks and even months.