Infection of humans with Plasmodium species, the parasites that cause malaria, remains a significant global health problem. There are approximately 300-500 million new cases of malaria each year, which results in the death of 1-3 million people annually. Vaccine development is complicated by the complex life cycle of Plasmodium, which exists as an asymptomatic liver-stage followed by a symptomatic blood-stage. Since the liver-stage is asymptomatic the most ideal vaccine would target and eliminate the parasite at this stage. Previous research has shown that the immune system uses both antibodies and T cells to prevent infection of or eliminate infected hepatocytes respectively. Unfortunately, there is little information regarding the quantitative requirements for antibodies and T cells in providing protection from infection, which would serve as an important benchmark for malaria vaccine development. The research in this proposal will fill this knowledge gap, thus providing valuable information in the rationale design of an effective malaria vaccine. In previous work it has been shown that the threshold of CDS T cells required for sterile Plasmodium liver-stage immunity is >1% of all peripheral blood leukocytes. In Specific Aim 1 of this proposal Plasmodium-specific antibodies or CD4 T cell responses will be added to an existing CDS T cell response to determine the effect on the threshold of CDS T cells required for sterile immunity. In Specific Aim 2 we will determine if an optimal relationship between Plasmodium-specific antibodies, CD4 T cells, and CDS T cells can be defined. These experiments have direct relevance to the mission of the NIAID because they will lead towards the prevention of Plasmodium infections. Thus, this research is of significant interest to public health because it will provide important information in the development of a vaccine for malaria.