Defining the genetic basis of differential susceptibility to infectious diseases is of importance for understanding the evolution of human genetic diversity, for identifying critical molecular pathways in disease resistance, and for the design of novel intervention strategies such as more effective vaccines.I propose to sequence the entire coding regions of all human genes in large numbers of cases of severe tuberculosis and fatal bacterial sepsis to identify variants that have a large impact on risk of developing severe tuberculosis or dying from sepsis. I shall then apply this exome sequencing approach to define the genetic basis of variable immune responsiveness in West Africans to hepatitis B vaccine, and to a new promising T cell-inducing vaccine, developed in my group, that targets the liver-stage of malaria.This programme will benefit from unique collections of 10,000 disease cases and in-house expertise in vaccine design, bioinformatics and statistical genetics, and will take genetic investigation of common infectious disease to near the ultimate level of analysis by using large-scale next generation sequencing.