Moving beyond discovery science to a mechanistic understanding of human malaria

We've had more than a hundred years of discovery-based human malaria research that has made steady progress in observing disease processes (such as sequestration and vascular occlusion) as well as potential mechanisms of immunity. These observations now take centre stage as we enter an era of mass vaccination that will alter the natural history and epidemiology of malaria. We will need to understand how to protect individuals from breakthrough infections and populations from a shift in the mean age of exposure. It is therefore paramount that we start to directly test our long-standing hypotheses about the causes of disease and the pathways to protection. This is now made possible by improvements to complex cellular model systems as well as a sea-change in our attitude towards human intervention studies. Mechanistic insight is therefore no longer limited to animal models, which are always imperfect, but can be achieved in people and in vivo.