Experimentally induced blood-stage malaria in Kenyan adults: understanding disease mechanisms and protection in the context of background immunity

Plasmodium falciparum malaria causes an estimated 500 million cases per year and hundreds of thousands of deaths annually. Substantial morbidity and mortality occurs in Africa. An effective vaccine is needed, and vaccine development is essential to provide an effective sustainable and cost-effective control of disease. Rational vaccine development would be based on clearly described mechanisms that lead to clearance of parasites and the correlates of immunity. The current lead vaccine, based on the first falciparum gene ever cloned, delivers ~30% protection over 4 years. An understanding and identification of the underlying mechanisms that lead to naturally acquired immunity has the potential to inform rational vaccine design. We need to identify the antigenic targets for protective immune responses; and the threshold required and functional properties. The study of naturally acquired immunity has been conducted using observational field studies to date, based on surveillance of naturally exposed children. However, adults living in endemic areas acquire resistance to infection and/or disease with repeated exposure to malaria causing parasites. To understand how this immunity impacts infection, we recently conducted a deliberate infection study using parasite stages that are infective from the mosquito, sporozoites. Out of a total of 142 volunteers, 33 were observed to be malaria parasite free and remained uninfected throughout monitoring for infection in the study. These studies in non-endemic volunteers, with 100% developing infection, have recently been used to investigate pathophysiological mechanisms of disease utilising the stage of the parasite responsible for disease, blood stages i.e. deliberate infection with parasite infected red blood cells. We now propose to deliberately infect volunteers who we found to be previously malaria-free with parasite-infected red blood cells that directly results in the signs and symptoms associated with disease. We intend to evaluate pathophysiological mechanisms of disease and determine the contribution and mechanisms of immunity resulting from the disease stage of infection. We will adopt a biomarker and systems immunology approach to identify mechanisms associated with disease outcome including detailed characterisation of biomarkers of immune activation including endothelial activation and microvascular function; typing of antibody specificities and function, analysis of cellular immunity; and analysis of the metabolome. This study will define mechanisms associated with disease in the context of pre-existing immunity and help inform targets for the next generation blood-stage vaccines.