. Osier, KEMRI-CGMRC, Defining the merozoite targets of protective immunity against Plasmodium falciparum malaria through multi-centre cohort studies

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Malaria is still a major public health problem for many parts of sub-Saharan Africa. The World Health Organization estimates that nearly ninety children under the age of five years die from malaria each hour, in this region. Many tools can be used to control malaria including, insecticide-treated bed-nets, rapidly acting and effective medications, and better control of mosquitoes. Although these have been used in Africa with varying degrees of success, many experts now agree that novel measures will be needed to achieve better control, and move towards elimination. Vaccines have historically been the most effective and cost-effective public health tools against infectious diseases.There is currently no licensed malaria vaccine. The most promising vaccine so far is still being tested in clinical trials but early data show that it only offers 30% protection against clinical episodes of malaria. Whilst this marks significant progress, there is an urgent need to improve on this vaccine efficacy. The conviction that it will be possible to develop an effective malaria vaccine comes partly from observations of disease patterns in areas that experience a lot of malaria. Young children under the age of five are susceptible to severe and complicated forms of malaria, while older children and young adults experience only milder forms of the illness, and gradually remain symptom-free despite being infected. How is this immunity acquired? Studies conducted over fifty years ago showed that antibodies taken from adults who had become immune to malaria could be used to successfully treat individuals hospitalized with malaria. We know that antibodies act by binding to specific molecules on microbes or infecting agents, thus halting their progress. With advances in technology, we have now been able to identify the thousands of proteins that make up a malaria parasite. What we have failed to do is to identify which of these thousands of proteins are the targets of the protective antibodies. Previous studies have concentrated only on a small number of antigens, in small studies, used varied methodologies, and not taken into account the wide differences in malaria transmission intensity that affect antibody measurements. For these reasons, it is still not clear which parasite proteins induce protective antibodies.I propose to overcome these shortcomings in four main ways. First, I will test a large number of parasite proteins, selecting only those that are plausible biological targets by virtue of being exposed to antibodies in the body. Second, I will study antibody responses in samples collected from multiple sites in sub-Saharan Africa (sSA) that are representative of the varying levels of malaria transmission experienced on the continent. Third, I will conduct a very large study using blood samples that have already been collected from the different sites. This has three important advantages: i) the study will be sufficiently large, allowing me to test antibody responses to many parasite proteins with the confidence that any protective associations identified are not due to chance, ii) all assays and analyses will be performed in an identical manner, allowing us to directly compare data from individual sites, iii) the study will be extremely cost-effective, avoiding the prohibitive costs that would be required to set up and longitudinally monitor children in multiple sites in Africa. Finally, I will examine the mechanisms of action of the antibodies directed against the parasite proteins that we find to be important.This study will therefore be the most comprehensive to date with regards to number of specific parasite proteins tested, generalizability of results across sSA, and supported by the demonstration of antibody mechanisms of action for the best candidates. This information will be extremely valuable for the development of the next generation of malaria vaccines.