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Human Pathology & Disease Response

By Sam Wassmer

The deployment of key interventions to prevent and treat malaria, such as long-lasting insecticide treated nets and artemisinin-combination therapies, has led to a steady decrease in malaria cases reported worldwide over the past decade. Despite tremendous global efforts, this trend has now stalled. Novel approaches are therefore needed to continue curbing malaria transmission and mortality, including new vaccine strategies, parasite evolution surveillance, better tools to detect low parasitaemia and estimate malaria transmission levels, fast and reliable assessment of drug safety for patients, and effective adjunct therapies for severe cases. Researchers within the Malaria Centre are contributing to each of these fields, with promise for new intervention strategies.

While the safety and protective effect of the RTS,S vaccine shown in advanced clinical trials is currently being assessed by the WHO in real-life settings, its optimal efficacy requires 4 doses and has been reported to wane rapidly in high exposure areas. Several members of the Malaria Centre are evaluating the role of specific malaria parasite epitopes and host immune response pathways that lead to the building of an effective and long-lasting anti-malaria immunity, in order to optimise pre-erythrocytic or blood stage vaccine design. These could then be combined with an “altruistic” vaccine aimed at blocking the transmission of parasites from infected patients, another approach currently being evaluated at LSHTM.

Antigen-detecting RDTs play a key role in malaria control successes in many parts of the world, and most tests currently in use detect Plasmodium falciparum HRP2 and/or pLDH antigens. Researchers within the Malaria Centre are investigating the impact of recently reported pfhrp2 gene deletions or mutations in African parasite populations on both false-negative results and clinical outcome. 

 

The active detection of asymptomatic and sub-microscopic infections that can contribute to malaria transmission is a priority in current elimination programmes. However, these infections remain undetected by the standard diagnostic and surveillance tools. Members of the LSHTM staff are using antibodies as an indication of recent exposure to Plasmodium parasites, as well as current or past infections, through custom microarrays and bead-based malaria serology screening assays. These tools are also used by our researchers to estimate malaria transmission levels in specific settings, monitor the efficacy of treatment programs, and assess the impact of specific interventions such as targeted indoor residual spraying.

 

Once successfully detected, another challenge faced by clinicians is the effective treatment of asymptomatic and symptomatic infections by P. vivax and P. falciparum. Currently, the drug family that includes primaquine is only option available to clear individuals from P. vivax parasites and therefore reduce their transmission. Unfortunately, approximately 400 million people worldwide are affected by G6PD deficiency, a common enzyme defect leading to severe adverse reactions if exposed to these drugs at certain doses. Staff at LSHTM are investigating molecular mechanisms resulting in such reactions and evaluating reliable tools to detect this defect in patients before treatment. Similarly, a better understanding of the pathogenetic mechanisms leading to cerebral malaria, the most severe and lethal form of P. falciparum infections, necessary to identify patients at risk and develop adjunct therapies to decrease mortality. Researchers from the Centre are using a combination of state-of-the-art neuroimaging techniques in patients with cerebral malaria, assessment of markers of severity, and in vitro modelling to this end.