Novel tools and approaches for safer and more effective treatment of Plasmodium vivax malaria

Context and challenges Plasmodium vivax is the commonest cause of malaria outside sub-Saharan Africa and causes significant morbidity and mortality. Over 3 billion people are at risk of infection in 45 countries. P. vivax forms asexual parasites that cause an acute febrile illness, in addition to dormant asymptomatic liver stage parasites (hypnozoites) that can activate weeks to months after initial infection to cause repeated episodes of malaria known as relapses. Successful P. vivax treatment requires radical cure – the combination of a schizonticidal drug to kill blood stage parasites, plus an hypnozoitocidal (antirelapse) drug to kill hypnozoites – either primaquine or tafenoquine. Control and elimination of P. vivax faces two major challenges. First, recurrent episodes of P. vivax parasitaemia can arise from recrudescence (schizonticidal failure), relapse (hypnozoitocidal failure), or re-infection from a new mosquito bite. Since it is not currently possible to distinguish between these causes, antirelapse drug clinical trials quantify reduction in all recurrences, rather than prevention of true relapses, thus underestimating true drug efficacy. Second, individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked enzyme deficiency common in vivax-endemic areas, can develop severe haemolysis following primaquine or tafenoquine treatment. The risk of haemolysis in heterozygous females (with one normal and one deficient copy of the G6PD gene) is poorly defined, meaning the best antirelapse treatment strategy for these females is unclear. The degree of haemolysis is determined by the G6PD genetic variant (>200 polymorphisms exist), enzyme activity, and dose of drug administered; the relative contribution of each has not been characterised. Aims My fellowship aims to define accurate estimates of antirelapse drug efficacy in diverse endemic areas and quantify the risk of drug-induced haemolysis in G6PD heterozygous females. Aim 1: Antirelapse drug efficacy The genetic relatedness of parasites causing initial and recurrent infections can inform the aetiology of recurrences. A novel, scalable parasite microhaplotype genotyping strategy has been developed to obtain genetic signatures of P. vivax parasites. I will combine these genetic data with clinical data collected from >3000 patients enrolled into multinational clinical trials and use mathematical modelling to determine the likely aetiology of recurrences. By excluding likely recrudescences and re-infections, I will define true antirelapse drug efficacies, optimal clinical trial follow-up durations, and identify risk factors for relapse in diverse endemic areas. Aim 2: Antirelapse drug safety A novel, scalable genotyping assay (G6PD MinION) has been developed to identify patients with G6PD deficiency and the causative genetic variant. I will combine assay results with clinical data from >2000 patients enrolled in multinational clinical studies to determine the relationships between G6PD variant and enzyme activity in females, and the risk of antirelapse drug-induced haemolysis in heterozygous females according to drug dose and G6PD variant. Applications and benefits My fellowship will provide critical evidence to define the efficacy and safety of different antirelapse treatment strategies that will inform national and international antimalarial treatment guidelines. Understanding the timing of relapses and re-infections in diverse endemic regions will provide important insights into parasite transmission dynamics, enabling better targeting of control and elimination strategies. The approach I will develop for disentangling relapses and re-infections has the potential to optimise the way P. vivax clinical trials are conducted to generate more accurate assessments of antirelapse treatments. These applications will culminate in better patient outcomes and contribute to the control and elimination of malaria.