Abstract
Malaria remains a major public health burden despite approval for implementation of a partially effective pre-erythrocytic malaria vaccine. There is an urgent need to accelerate development of a more effective multi-stage vaccine. Adults in malaria endemic areas may have substantial immunity provided by responses to the blood stages of malaria parasites, but field trials conducted on several blood-stage vaccines have not shown high levels of efficacy. We will use the controlled human malaria infection (CHMI) models with malaria-exposed volunteers to identify correlations between immune responses and parasite growth rates in vivo. Immune responses more strongly associated with control of parasite growth should be prioritized to accelerate malaria vaccine development. We aim to recruit up to 200 healthy adult volunteers from areas of differing malaria transmission in Kenya, and after confirming their health status through clinical examination and routine haematology and biochemistry, we will comprehensively characterize immunity to malaria using >100 blood-stage antigens. We will administer 3,200 aseptic, purified, cryopreserved Plasmodium falciparum sporozoites (PfSPZ Challenge) by direct venous inoculation. Serial quantitative polymerase chain reaction to measure parasite growth rate in vivo will be undertaken. Clinical and laboratory monitoring will be undertaken to ensure volunteer safety. In addition, we will also explore the perceptions and experiences of volunteers and other stakeholders in participating in a malaria volunteer infection study. Serum, plasma, peripheral blood mononuclear cells and whole blood will be stored to allow a comprehensive assessment of adaptive and innate host immunity. We will use CHMI in semi-immune adult volunteers to relate parasite growth outcomes with antibody responses and other markers of host immunity. Registration: ClinicalTrials.gov identifier NCT02739763.
Highlights
Malaria remains a disease of global health importance, despite the gains made against reducing morbidity and mortality
Blood-stage malaria infection after 6.5 days of incubation in the liver will be assayed twice daily to monitor the density of infection and anti-malarial treatment will be given either: (a) when the density of infection rises past a threshold of 500 parasites per μl without signs and symptoms; (b) if a volunteer develops symptoms or signs of illness and an immediate blood film examination shows any evidence of detectable malaria parasites; or (c) the volunteer reaches day 21 of monitoring, at which point controlled human malaria infection (CHMI) will be completed (Figure 1)
Accelerating the development of a malaria vaccine will be of substantial benefit
Summary
Malaria remains a disease of global health importance, despite the gains made against reducing morbidity and mortality. The latest estimates of the burden of malaria indicate that 3.3 billion people are exposed with 216 million cases and over 445,000 deaths being reported, with Africa accounting for ~91% of deaths due to malaria[1]. There has been encouraging progress made in some areas of Africa, but progress has stalled[2]. Elimination does not appear realistic in many areas with higher transmission[3], and progress is threatened by insecticide and drug resistance[4,5]. An effective vaccine strategy is required to deliver sustainable and cost-effective control[6]. Sub-unit vaccine development to date has focused on a limited pool of empirically selected candidate antigens, and field trials have not shown high levels of efficacy[7]
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