A Pilot Randomised Trial of Induced Blood-Stage Plasmodium falciparum Infections in Healthy Volunteers for Testing Efficacy of New Antimalarial Drugs

Abstract

BackgroundCritical to the development of new drugs for treatment of malaria is the capacity to safely evaluate their activity in human subjects. The approach that has been most commonly used is testing in subjects with natural malaria infection, a methodology that may expose symptomatic subjects to the risk of ineffective treatment. Here we describe the development and pilot testing of a system to undertake experimental infection using blood stage Plasmodium falciparum parasites (BSP). The objectives of the study were to assess the feasibility and safety of induced BSP infection as a method for assessment of efficacy of new drug candidates for the treatment of P. falciparum infection.Methods and FindingsA prospective, unblinded, Phase IIa trial was undertaken in 19 healthy, malaria-naïve, male adult volunteers who were infected with BSP and followed with careful clinical and laboratory observation, including a sensitive, quantitative malaria PCR assay. Volunteers were randomly allocated to treatment with either of two licensed antimalarial drug combinations, artemether–lumefantrine (A/L) or atovaquone-proguanil (A/P). In the first cohort (n = 6) where volunteers received ∼360 BSP, none reached the target parasitemia of 1,000 before the day designated for antimalarial treatment (day 6). In the second and third cohorts, 13 volunteers received 1,800 BSP, with all reaching the target parasitemia before receiving treatment (A/L, n = 6; A/P, n = 7) The study demonstrated safety in the 19 volunteers tested, and a significant difference in the clearance kinetics of parasitemia between the drugs in the 13 evaluable subjects, with mean parasite reduction ratios of 759 for A/L and 17 for A/P (95% CI 120–4786 and 7–40 respectively; p<0.01).ConclusionsThis system offers a flexible and safe approach to testing the in vivo activity of novel antimalarials.Trial Registration:ClinicalTrials.gov NCT01055002

Controlled Human Blood Stage Malaria Infection: Current Status and Potential Applications

“…Fifty-nine volunteers have been infected in this manner by using the same frozen starting material, 4,6,[9][10][11][12] extending the safety database for this parasite stock. There is an extremely low risk of blood-borne virus transmission because of stringent screening of the original donor, and requirements for seropositivity for Epstein-Barr virus (EBV) and cytomegalovirus (CMV) in recipients (because of donor seropositivity).…”

“…7 Similarly, there are indications that a larger BSP inoculum (3,000 -6,000 parasites) may increase the frequency of symptoms. 4,12 Further work is thus needed to explore the phenotype of the host response to cryopreserved BSPs.…”

Using Population Genetics to Guide Malaria Vaccine Design

“…This vaccine, which is discussed in more detail later, was shown to be efficacious, reducing parasite densities significantly with most of the activity attributed to MSP2 [6]. A combination vaccine, MSP1-C1 containing both the 3D7 and FC27 alleles has recently been tested but showed unacceptable reactogenicity due to the adjuvant used and the trial was terminated [132].…”

“…Examples include vaccines for Streptococcus pneumonia, Neisseria meningitidis, and influenza. Among malaria vaccines, multivalent vaccines are in development for several antigens including MSP2 [132] and AMA1 [195] of P. falciparum. The level of polymorphism seen among different candidate antigens varies substantially, being high for some candidate antigens, such as AMA1, compared to others, such as EBA175 [8].…”

“…This implies that the vaccine only had substantial efficacy against infections containing the vaccine allele, 3D7. To address this, an MSP2 vaccine containing both of the major allelic types is in development [132]. A more recent example of the challenge of antigenic diversity in malaria vaccines is AMA1.…”