Controlled human blood stage malaria infection: current status and potential applications

Abstract

Controlled human malaria infection by blood stage parasite (BSP) inoculation is an alternative to the well-established model of infection with Plasmodium falciparum sporozoites delivered by mosquito bites. The BSP model has been utilized less frequently, but its use is increasing. Advantages of BSP challenge include greater ease of administration, better standardization of the infecting dose per volunteer, and good inter-study reproducibility of in vivo parasite dynamics. Recently, a surprising reduction in clinical symptoms at microscopic patency in the BSP model has been identified, which has an undefined and intriguing pathophysiologic basis, but may make this approach more acceptable to volunteers. We summarize clinical, parasitologic, and immunologic data from all BSP challenges to date, explore differences between the BSP and sporozoite models, and propose future applications for BSP challenge.

Figure 1.

Confidence of parasite multiplication rate (PMR) calculations and frequency of malaria symptoms at blood film diagnosis. A, Individual PMRs ± 95% confidence intervals (modeled from quantitative polymerase chain reaction [qPCR] data as described),, for seven volunteers with sufficient data from a recent blood stage challenge trial and unimmunized infectivity controls from a recently conducted sporozoite challenge study (n = 12 volunteers) (Ewer KJ, and others, unpublished data). See also Sanderson and others for a similar analysis. B, Clinical symptoms from two blood-stage challenge trials conducted in Oxford (n = 13 volunteers), and unimmunized infectivity controls from a recently conducted sporozoite challenge study (n = 12 volunteers) (Ewer KJ, and others, unpublished data). Two of eight and one of five volunteers were symptomatic in the respective blood stage parasite (BSP) infection studies compared with 10 of 12 sporozoite (Spz) infection volunteers. Methods of qPCR and clinical assessment of symptoms were identical in all studies. Significance testing by Fisher's exact test (Prism version 5.0).

Figure 2.

Comparison of in vivo parasite growth by quantitative PCR (qPCR). Mean ± 95% confidence intervals of parasitemia by qPCR in immunized and unimmunized volunteers infected with blood stage parasites (BSP) in Oxford (n = 8 volunteers) were compared with unimmunized volunteers infected with sporozoites (Spz) from a recent study (n = 12 volunteers) (Ewer KJ and others, unpublished data) by identical qPCR assays. Day zero for BSP challenge corresponds to the day of inoculation, and equals day 6 post-Spz challenge when parasites may begin to seed the blood and monitoring of blood stage parasitaemia by qPCR begins. No significant difference in parasitemia at blood film diagnosis was observed. There is a prolonged sub-patent phase (undetectable by qPCR) of parasite growth after BSP inoculation (3–5 days), in comparison with the much shorter blood stage pre-patent period after Spz challenge (1–2 days).