Repeat controlled human malaria infection of healthy UK adults with blood-stage Plasmodium falciparum : safety and parasite growth dynamics

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Abstract In endemic settings it is known that natural malaria immunity is gradually acquired following repeated exposures. Here we sought to assess whether similar acquisition of blood-stage malaria immunity would occur following repeated parasite exposure by controlled human malaria infection (CHMI). We report the findings of a repeat homologous blood-stage Plasmodium falciparum (3D7 clone) CHMI study (VAC063C; ClinicalTrials.gov NCT03906474 ). In total, 24 healthy, unvaccinated, malaria-naïve UK adult participants underwent primary CHMI followed by drug treatment. Ten of these then underwent secondary CHMI in the same manner, and then six of these underwent a final tertiary CHMI. As with primary CHMI, malaria symptoms were common following secondary and tertiary infection, however, most resolved within a few days of treatment and there were no long term sequelae or serious adverse events related to CHMI. Despite detectable induction and boosting of anti-merozoite serum IgG antibody responses following each round of CHMI, there was no clear evidence of anti-parasitic immunity (manifest as reduced parasite growth in vivo ) conferred by repeated challenge with the homologous parasite in the majority of volunteers. However, three volunteers showed some variation in parasite growth dynamics in vivo following repeat CHMI that were either modest or short-lived. We also observed no major differences in clinical symptoms or laboratory markers of infection across the primary, secondary and tertiary challenges. However, there was a trend to more severe pyrexia after primary CHMI and the absence of a detectable transaminitis post-treatment following secondary and tertiary infection. We hypothesize that this could represent the initial induction of disease tolerance or clinical malaria immunity. Repeat homologous blood-stage CHMI is thus safe and provides a model with the potential to further the understanding of the acquisition of blood-stage immunity in a highly controlled setting.

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