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

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 repeat homologous blood-stage Plasmodium falciparum (3D7 clone) CHMI studies VAC063C (ClinicalTrials.gov NCT03906474) and VAC063 (ClinicalTrials.gov NCT02927145). 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-parasite 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 clinical immunity. Repeat homologous blood-stage CHMI is thus safe and provides a model with the potential to further the understanding of naturally acquired immunity to blood-stage infection in a highly controlled setting.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT03906474, NCT02927145.

A systematic analysis of the human immune response to Plasmodium vivax

“…Last of all, we performed direct comparative analyses to ask whether the immune response to P. vivax differed from that to P. falciparum . Thirteen malaria-naive volunteers were infected with P. falciparum (clone 3D7) by direct blood challenge during the VAC063 ( 42 ) and VAC063C ( 43 ) CHMI trials; crucially, diagnosis and treatment thresholds were analogous to VAC069A ( P. vivax ) and circulating parasite densities were comparable at the peak of infection ( Figure 7A and Supplemental Figure 7 ). Moreover, the magnitude and kinetics of lymphopenia were equivalent between parasite species ( Figure 7B ).…”

“…To compare the immune response induced by P. vivax versus P. falciparum , we used data from 2 previously conducted CHMI trials (VAC063 and VAC063C); the VAC063 trial is described in full in Minassian et al ( 42 ) and the VAC063C trial is reported in Salkeld et al ( 43 ). In brief, 13 malaria-naive adult volunteers (10 in VAC063 and 3 in VAC063C) were inoculated with P. falciparum (clone 3D7) by intravenous injection of infected red cells (452–857 parasites per volunteer).…”

Repeat controlled human Plasmodium falciparum infections delay bloodstream patency and reduce symptoms

“…Additional support for the role of pre-erythrocytic immunity in delaying the onset of patency is suggested by an alternate CHMI model that challenged participants with blood-stage parasites and did not observe a patency delay 45 , 46 . Conversely, at peak parasitemia on treatment day the cytokine profile for both studies is similar, including an increase in both IL-10 and IL-1RA levels that could reduce inflammation 45 .…”

The Dantu blood group prevents parasite growth in vivo: Evidence from a controlled human malaria infection study

“…Participants were treated earlier if signs and symptoms were observed in association with blood film positivity at any parasite density, and on day 21 post-inoculation regardless of outcome. While qPCR was used as the primary measurement of parasitaemia because it is much more sensitive than microscopy at low density ( Bejon et al, 2006 ), thick film blood smears were also performed as an additional precaution, and participants were treated if they became blood film positive at any density, an approach that accords with that used in other CHMI studies ( Sheehy et al, 2012 ; Murphy et al, 2012 ; Hodgson et al, 2014 ; Kamau et al, 2014 ; Hodgson et al, 2015 ; Seilie et al, 2019 ; Salkeld et al, 2022 ). Participants were recruited during 2016, 2017, and 2018 into three successive cohorts from three different malaria transmission zones: Kilifi North (no- to low-transmission) and Kilifi South (moderate transmission), both on the coast, and Ahero (moderate to high transmission) in Western Kenya.…”