Serologic Markers of Previous Malaria Exposure and Functional Antibodies Inhibiting Parasite Growth Are Associated With Parasite Kinetics Following a Plasmodium falciparum Controlled Human Infection

Abstract

Background: We assessed the impact of exposure to Plasmodium falciparum on parasite kinetics, clinical symptoms, and functional immunity after controlled human malaria infection (CHMI) in 2 cohorts with different levels of previous malarial exposure.

Methods: Nine adult males with high (sero-high) and 10 with low (sero-low) previous exposure received 3200 P. falciparum sporozoites (PfSPZ) of PfSPZ Challenge by direct venous inoculation and were followed for 35 days for parasitemia by thick blood smear (TBS) and quantitative polymerase chain reaction. Endpoints were time to parasitemia, adverse events, and immune responses.

Results: Ten of 10 (100%) volunteers in the sero-low and 7 of 9 (77.8%) in the sero-high group developed parasitemia detected by TBS in the first 28 days (P = .125). The median time to parasitemia was significantly shorter in the sero-low group than the sero-high group (9 days [interquartile range {IQR} 7.5-11.0] vs 11.0 days [IQR 7.5-18.0], respectively; log-rank test, P = .005). Antibody recognition of sporozoites was significantly higher in the sero-high (median, 17.93 [IQR 12.95-24] arbitrary units [AU]) than the sero-low volunteers (median, 10.54 [IQR, 8.36-12.12] AU) (P = .006). Growth inhibitory activity was significantly higher in the sero-high (median, 21.8% [IQR, 8.15%-29.65%]) than in the sero-low group (median, 8.3% [IQR, 5.6%-10.23%]) (P = .025).

Conclusions: CHMI was safe and well tolerated in this population. Individuals with serological evidence of higher malaria exposure were able to better control infection and had higher parasite growth inhibitory activity.

Clinical trials registration: NCT03496454.

Keywords: clinical outcomes; controlled human malaria infection; functional antibodies; malaria exposure; parasite kinetics.

Figure 1.

Antibody histogram plots for screened volunteers in The Gambia controlled human malaria infection study. Light colors are the sero-low group, dark colors are the sero-high group, and gray colors are the other screened volunteers with intermediate immunological profile. Abbreviations: AMA-1, apical membrane antigen 1; Etramp5.Ag1, early transcribed membrane protein; GEXP18, gametocyte exported protein; GLURP.R2, glutamate-rich protein; MSP-1.19, merozoite surface protein 1.19; Rh2.2030, reticulocyte-binding protein homologue.

Figure 2.

Comparison of parasite kinetics between the 2 exposure groups following controlled human malaria infection. Kaplan–Meier curve for time from inoculation to parasitemia detected by thick blood smear (A) and quantitative polymerase chain reaction (qPCR) (B). Differences in parasite density by qPCR at treatment (C) and peak parasitemia (D).

Figure 3.

Individual-level kinetics of parasitemia by quantitative polymerase chain reaction (qPCR) following controlled human malaria infection with Plasmodium falciparum (Pf).

Figure 4.

Differences in clinical outcomes following controlled human malaria infection in the 2 exposure groups, showing proportion of participants without symptoms, number of adverse events (AEs) per participant, and total number of AEs per group.

Figure 5.

Antibody-mediated responses to Plasmodium falciparum in high- and low-exposure groups. A, The sero-high group had significantly higher (P = .006) titers of antibodies to sporozoite antigens, expressed as arbitrary units (AU). B, There were no significant differences between groups in their ability to block sporozoite invasion of HC04 hepatocytes. C, Plasma from the sero-high group also had significantly higher (P = .0003) levels of antibodies to asexual-stage antigens, also expressed as AU. D, Purified immunoglobulin G from the sero-high exposure group also had significantly higher growth inhibitory activity (P = .025) against blood-stage 3D7 parasites.