Work

Sex-based differences in Plasmodium infection in the control groups of controlled human malaria infection trials in malaria-naive populations in the USA and the Netherlands: a pooled analysis

Year: 2026

Type: article

Abstract: BACKGROUND: Before infecting red blood cells and causing the clinical manifestations of malaria, the hepatotropic parasite Plasmodium falciparum completes a complex liver stage. Sex-based differences in pathogenesis by hepatotropic micro-organisms are well documented but unstudied for P falciparum in humans. We aimed to evaluate the effect of sex on the time to blood-stage positivity and initial blood-stage parasite densities as indicators of liver-stage dynamics and parasite replication. METHODS: We conducted a pooled analysis of data from malaria-naive participants in control groups from controlled human malaria infection (CHMI) studies conducted between Jan 1, 2010, and Dec 31, 2024, in which samples were tested using Plasmodium 18S ribosomal RNA nucleic acid amplification tests (18S NAATs) at laboratories in Seattle (WA, USA) and Leiden (Netherlands). Participants aged 18-48 years were eligible for inclusion if they were in placebo or infectivity control groups in any CHMI study at the two laboratories and developed parasitaemia following CHMI. Patient demographics and 18S NAAT data were obtained from study leads at each centre and collated, standardised, and reviewed. Information on P falciparum strain, challenge route, and sampling schedule were extracted from study protocols or publications. The main outcome, time to positivity (TTP), was calculated as the study day of the first positive 18S NAAT of any density, measured during a 28-day monitoring period following CHMI. Using an interval-censored generalised gamma accelerated failure time model, we compared time to blood-stage positivity by sex, adjusting for challenge route, P falciparum strain, and study site. Odds of developing detectable infection after 7 days post-challenge was compared between male and female participants using a linear mixed-effects model adjusted for the same terms. FINDINGS: =31% [95% CI 0-57]). There were no notable demographic differences between male and female participants regarding age, challenge route, or strain. The mean time to first detectable parasitaemia was slightly longer in male participants (7·59 days [SD 1·15]) than in female participants (7·17 days [0·91]). Adjusted accelerated failure time analysis suggested that TTP occurred 8% later in male participants than female participants (time ratio 1·08 [1·03-1·16]). Male participants were significantly more likely than female participants to have a detectable infection after day 7 (19 [35%] of 54 male participants vs six [13%] of 48 female participants), with adjusted odds of delayed infection 5·20 times (95% CI 1·52-17·70) higher in male than female participants. INTERPRETATION: Our findings suggest that male individuals are more likely to have a delayed detection of blood-stage parasites following CHMI with P falciparum compared with female individuals. Although the inability to directly measure liver-stage burden is a limitation, CHMI offers a controlled system to infer liver-stage dynamics. Thus, P falciparum infection is likely to involve a sex-specific host-pathogen interaction in the liver, emphasising the importance of considering sex as a biological variable in liver-targeting clinical interventions. FUNDING: The Gates Foundation and the University of Washington.

Source: The Lancet Microbe

DOI: 10.1016/j.lanmic.2025.101265