Sex-based differences in clearance of chronic Plasmodium falciparum infection

Background: Multiple studies have reported a higher prevalence of malaria infection in males compared to females. However, it remains unknown whether this is due to differences in behavioral factors or biological sex playing a direct role in the host response to the malaria parasite. Methods and Findings: To test the hypothesis that sex-based differences in host-parasite interactions affect the epidemiology of malaria, we intensively followed a cohort of individuals living in a malaria endemic area of eastern Uganda. By performing frequent sampling, ultrasensitive quantitative PCR (qPCR), and amplicon deep sequencing, we followed P. falciparum infections over time to estimate both force of infection (FOI) and rate of clearance by sex. Prevalence of malaria infection by qPCR was 14.4% in males versus 9.2% in females (difference 5.2%, 95% confidence interval [CI] 3.8% to 6.5%). There was no evidence of differences in behavioral risk factors, incidence of malaria, or FOI by sex. In contrast, females cleared asymptomatic infections at a faster rate than males (hazard ratio [HR] = 1.82, 95% CI 1.20 to 2.75 by clone and HR = 2.07, 95% CI 1.24 to 3.47 by infection event) in multivariate models adjusted for age, timing of infection onset, and parasite density. Conclusions: In this study, differences in P. falciparum prevalence between males and females observed in endemic settings were driven by faster clearance rates in females and not by increased infection rates in males. These findings implicate biological sex-based differences as an important factor in the host response to this globally important pathogen.