Sickle Cell Trait Is Associated with a Delayed Onset of Malaria: Implications for Time‐to‐Event Analysis in Clinical Studies of Malaria

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Abstract
Background. The World Health Organization (WHO) recently recommended that the time to first malaria episode serve as the primary end point in phase III malaria vaccine trials—the first of which will be held in Africa. Although common red blood cell (RBC) polymorphisms such as sickle hemoglobin (HbS) are known to protect against malaria in Africa, their impact on this end point has not been investigated. Methods. A longitudinal study of 225 individuals aged 2–25 years was conducted in Mali. The association between common RBC polymorphisms and the time to first malaria episode was evaluated. Results. Among children aged 2–10 years, sickle cell trait (HbAS) was associated with a 34-day delay in the median time to first malaria episode (P = .017). Cox regression analysis showed that greater age (hazard ratio [HR], 0.87 [95% CI, 0.80–0.94]; P = .001), HbAS (HR, 0.48 [95% CI, 0.26–0.91]; P = .024), and asymptomatic parasitemia at enrollment (HR, 0.35 [95% CI, 0.14–0.85]; P = .021) were associated with decreased malaria risk. Conclusion. Given the delay in the time to first malaria episode associated with HbAS, it would be advisable for clinical trials and observational studies that use this end point to include Hb typing in the design of studies conducted in areas where HbAS is prevalent.