National Institute of Allergy and Infectious Diseases 1R01AI199483-01

Impact of Effective Chemoprevention in Early Childhood on the Development of Naturally Acquired Immunity to Malaria.

This award funds a study to evaluate how effective chemoprevention in early childhood impacts the development of naturally acquired immunity to malaria, using advanced molecular and immunological techniques on a Ugandan birth cohort.

Description

Perennial malaria chemoprevention (PMC) can alter the development of naturally acquired immunity (NAI) to malaria by preventing infections during early childhood. Evidence on the effect of PMC on NAI is inconsistent. After withdrawal of PMC, some studies show rebound malaria, while some show sustained protection, potentially due to enhanced development of pre-erythrocytic immunity through reduced immune exhaustion by limiting exposure to blood-stage antigens. These divergent findings may reflect differences in transmission intensity, drug efficacy, or trial design, but may also reflect the limitations of relying solely on the incidence of malaria to assess immunity. Because clinical malaria occurs only when parasites bypass pre-erythrocytic immunity and reach fever-inducing densities, differences in the rate at which parasite clones successfully establish blood-stage infection (molecular force of infection, mFOI) and the proportion of infections that become symptomatic are obscured by incidence metrics. Frequent sampling and longitudinal genotyping provide a powerful approach to more fully characterize the development of NAI. We propose a comprehensive evaluation of Plasmodium falciparum (Pf) infection and immunity in samples already collected from a Ugandan birth cohort of 924 children randomized to receive placebo vs. highly effective PMC with monthly dihydroartemisinin-piperaquine (DP) up to 1 or 2 years of age, and followed to 4 years of age. By leveraging ultra-sensitive quantitative PCR, amplicon sequencing, and high-resolution antibody profiling, we will define how PMC affects the development of pre-erythrocytic and blood-stage immunity over time and compare differences across arms.

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