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

About This Grant

ABSTRACT: 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. In Aim 1, we will genotype all Pf infections in the cohort to estimate mFOI and assess whether mFOI differs between arms after DP cessation. In Aim 2, we will distinguish new from persistent infections and track the outcomes of incident blood-stage infections to compare the development of anti- disease and anti-parasite immunity across arms. We hypothesize that after DP cessation, DP arm children will have improved pre-erythrocytic immunity (lower mFOI) compared to placebo arm children and lower blood- stage immunity (higher probability of becoming symptomatic upon detection of an incident infection) compared to placebo arm children. In Aim 3, we will use two complementary approaches – ultra-high throughput long peptide arrays and bead arrays with conformational antigens – to longitudinally assess pre-erythrocytic and blood-stage Pf antibody responses, compare responses across arms, and evaluate associations with clinical immune phenotypes established in Aims 1 and 2. Finally, to identify antibody profiles associated with clinical outcomes, we will perform feature selection to identify combinations of antibodies associated with immunity. The proposed studies will define the extent to which PMC modulates pre-erythrocytic and blood-stage immunity, identify antibody profiles associated with protection, and generate evidence that can be used to optimize the delivery of immunomodulatory interventions and guide next-generation malaria control strategies.