Abstract

Plasmodium vivax remains a major challenge for malaria elimination due to dormant liver-stage hypnozoites that trigger relapse and sustain transmission. Although relapse dynamics are well studied in adults, they remain poorly characterized in African infants—the age when hypnozoite reservoirs are first established. Understanding relapse mechanisms in early life is critical to inform radical cure and prevention strategies. Ethiopia’s southwest regions (Jimma, Bonga, Gambella) provide an ideal setting with perennial transmission and high P. vivax incidence.

We established a longitudinal birth cohort to follow infants for 24 months, capturing first P. vivax infections and subsequent recurrences. Parasite genotyping using identity-by-descent (IBD) and multiplicity of infection (MOI) metrics will distinguish relapse, reinfection, and recrudescence. Primaquine (PQ) pharmacokinetics and host CYP2D6 genotypes are analyzed to assess how drug exposure and metabolism affect relapse risk. Statistical modeling integrates parasite genetics, PQ exposure, and CYP2D6 activity to identify determinants of recurrence.

The majority of recurrent infections will be genetically related to initial infections, confirming relapse as the dominant mechanism. Infants with impaired CYP2D6 activity or low PQ exposure are expected to experience higher relapse rates. Multiclonal primary infections are predicted to produce heterologous relapses, indicating activation of diverse hypnozoite clones.

This is the first prospective study to investigate P. vivax relapse biology in African infants. By linking pharmacogenomics, pharmacokinetics, and parasite genotyping, it clarified the biological drivers of PQ treatment failure and relapse. The findings will guide evidence-based interventions such as CYP2D6-informed dosing, supervised PQ administration, and targeted relapse prevention strategies to strengthen malaria elimination efforts.