Child Health and Infection with Low Density (CHILD) malaria: a protocol for a randomised controlled trial to assess the long-term health and socioeconomic impacts of testing and treating low-density malaria infection among children in Tanzania.

INTRODUCTION: As malaria declines, low-density malaria infections (LMIs) represent an increasing proportion of infections and may have negative impacts on child health and cognition, necessitating development of targeted and effective solutions. This trial assesses the health, cognitive and socioeconomic impact of two strategies for detecting and treating LMI in a low transmission setting. METHODS AND ANALYSIS: The study is a 3-arm open-label individually randomised controlled trial enrolling 600 children aged 6 months to 10 years in Bagamoyo district, Tanzania. Children are randomised to one of three arms: active case detection with molecular (ACDm) testing by high volume quantitative PCR (qPCR), passive case detection also with molecular testing (PCDm) and a control of standard PCD using rapid diagnostics tests (RDTs). Over the 2-year trial, ACDm participants receive malaria testing using RDT and qPCR three times annually, and malaria testing by RDT only when presenting with fever. PCDm and PCD participants receive malaria testing by RDT and qPCR or RDT only, respectively, when presenting with fever. RDT or qPCR positive participants with uncomplicated malaria are treated with artemether lumefantrine. The primary outcome is cumulative incidence of all-cause sick visits. Secondary outcomes include fever episodes, clinical failure after fever episodes, adverse events, malaria, non-malarial infection, antibiotic use, anaemia, growth faltering, cognition and attention, school outcomes, immune responses, and socioeconomic effects. Outcomes are assessed through monthly clinical assessments and testing, and baseline and endline neurodevelopmental testing. The trial is expected to provide key evidence and inform policy on health, cognitive and socioeconomic impact of interventions targeting LMI in children. ETHICS AND DISSEMINATION: Study is approved by Tanzania NatHREC and institutional review boards at University of California San Francisco and Ifakara Health Institute. Findings will be reported on ClinicalTrials.gov, in peer-reviewed journals and through stakeholder meetings. TRIAL REGISTRATION NUMBER: NCT05567016.

Pre-vaccination monocyte-to-lymphocyte ratio as a biomarker for the efficacy of malaria candidate vaccines: A subgroup analysis of pooled clinical trial data.

BACKGROUND: Pre-vaccination monocyte-to-lymphocyte ratio was previously suggested as a marker for malaria vaccine effectiveness. We investigated the potential of this cell ratio as a marker for malaria vaccine efficacy and effectiveness. Effectiveness was investigated by using clinical malaria endpoint, and efficacy was investigated by using surrogate endpoints of Plasmodium falciparum prepatent period, parasite density, and multiplication rates in a controlled human malaria infection trial (CHMI). METHODS: We evaluated the correlation between monocyte-to-lymphocyte ratio and RTS,S vaccine effectiveness using Cox regression modeling with clinical malaria as the primary endpoint. Of the 1704 participants in the RTS,S field trial, data on monocyte-to-lymphocyte ratio was available for 842 participants, of whom our analyses were restricted. We further used Spearman Correlations and Cox regression modeling to evaluate the correlation between monocyte-to-lymphocyte ratio and Whole Sporozoite malaria vaccine efficacy using the surrogate endpoints. Of the 97 participants in the controlled human malaria infection vaccine trials, hematology and parasitology information were available for 82 participants, of whom our analyses were restricted. RESULTS: The unadjusted efficacy of RTS,S malaria vaccine was 54% (95% CI: 37%-66%, p <0.001). No correlation was observed between monocyte-to-lymphocyte ratio and RTS,S vaccine efficacy (Hazard Rate (HR):0.90, 95%CI:0.45-1.80; p = 0.77). The unadjusted efficacy of Whole Sporozoite malaria vaccine in the appended dataset was 17.6% (95%CI:10%-28.5%, p<0.001). No association between monocyte-to-lymphocyte ratio and the Whole Sporozoite malaria vaccine was found against either the prepatent period (HR = 1.16; 95%CI:0.51-2.62, p = 0.72), parasite density (rho = 0.004, p = 0.97) or multiplication rates (rho = 0.031, p = 0.80). CONCLUSION: Monocyte-to-lymphocyte ratio alone may not be an adequate marker for malaria vaccine efficacy. Further investigations on immune correlates and underlying mechanisms of immune protection against malaria could provide a clearer explanation of the differences between those protected in comparison with those not protected against malaria by vaccination.