Rethinking a hybrid malaria chemoprevention delivery strategy for children in sub-perennial settings: a modelling study integrating age- and seasonally-targeted delivery.

BACKGROUND: The World Health Organization recommends perennial malaria chemoprevention (PMC), generally using sulfadoxine-pyrimethamine (SP) to children at high risk of severe Plasmodium falciparum malaria. Currently, PMC is given up to age two in perennial transmission settings. However, no recommendation exists for perennial settings with seasonal variation in transmission intensity, recently categorized as 'sub-perennial'. Tailored chemoprevention strategies are needed to protect children during seasons and ages of highest malaria risk. The seasonal dimension must adequately cover seasonally increased risk periods, alongside interventions that address year-round, lower intensity transmission. This study proposes a hybrid malaria chemoprevention (HMC) strategy, integrating two delivery components: (1) existing PMC, and (2) additional monthly SP doses during the higher-risk rainy season, ensuring a one-month gap between any two doses. METHODS: Using a validated individual-based malaria model combined with pharmacological models of drug action (OpenMalaria), the potential public health impact of the proposed HMC (for children 03-24 months), and an age-expanded HMC (referred to as HMC + , for children 03-36 months), under different drug sensitivity, coverage, and prevalence (5-70%) assumptions were examined. RESULTS: The models predicted higher efficacy of HMC and HMC + compared to PMC alone in children under age three, estimating HMC and HMC + provide 2.1 (1.6-2.6) (median (interquartile range)) and 2.9 (2.2-3.6) times (relative fold increase in burden averted) against clinical, and 2.0 (0.6-3.4) and 3.3 (0.8-5.8) against severe cases, respectively. This led to a median protective efficacy of 31.8% (25.4-38.2%), 44.9% (36.9-52.9%) against clinical, and 16.1% (7.0-25.2%), 26.4% (14.4-38.4%) against severe cases by HMC and HMC + , respectively, across the prevalence, drug sensitivity, and coverage assumptions. Under model assumptions, the results indicated a positive net impact for children under five years of age, outweighing the limited potential for delayed malaria. CONCLUSION: Substantially increased public health benefits might be achieved by adding seasonally-targeted chemoprevention to current PMC in sub-perennial malaria transmission settings. Effectiveness-implementation studies will be crucial to generate empirical evidence of public health impact including on the disease burden averted, safety, and cost-effectiveness of the hybrid approach. Such studies should also explore determinants of implementation success including operational feasibility, coverage, and acceptability of proposed dosing strategies to inform deployment decisions.