Background: Vaccines, monoclonal antibodies, and long-acting injectables are being developed to prevent Plasmodium falciparum malaria. These therapeutics may target multiple stages of the parasite life cycle, and evidence is needed to articulate their benefits with chemoprevention and prioritise candidates for clinical development. Methods: We used an individual-based malaria transmission model to estimate the health impact of combining new therapeutics with seasonal malaria chemoprevention (SMC). Our modelling framework used emulator-based methods with models of pre-liver and blood stage therapeutic dynamics. We evaluated the benefit of combining therapeutics with SMC in children under five by estimating reductions in the cumulative incidence of uncomplicated and severe malaria, relative to SMC or the new therapeutic alone, during and five years after deployment. Results: New therapeutics may require extended pre-liver stage duration or multi-stage activity to combine with SMC. For three SMC cycles in a high transmission setting, a pre-liver stage therapeutic with partial initial efficacy (>50%) required a protection half-life >230 days to reduce cumulative severe cases by >5% five years after deployment stopped (>23% during interventions). Longer protection was needed when combined with four or five SMC cycles. Combining SMC with a multi-stage therapeutic increased public health impact both during and after deployment. Conclusions: Combining SMC with malaria therapeutics active against multiple stages of the parasite life cycle can improve the effectiveness of SMC, highlighting the need to prioritise the clinical development of these therapeutics for combination with malaria chemoprevention.

The authors have declared no competing interest.

LBM, JM, NN, and SLK were funded by the Bill & Melinda Gates Foundation (INV-002562 to MAP). MAP acknowledges support from the Swiss National Science Foundation (SNF Professorship PP00P3_170702 and PP00P3_203450). JJM was an employee of Medicines for Malaria Venture (MMV).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes