Performance characteristics and potential public health impact of improved pre-erythrocytic malaria vaccines targeting childhood burden

New malaria vaccine development builds on groundbreaking recommendations and roll-out of two approved pre-erythrocytic vaccines (PEVs); RTS,S/AS01 and R21/Matrix-M. Whilst these vaccines are effective in reducing childhood malaria within yearly routine immunization programs or seasonal vaccination, there is little evidence on how different PEV efficacies, durations of protection, and spacing between doses influence the potential to avert uncomplicated and severe childhood malaria. Mainly, lacking understanding of the required vaccine properties and delivery strategies that lead to an effective childhood vaccine with multi-year protection. We used an individual-based model of malaria transmission informed by trial data to quantify trade-offs between PEV performance properties and impact across different endemicities, deployment schedules, and coverage levels. We found that deploying a vaccine with 90% initial efficacy against infection, with a six to 12-month half-life duration of protection, co-administered with a blood-stage drug, followed by yearly boosters, results in 60-80% yearly incidence reduction, consistent with seasonal RTS,S and R21 trials. Halting vaccination after five years, leads to sustained protection of at least a 35% incidence reduction in children less than six years in the 12 months following cessation in settings where PfPR2-10 < 30%. Increasing the half-life duration to 12-18 months or reaching more children provides the same health impact with lower vaccine efficacy. Without a booster (fourth dose), high efficacy against infection (>90%) and longer half-life duration (>12 months) are required to sustain impact beyond primary vaccination, averting up to half the preceding year's burden. The contribution of each property to the overall impact varies by setting and clinical endpoint, indicating that public health goals should dictate key vaccine performance criteria. Overall, our findings support the need for well-defined target product profiles for long duration vaccines linking priority use cases of where, how, and to whom to deploy new malaria vaccines, to maximize public health impact.