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Abstract Background The only licensed malaria vaccine, RTS,S/AS01E, confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy (VE).Methods 1,500 children aged 5–17 months were randomized to receive four different RTS,S/AS01E regimens or a rabies control vaccine in a phase 2b clinical trial in Ghana and Kenya. We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods in over 36K participant specimens. We performed a post hoc analysis of VE based on malaria infection status at first vaccination and force of infection.Results We observed significant and comparable VE (25–43%, 95% CI union 9–53%) against first new infection for all four RTS,S/AS01E regimens across both follow-up periods (12 and 20 months). Each RTS,S/AS01E regimen significantly reduced the number of new infections in the 20-month follow-up period (control mean 4.1 vs. RTS,S/AS01E mean 2.6–3.0). VE against first new infection was significantly higher in participants who were malaria-infected (68%; 95% CI, 50 to 80%) versus uninfected (37%; 95% CI, 23 to 48%) at the first vaccination (P=0.0053) and in participants experiencing greater force of infection between dose 1 and 3 (P=0.059).Conclusions All tested dosing regimens blocked some infections to a similar degree. Improved VE in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation. (ClinicalTrials.gov number, NCT03276962)
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