Malaria vaccine protection against intradermal or venous parasites: a randomized phase 2b human challenge trial

Abstract Two licensed vaccines block Plasmodium falciparum malaria sporozoites through anticircumsporozoite protein antibodies. In animal models, intradermal (ID) sporozoites are more readily blocked than intravenous sporozoites. We hypothesized that this complicates human studies, where infectious mosquito bites deliver a mixture of ID and venous sporozoites. Here, to test whether vaccine efficacy varies by route of inoculation, we undertook a phase 2b open, randomized controlled trial, recruiting healthy volunteers in Kenya for randomization to the circumsporozoite protein-based R21/Matrix-M vaccine ( n  = 38), thrombospondin-related adhesive protein fused to a multi-epitope string (ME-TRAP)-based vaccines ( n  = 24) or to control ( n  = 18). We enrolled 37 of these volunteers to controlled human malaria infection (CHMI) using ID or direct venous injection (DVI) of sporozoites, with PCR monitoring of parasitemia. Systemic and local postvaccination adverse events and systemic CHMI-related events were detected in 4.8%, 12.9% and 72.9% of volunteers, respectively, most commonly fever, headache and fatigue. No serious or severe adverse events were seen. Seven of 8 (88%) control volunteers and 11 of 12 (92%) ME-TRAP vaccinated volunteers, but none of the 12 R21 vaccinated volunteers receiving ID challenge met the prespecified treatment criteria for the primary endpoint. However, five of five R21 vaccinated volunteers receiving DVI sporozoites met the primary endpoint ( P  < 0.0005 by log rank across all groups). Secondary efficacy outcomes were similar; that is, R21 vaccinated volunteers receiving ID challenge did not meet any secondary endpoints, whereas volunteers for other groups met secondary endpoints between days 7 and 21 ( P  < 0.0005, P  = 0.0001, P  = 0.0007 and P  < 0.0005 by log rank for time to parasitemia >20, >500, >1,000 and >10,000, respectively). R21/Matrix-M was highly protective against CHMI using ID. inoculation of sporozoites, but not against DVI sporozoites. CHMI is used in clinical development to select efficacious vaccines and to define correlates of efficacy. Correlates of efficacy for antibodies to sporozoites should also be assessed by separate DVI and ID challenges. The study was registered with ClinicalTrials.gov ( NCT03947190 ) and PACTR ( PACTR202108505632810 ).