R21/Matrix-M Protects Against Dermal but not Against Venous Parasites in Human Challenge Studies

Both licensed Plasmodium falciparum malaria vaccines induce anti-circumsporozoite protein antibodies that block the malaria sporozoites injected by mosquitoes. Animal models show that sporozoites in the skin are more readily blocked than intravenous sporozoites. Controlled human malaria infections (CHMI) is usually done using infectious mosquito bites to predict efficacy in the field, but mosquito bites deliver a mixture of sporozoites into dermal layers and into capillaries. We undertook CHMI in volunteers vaccinated with the CSP-based R21/Matrix-M vaccine or with ME-TRAP-based viral vectored vaccines. R21/Matrix-M was highly protective against CHMI using intradermal inoculation of sporozoites (i.e. 0 out of 12 volunteers met treatment criteria) but not protective against direct venous inoculation (i.e. 5 out of 5 volunteers met treatment criteria). Volunteers vaccinated with viral vectors encoding ME-TRAP antigens were not protected against intradermal inoculation. Defining protective efficacy separately against direct venous inoculation and against intradermal inoculation enhances our mechanistic understanding of vaccination. The study was registered with the ClinicalTrials.gov ( NCT03947190 ) and with PACTR (PACTR202108505632810).