R21/Matrix-M protects against dermal but not against venous parasites in a randomised controlled human challenge study

Journal article

Two licensed Plasmodium falciparum malaria vaccines induce anti-circumsporozoite protein antibodies that block 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, 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. Non-severe self-limiting general and local solicited adverse events were detected in 4.8% and 12.9% of volunteers after vaccination, respectively, and general adverse events were detected in 72.9% during CHMI. No adverse event was classified as serious or severe.

R21/Matrix-M was highly protective against CHMI using intradermal (ID) inoculation of sporozoites (i.e. 0 out of 12 volunteers met the primary endpoint) but not protective against direct venous inoculation (DVI) (i.e. 5 out of 5 volunteers met the primary endpoint), p<0.001 by Fisher’s exact test. Volunteers vaccinated with viral vectors encoding ME-TRAP antigens were not protected against intradermal inoculation.

Antibody-based correlates of protection for sporozoite vaccines should be defined separately for DVI vs ID inoculation.

The study was registered with ClinicalTrials.gov (NCT03947190) and PACTR (PACTR202108505632810).

Authors: Kapulu, M; Orenge, F; Kimani, D; Datoo, MS; Bellamy, D

• Publication status: Accepted
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Nature Medicine
• Acceptance date: 2025-09-22
• EISSN: 1546-170X
• ISSN: 1078-8956
• Language: English