R21 malaria vaccine is protective against intradermal but not intravenous Plasmodium falciparum sporozoites in a randomized controlled human malaria infection study in Kenyan adults

Falciparum malaria is a substantial public health problem. Vaccines and monoclonal antibodies targeting the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) are promising control strategies. The protective mechanisms of anti-PfCSP antibodies are incompletely understood, and levels of anti-PfCSP antibodies are inconsistently predictive of protection. We undertook controlled human malaria infections in volunteers vaccinated with the PfCSP-based vaccine R21/Matrix-M, using either intradermal injection (ID) or direct venous inoculation (DVI) of P. falciparum sporozoites (PfSPZ Challenge). R21/Matrix-M was highly protective against intradermal inoculation of PfSPZ Challenge (i.e. 100%, 12 out of 12) but not protective against PfSPZ Challenge by DVI (i.e. 0%, 0 out of 5). These findings imply that the variable delivery of Pf sporozoites into capillaries rather than the subdermal layers by infectious mosquito bites can account for the inconsistent protection provided by anti-PfCSP antibodies.