Two vaccines are now approved for use against Plasmodium falciparum malaria in young African children; these can prevent liver infection. However, if a single parasite slips through the net, blood-stage infection is established causing clinical disease. An effective blood-stage vaccine (or second line of defence), however, has proved elusive. We have developed vaccines targeting the P. falciparum RH5 antigen, which mediates a conserved and essential invasion pathway into the human red blood cell. Rational vaccine design has built on our understanding of how vaccine-induced anti-RH5 human antibodies inhibit parasite growth. This talk will describe our work to understand human anti-malarial antibodies and present data from Phase 1/2 clinical trials of RH5-based blood-stage vaccines undertaken in the UK and across Africa.