Malaria vaccines: are we getting closer?

Forty years ago, researchers first demonstrated that immunization with irradiated sporozoites could protect against malaria infection, providing the impetus for the development of a malaria vaccine. Twenty five years ago, the circumsporozoite protein (CSP), a sporozoite surface antigen that is required to establish infection, became the first Plasmodium falciparum gene to be cloned, and a vaccine based on this antigen appeared imminent. However, today we are still without a highly effective malaria vaccine, despite considerable progress achieved during many years of research and development. This review highlights the most recent test-of-concept studies involving subunit vaccines; to illustrate this field of research, five antigens--CSP, TRAP/SSP2, LSA1, MSP1 and AMA1--are discussed. These antigens have all entered clinical trials evaluating efficacy against experimental sporozoite challenge (phase IIa) and/or exposure to natural infection (phase IIb). Challenges facing the development of subunit-based vaccines are discussed, and strategies for improving their efficacy above that observed with the current leading vaccine candidate, RTS,S, are described. In addition, recent progress in the development of whole-organism vaccines is presented.