Pronouncements have been made for more than 25 years that the development and implementation of a highly effective malaria vaccine is imminent. In the case of pre-erythrocytic stage malaria vaccines, these hopes have been based largely on the observation that immunization of volunteers by the bite of mosquitoes carrying radiation-attenuated, live Plasmodium falciparum sporozoites induces immune responses that completely prevent infection upon challenge with fully virulent sporozoites. 1-12 Live, attenuated, infectious agent vaccines represent about 50% percent of currently licensed vaccines; 13 providing a record of safety and efficacy over many years and billions of doses. In the eighteenth century Jenner demonstrated the protective effect of vaccination with cowpox infection against smallpox. 14 Numerous successful vaccines were subsequently developed, despite minimal understanding of the biological mechanisms and protein and epitope targets of protective immunity. These successes include the development and widespread deployment in the twentieth century of attenuated vaccines against viruses (eg, polio, measles, mumps rubella, yellow fever, Japanese encephalitis), and bacteria (eg, the BCG vaccine for tuberculosis, 15 cholera and typhoid fever16, 17).

In 2002 we updated and summarized the published literature on immunizing humans by the bite of radiation-treated Anopheles mosquitoes infected with P. falciparum sporozoites. 12 Fourteen volunteers were immunized by the bite of greater than 1,000 P. falciparum sporozoite-infected, irradiated mosquitoes during a minimum of 5 and a maximum of 19 immunizing mosquito biting sessions (median= 9.5). When challenged by the bite of five non-irradiated P. falciparum-infected mosquitoes 2–10 weeks after their final primary immunization, 13 of the 14 volunteers (93%) were protected against asexual erythrocytic stage infection with P. falciparum. Six of the volunteers were re-challenged a total of 15 times within 2–10 weeks of final primary (n= 1) or secondary (n= 5) immunization and all six volunteers were entirely protected in all 15 challenges (100%). Six volunteers were challenged between 23 and 42 weeks (weeks 23, 36, 36, 39,