free in the circulation prior to invading other erythrocytes; the asexual parasite that develops within red blood cells; exogenous parasite material released from infected erythrocytes; and the sexual-stage parasite, which occurs both inside erythrocytes and in mosquitoes. The optimal vaccine would include antigens from the sporozoite, asexual, and sexual stages of the parasite, thus providing multiple levels of control, but vaccines effective against individual stages could also prove highly useful. In addition, a vaccine against the Anopheles mosquito itself, which reduced the insect's life span and prevented complete development of the parasite, could be valuable.

Regardless of the stage of parasite targeted for vaccine development, a similar strategy is envisioned. Based on knowledge of the mechanisms of protective immunity, specific parasite antigens (immunogens) are identified that induce a protective immune response, and synthetic or recombinant vaccines that accurately mimic the structure of that antigen are prepared.

In the subunit approach to vaccine development, this is done by combining the immunogen with carrier proteins, adjuvants, and live vectors or other delivery systems. This approach is being pursued throughout the world in laboratories studying infectious diseases. Clinical utility has yet to be demonstrated for the majority of these efforts, and barriers to obtaining satisfactory immunization by the subunit approach remain. Nevertheless, research on malaria subunit vaccines will continue to be at the cutting edge of this innovative and important approach to vaccine development.

Pre-Erythrocytic Vaccines

A pre-erythrocytic vaccine is designed to prevent malaria infection. If all sporozoites and liver stages of the parasite are destroyed before they can mature to cause blood-stage infection, all clinical manifestations of malaria will be prevented. Such a vaccine, even if it induced protection that lasted for only a few months, would be especially useful for tourists, diplomats, businessmen, military personnel, and other short-term visitors to malarious areas, since nonimmune individuals are highly susceptible to the rapid development of severe and fatal malaria. A pre-erythrocytic vaccine could be useful for long-term residents of malarious areas if it induced long-lasting protection, or if immunity could be boosted by natural exposure to malaria.

Mechanisms of Immunity

In the 1960s and 1970s a number of researchers showed that immunization with live sporozoites that were treated in such a way as to be noninfective



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