insertion of the CS protein gene into attenuated strains of Salmonella creates a vaccine that can protect mice from sporozoite-induced malaria (Sadoff et al., 1988; Aggarwal et al., 1990). Although it is relatively easy to produce vaccines for animal immunization studies, production of subunit vaccine antigens of sufficient purity for trials in human volunteers is more difficult and expensive. Research laboratories studying malaria immunity are not equipped to produce these high-quality vaccines, and collaboration with pharmaceutical or biotechnology companies is generally necessary.

Induction of the Appropriate Immune Response

ANTIBODIES Administration of monoclonal antibodies directed against specific sporozoite B-cell epitopes can protect animals against sporozoite-induced malaria. Inducing high levels of antibody is thus one objective of immunization with sporozoite vaccines. Early subunit vaccines conferred complete protection from sporozoite-induced malaria in a small number of immunized volunteers who were experimentally exposed to the bites of infected mosquitoes, and they delayed the onset of blood-stage infection in other volunteers who had antibodies (Ballou et al., 1987; Herrington et al., 1987). Overall, however, these vaccines induced relatively low levels of antibody (Chulay, 1989). These antibody levels were lower than those to the same vaccine in mice and rabbits. They were also lower than the highest antibody levels induced by natural exposure to the bites of sporozoite-infected mosquitoes (Hoffman et al., 1987), and such levels of antibody are not protective.

One way to increase the level of antibody induced by sporozoite vaccines is to change the carrier protein and the adjuvant. Early results suggest this approach can increase the level of antibody 10-fold (Rickman et al., 1991).

The quantity of antibody is not the only determinant of protection, however. High levels of antisporozoite antibodies were achieved after immunization with the P. falciparum repetitive B-cell epitope coupled to a bacterial protein, but only one of eight volunteers was protected against malaria, and that individual did not have one of the highest levels of antibody (L. Fries, Associate Professor of International Health, Center for Immunization Research, Johns Hopkins School of Hygiene and Public Health, personal communication, 1990). The specificity of the antibody response is also important. For example, monkeys can be protected from sporozoite-induced P. vivax malaria by administration of a monoclonal antibody directed against the CS protein (Charoenvit et al., 1991b). This monoclonal antibody recognizes a four-amino-acid B-cell epitope contained within the nine amino acids of the repetitive portion of the CS protein (Charoenvit et al., 1991b). A recombinant P. vivax sporozoite vaccine containing all

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