by zygotes (Kaslow et al., 1988). Analogous targets of transmission-blocking antibodies have been identified for P. vivax (Peiris et al., 1988) and various animal malaria parasites.

Impediments to Transmission-Blocking Vaccine Development

Production of Antigen It has been difficult to clone the genes encoding the antigens that are targets of transmission-blocking immunity. Monoclonal antibodies against these antigens appear to recognize conformational epitopes that are not faithfully reproduced by the bacteria in which recombinant DNA libraries are prepared. The use of polyclonal antisera has resulted in cloning other, nontarget antigen genes. It is difficult to culture amounts of sexual stage parasites sufficient to determine the amino acid sequence, which would allow an alternative approach to antibody-based identification. This has slowed the research pace, but various groups appear to have cloned the genes for most or all of the P. falciparum sexual-stage target antigens. Even when the genes are cloned, however, the fact that protective monoclonal antibodies recognize conformational epitopes suggests that expression of recombinant proteins or synthetic peptides that mimic that conformation may be difficult.

Genetic Restriction of the Immune Response Target antigens of transmission blocking antibodies appear to fall into two categories. For Pfs230, Pfs48/ 45, and Pfs40/10, there is significant genetic restriction of T-cell responses in inbred mice (Good et al., 1988b), and only a minority of people living in malaria-endemic areas develop antibodies against these antigens after repeated malaria infections (Graves et al., 1988; Carter et al., 1989; Quakyi et al., 1989). In addition, antigenic variants of Pfs48/45 have been detected (Graves et al., 1985). If genetic restriction proves to be responsible for the limited human immune response to these antigens, this could have an impact on the development of subunit vaccines.

In contrast, Pfs25 is immunogenic and induces transmission-blocking antibodies in all congenic mouse strains tested (Good et al., 1988b; Kaslow et al., 1991), and antibodies are never found in humans living in endemic regions. Pfs25 also was found to lack significant antigenic diversity (Kaslow et al., 1989).

These data suggest that the first group of antigens has been under selective pressure by the host immune system. The absence of genetic restriction in mice and the lack of antibodies to Pfs25 in people living in endemic areas suggest that Pfs25 may be expressed in abundant amounts only when the parasite is in the mosquito midgut, not while circulating in the host's blood, and thus has not been under immune pressure. In either case, the poor or absent human immune response suggests that we may not



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