Malaria is a public health problem of overwhelming importance for the developing world. The long-term objective of this proposal is to develop a vaccine that reduces the morbidity and mortality of Plasmodium falciparum malaria. Toward that objective we propose to enhance the immunogenicity of malaria parasite antigens by using a multipurpose plasmid vector for the expression of fusion polypeptides that has been shown to enhance the immunogenicty of otherwise non-immunogenic heterologous antigens in a Salmonella carrier. Previous studies indicate that such constructs may be given orally and may be equally effective live or killed, thus potentially obviating the problem of giving a live bacterial vaccine to persons with HIV infection. The antigen we have chosen to study is Merozoite Surface Protein-1 (MSP-1), which has been shown to protect against infection with P. falciparum in vitro and in vivo by an antibody-dependent mechanism.
The specific aims of this proposal are to 1] develop novel plasmid constructs expressing the 42 kDa C-terminal fragment of MSP-1 (MSP-142) using this approach, 2] Test the immunogenicity of these constructs in mice, and determine whether they elicit antibodies that inhibit the growth of P. falciparum in vitro, 3] Test the immunogenicity of these constructs in monkeys, 4] Challenge immunized monkeys to determine whether immunization protects against infection with the homologous FVO P. falciparum parasite, and 5] Challenge immunized monkeys to determine whether immunization protects against infection with a heterologous (FUP) P. falciparum parasite. This strategy, if successful, offers the potential for an economical malaria vaccine based on the oral administration of killed (and therefore nontoxic) Salmonella.
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