The broad objective of this research is to develop a Salmonella typhi- based live vector vaccine to prevent Plasmodium falciparum malaria. To achieve the broad objective we must successfully express in a suitable attenuated S. typhi strain protective antigens from the sporozoite, liver and asexual erythrocytic stages of P. falciparum and must demonstrate that these constructs can elicit the relevant types of immune responses in a mouse model. By independently attaining partial protection against the further development of each of these stages of the parasite, and by these effects working in concert, we will expect ultimately to have a vaccine that will prevent disease completely in some subjects and limit the severity of disease in others. At some future point, if sexual stage antigens are added, we might also expect to interfere with transmission of infection to susceptibles in the community. We will express in attenuated S. typhi strain CVD 908 (or further derivative strain CVD 908-htrA) antigens from the sporozoite (TBT) liver (SSP2) and asexual erythrocytic (MSP-1 carboxyl terminus and SERA N-terminus) stages of P. falciparum. We will attempt to enhance the serologic response by co-expressing a mutant heat-labile enterotoxin of Escherichia coli (""""""""K63"""""""") that exhibits powerful adjuvant activity but is non-toxic. We will also attempt to increase the stimulation of cytotoxic lymphocytes (CTLs) by modifying the S. typhi live vector so that it expresses the relevant plasmodial antigens (e.g., TBT, SSP2) of interest as secreted moieties. It is recognized that for intracellular bacteria such as Salmonella, that reside at length within phagosomes of macrophages, secreted proteins tend to elicit the earliest and strongest CTL responses. The mouse intranasal immunization model will be used to compare responses to individual constructs, mixtures of constructs and live vector co-expressing multiple foreign antigens. other research with CVD 908 and CVD 908-htrA live vectors expressing multiple foreign bacterial antigens has clearly demonstrated that it is possible to elicit strong, functional immune responses to the various multiple co-administered antigens.
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