SALMONELLA-TYPHI VACCINE STRAIN CVD-908 EXPRESSING THE CIRCUMSPOROZOITE PROTEIN OF PLASMODIUM-FALCIPARUM - STRAIN CONSTRUCTION AND SAFETY AND IMMUNOGENICITY IN HUMANS

rcsp, encoding amino acids 21-398 of Plasmodium falciparum circumsporozoite protein (CSP), under control of P-tac was integrated into the chromosomal Delta aroC locus of attenuated Delta aroC, Delta aroD Salmonella typhi CVD 908. By immunoblot and ELISA, rCSP expression was greater from a multicopy plasmid than from the single chromosomal gene. CVD 908 Omega(Delta aroC1019::P-tac-rcsp) was well tolerated by 10 volunteers who were fed two doses of 5 x 10(7) organisms 8 days apart. Seven subjects excreted the vaccine strain for 1-3 days. All subjects developed serologic responses to O and H antigens of the live vector, whereas 3 vaccinees responded to the foreign antigen: 1 developed an 80-fold rise in serum anti-sporozoite antibody, another had a 4-fold rise in antibody to a recombinant portion of CSP (residues 309-345), while a third vaccinee developed CSP-specific CD8(+) cytotoxic T lymphocyte activity. This is the first report of attenuated S. typhi eliciting a human serologic or a cytotoxic T lymphocyte response to a foreign protein. Improved foreign gene expression should enhance immunogenicity.