Vaccination against shigellosis with attenuated Shigella flexneri 2a strain SC602

The Shigella flexneri 2a SC602 vaccine candidate carries deletions of the p lasmid-borne virulence gene icsA (mediating intra- and intercellular spread ) and the chromosomal locus iuc (encoding aerobactin) (S. Barzu, A. Fontain e, P. J. Sansonetti, and A. Phalipon, Infect. Immun. 64:1190-1196, 1996). D ose selection studies showed that SC602 causes shigellosis in a majority of volunteers when 3 x 10(8) or 2 x 10(6) CFU are ingested. In contrast, a do se of 10(4) CFU was associated with transient fever or mild diarrhea in 2 o f 15 volunteers. All volunteers receiving single doses of greater than or e qual to 10(4) CFU excreted S. flexneri 2a, and this colonization induced si gnificant antibody-secreting cell and enzyme-linked immunosorbent assay res ponses against S. flexneri 2a lipopolysaccharide in two-thirds of the vacci nees. Seven volunteers who had been vaccinated 8 weeks earlier with a singl e dose of 104 CFU and 7 control subjects were challenged with 2 x 10(3) CFU of virulent S. flexneri 2a organisms. Six of the control volunteers develo ped shigellosis with fever and severe diarrhea or dysentery, while none of the vaccinees had fever, dysentery, or severe symptoms (P = 0.005). Three v accinees experienced mild diarrhea, and these subjects had lower antibody t iters than did the fully protected volunteers. Although the apparent window of safety is narrow, SC602 is the first example of an attenuated S. flexne ri 2a candidate vaccine that provides protection against shigellosis in a s tringent, human challenge model.