Auxotrophic live oral Shigella flexneri vaccine protects monkeys against challenge with S. flexneri of different serotypes.

The aromatic-dependent live Shigella flexneri Y strain SFL114, attenuated by a Tn10-inactivated aroD gene, was given as an oral vaccine to 14 Macaca fascicularis monkeys. A significant clinical attenuation of SFL114 was seen (p = 0.0058) as all vaccinated monkeys tolerated 2 x 10(10)-1 x 10(11) bacteria of SFL114, whereas four out of seven monkeys orally given 1 x 10(11) of the virulent parent strain SFL1 developed shigellosis. The average excretion time for SFL114 and SFL1 were 2 and 18 days, respectively. As seen endoscopically SFL1 caused colonic lesions, whereas SFL114 did not. Histopathologic examination of colonic biopsies showed that SFL114 induced only slight acute inflammation, whereas SFL1 caused severe acute inflammation (p less than 0.01). The vaccine strain SFL114 elicited significant species-specific serum immune responses (p less than 0.005) as seen in enzyme immune assays using lipopolysaccharides from S. flexneri serotypes Y, 1b, and 2a and Escherichia coli K-12 as antigens. The titres were comparable to those seen in monkeys given virulent S. flexneri strains. Western blot analyses showed that many prevaccination sera contained antibodies directed against the invasion plasmid-coded polypeptides. However, after vaccination with SFL114 increased amounts of such anti-polypeptide antibodies were seen, particularly in sera from monkeys having a low prevaccination antibody level. SFL114 also elicited a significant species-specific (p less than 0.025) local intestinal sIgA response against the homologous lipopolysaccharide antigen. Vaccinated monkeys were clinically protected against an oral challenge with 1-2 x 10(11) live, virulent S. flexneri strains of any of serotypes Y (strain SFL1), 1b (strain SFL27), or 2a (strain M4243).(ABSTRACT TRUNCATED AT 250 WORDS)