SAFETY AND IMMUNOGENICITY STUDY OF THE AUXOTROPHIC SHIGELLA-FLEXNERI 2A VACCINE SFL1070 WITH A DELETED AROD GENE IN ADULT SWEDISH VOLUNTEERS

The live auxotrophic Shigella flexneri 2a vaccine strain SFL1070 with a deleted aroD gene was given orally to 37 adult Swedish volunteers wh o received three doses within 5 days, Each dose comprised 1x10(5) (n=9 ), 1x10(7) (n=10), 1x10(8) (n=9) or 1x10(9) (n=9) c.f.u. S. flexneri S FLI070. One volunteer vaccinated with 1x10(7) and three vaccinated wit h 1x10(8) c.f.u. reported mild gastrointestinal symptoms after the fir st dose, Vaccination with 1x10(9) c.f.u. caused abdominal pain and wat ery diarrhoea in four volunteers who all recovered spontaneously withi n 72 h. S. flexneri SFL1070 was Mot recovered from volunteers given 1x 10(5) c.f.u., but was shed in faeces by six volunteers vaccinated with 1x10(7), by all nine vaccinated with 1x10(8), and by seven volunteers vaccinated with 1x10(9) c.f.u. The mean excretion time was 2.6 (range 0-4) days in the 1x10(8) and the 1x10(9) groups. Serum antibody respo nses against either S. flexneri 2a and Y lipopolysaccharides (LPSs) or Shigella invasion plasmid antigens (Ipa) were seen in eight volunteer s vaccinated with 1x10(9) (p<0.01 to p<0.05 for mean relative titres o f IgA and IgG against S. flexneri 2a and Y LPSs), in four vaccinated w ith 1x10(8), and in two and one volunteers each vaccinated with 1x10(7 ) and 1x10(5) c.f.u. of S. flexneri SFL1070. Intestinal sIg A response s to the same antigens were elicited in all volunteers in the 1x10(9) and the 1x10(8) groups, and in six and one volunteers vaccinated with 1x10(7) and 1x10(5) c.f.u., respectively. The sIgA responses against S . flexneri 2a and Y LPSs were significant in all but the 1x10(5) group (p<0.01 to p<0.05). Significant antibody-secreting cell (ASC) respons es specific to S. flexneri 2a LPS were seen in peripheral blood from e ight volunteers each in the 1x10(9) and 1x10(8) groups and from five v olunteers vaccinated with 1x10(7) c.f.u. (p<0.01 to p<0.05). The numbe r of volunteers showing anti-Shigella Ipa ASC responses in these group s were five (p<0.01 to p<0.05), three and one, respectively. Interfero n-gamma (IFN-gamma)-secreting T-cell responses were seen in all volunt eers vaccinated with 1x10(8) and 1x10(9) c.f.u. S. flexneri SFL1070 af ter stimulation of peripheral blood mononuclear cells with S. flexneri 2a polysaccharide antigen (p<0.01 to p<0.05), and in five volunteers in each of these groups after stimulation with Shigella Ipa (p<0.01 to p<0.05), S. flexneri SFL1070 is at least 100 000-fold attenuated comp ared with its wild-type pal ent strain 2457T. Immune responses, vaccin e excretion and side-effects are dose-dependent in Swedish volunteers orally vaccinated with live S. flexneri 2a SFL1070. The optimal dose o f S. flexneri SFL1070 is 1x10(8) c.f.u., which combines immunogenicity in all volunteers with mild gastrointestinal side-effects in three of nine volunteers only.