Abstract
The live auxotrophic Shigella flexneri 2a vaccine strain SFL1070 with a deleted aroD gene was given orally to 37 adult Swedish volunteers who received three doses within 5 days. Each dose comprised 1 × 10 5 ( n = 9), 1 × 10 7 ( n = 10), 1 × 10 8 ( n = 9) or 1 × 10 9 ( n = 9) c. f. u. S. flexneri SFL1070. One volunteer vaccinated with 1 × 10 7 and three vaccinated with 1 × 10 8 c. f. u. reported mild gastrointestinal symptoms after the first dose. Vaccination with 1 × 10 9 c. f. u. caused abdominal pain and watery diarrhoea in four volunteers who all recovered spontaneously within 72 h. S. flexneri SFL1070 was not recovered from volunteers given 1 × 10 5 c. f. u., but was shed in faeces by six volunteers vaccinated with 1 × 10 7, by all nine vaccinated with 1 × 10 8, and by seven volunteers vaccinated with 1 × 10 9 c. f. u. The mean excretion time was 2.6 (range 0–4) days in the 1 × 10 8 and the 1 × 10 9 groups. Serum antibody responses against either S. flexneri 2a and Y lipopolysaccharides (LPSs) or Shigella invasion plasmid antigens (Ipa) were seen in eight volunteers vaccinated with 1 × 10 9 ( p < 0.01 to p < 0.05 for mean relative titres of IgA and IgG against S. flexneri 2a and Y LPSs), in four vaccinated with 1 × 10 8, and in two and one volunteers each vaccinated with 1 × 10 7 and 1 × 10 5 c. f. u. of S. flexneri SFL1070. Intestinal sIgA responses to the same antigens were elicited in all volunteers in the 1 × 10 9 and the 1 × 10 8 groups, and in six and one volunteers vaccinated with 1 × 10 7 and 1 × 10 5 c. f. u., respectively. The sIgA responses against S. flexneri 2a and Y LPSs were significant in all but the 1 × 10 5 group ( p < 0.01 to p < 0.05). Significant antibody-secreting cell (ASC) responses specific to S. flexneri 2a LPS were seen in peripheral blood from eight volunteers each in the 1 × 10 9 and 1 × 10 8 groups and from five volunteers vaccinated with 1 × 10 7 c. f. u. ( p < 0.01 to p < 0.05). The number of volunteers showing anti- Shigella Ipa ASC responses in these groups were five ( p < 0.01 to p < 0.05), three and one, respectively. Interferon-γ (IFN-γ)-secreting T-cell responses were seen in all volunteers vaccinated with 1 × 10 8 and 1 × 10 9 c. f. u. S. flexneri SFL1070 after 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 compared with its wild-type parent strain 2457T. Immune responses, vaccine excretion and side-effects are dose-dependent in Swedish volunteers orally vaccinated with live S. flexneri 2a SFL1070. The optimal dose of S. flexneri SFL1070 is 1 × 10 8 c. f. u., which combines immunogenicity in all volunteers with mild gastrointestinal side-effects in three of nine volunteers only.
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