A phase I trial of WRSS1, a Shigella sonnei live oral vaccine in Bangladeshi adults and children

Abstract

Shigella sonnei live vaccine candidate, WRSS1, which was previously evaluated in US, Israeli and Thai volunteers, was administered orally to Bangladeshi adults and children to assess its safety, clinical tolerability and immunogenicity. In a randomized, placebo-controlled, dose-escalation, age-descending study, 39 adults (18-39 years) and 64 children (5-9 years) were enrolled. Each adult cohort (n = 13) received one dose of 3x10⁴, or three doses of 3 × 10⁵ or 3 × 10⁶ colony forming unit (CFU) of WRSS1 (n = 10) or placebo (n = 3). Each child cohort (n = 16) received one dose of 3x10³, or three doses of 3x10⁴, 3x10⁵, or 3 × 10⁶ CFU WRSS1 (n = 12) or placebo (n = 4). WRSS1 elicited mostly mild and transient reactogenicity events in adults and children. In the 3 × 10⁶ dose group, 50% of the adults shed the vaccine; no shedding was seen in children. At the highest dose, 100% of adults and 40% of children responded with a ≥ 4-fold increase of S. sonnei LPS-specific IgA antibody in lymphocyte supernatant (ALS). At the same dose, 63% of adults and 70% of children seroconverted with IgA to LPS, while in placebo, 33% of adults and 18% of children seroconverted. Both the vaccinees and placebos responded with fecal IgA to LPS, indicating persistent exposure to Shigella infections. In conclusion, WRSS1 was found safe up to 10⁶ CFU dose and immunogenic in adults and children in Bangladesh. These data indicate that live, oral Shigella vaccine candidates, including WRSS1 can potentially be evaluated in toddlers and infants (<2 years of age), who comprise the target population in an endemic environment.

Keywords: vaccine; Bangladesh; WRSS1; adult; children; endemic region; phase I trial.

Figure 1.

CONsolidated Standards of Reporting Trials (CONSORT) diagram showing screening, enrollment, allocation of vaccine/placebo, completion of intervention, and follow-up status of Bangladeshi (a) Adults and (b) Children participants. Each cohort of 13 adults (10 vaccinees and 3 placebo recipients) received either one dose of 3 × 10⁴ (cohort A1) or three doses of 3 × 10⁵ (cohort A2) or 3 × 10⁶ (cohort A3) CFU of WRSS1 vaccine or placebo. Each cohort of 16 children (12 vaccinees and 4 placebos) received either one dose of 3 × 10³ (cohort B1) or three doses of 3 × 10⁴ (cohort B2), 3 × 10⁵ (cohort B3) or 3 × 10⁶ (cohort B4) CFU of vaccine or placebo.

Figure 2.

Outline for administration of vaccine/placebo, follow-up and specimen collection. Schedule for multi-dose cohorts (cohorts A2, A3, B2, B3 and B4) is given here. First vaccination and immediate inpatient safety evaluation for 72h was performed at the Clinical Trials Unit (CTU) of icddr,b. The second and third doses were given on an outpatient basis at the field office. Outpatient follow-up at day 7, 35, 63 and 84 were carried out at the field office. Long term safety follow-up took place at day 224 at the participants’ home. cohorts A1 and B1were given single dose on day 0, followed-up on day 7 and 28, and long term safety follow-up was made on day 168.

Figure 3.

S. sonnei LPS-specific serum IgA and IgG antibody titers before and after administration of WRSS1vaccine or placebo in Bangladeshi adults (panels A, C) and children (panels B, D). Data are presented as Geometric mean with 95% confidence interval.