Phase I evaluation of delta virG Shigella sonnei live, attenuated, oral vaccine strain WRSS1 in healthy adults

Abstract

We conducted a phase I trial with healthy adults to evaluate WRSS1, a live, oral Delta virG Shigella sonnei vaccine candidate. In a double-blind, randomized, dose-escalating fashion, inpatient volunteers received a single dose of either placebo (n = 7) or vaccine (n = 27) at 3 x 10(3) CFU (group 1), 3 x 10(4) CFU (group 2), 3 x 10(5) CFU (group 3), or 3 x 10(6) CFU (group 4). The vaccine was generally well tolerated, although a low-grade fever or mild diarrhea occurred in six (22%) of the vaccine recipients. WRSS1 was recovered from the stools of 50 to 100% of the vaccinees in each group. The geometric mean peak anti-lipopolysaccharide responses in groups 1 to 4, respectively, were 99, 39, 278, and 233 for immunoglobulin (IgA) antibody-secreting cell counts; 401, 201, 533, and 284 for serum reciprocal IgG titers; and 25, 3, 489, and 1,092 for fecal IgA reciprocal titers. Postvaccination increases in gamma interferon production in response to Shigella antigens occurred in some volunteers. We conclude that WRSS1 vaccine is remarkably immunogenic in doses ranging from 10(3) to 10(6) CFU but elicits clinical reactions that must be assessed in further volunteer trials.

FIG. 1.

Excretion of vaccine. Panel A shows the percentage of subjects shedding vaccine on each postinoculation day after receiving a single oral dose of either 10³, 10⁴, 10⁵, or 10⁶ CFU of strain WRSS1. Stools were inoculated in enrichment broth and plated on enteric media. Panel B shows the geometric mean number of CFU per gram of stool on the first 6 postinoculation days in each of the four groups of volunteers. To quantify excretion, stools were serially diluted and plated on MacConkey agar.

FIG. 2.

Reverse cumulative distribution curves (reference 23) by vaccine inoculum for ASC responses to S. sonnei LPS and Ipa. Each curve plots the proportion of vaccine or placebo recipients (ordinate) whose peak ASC count (per 10⁶ PBMC), measured 7 to 10 days postinoculation, equals or exceeds the count shown on the abscissa.

FIG. 3.

IFN-γ production by volunteers following oral immunization with S. sonnei. PBMC obtained from volunteers before immunization and at 28 days after immunization were evaluated for IFN-γ production in response to BSA (negative control) or Shigella antigens (IpaB, IpaC, IpaD, SSh [S. sonnei homogenate], and SSp [S. sonnei particulate]) as described in Materials and Methods. Results are expressed as mean net increases in IFN-γ production following immunization and include all of the evaluated volunteers in each group.