Community-based safety, immunogenicity, and transmissibility study of the Shigella sonnei WRSS1 vaccine in Israeli volunteers

Abstract

We describe the first community-based evaluation of Shigella sonnei strain WRSS1, a live, oral candidate vaccine attenuated by a 212-bp deletion in the virG (or icsA) plasmid virulence gene. Three single-dose regimens of WRSS1 (5 x 10(3) CFU, 2 x 10(4) CFU, and 4 x 10(5) CFU) were tested with cohorts of 15 adult volunteers. The vaccine was generally well tolerated at the 10(3)- and 10(4)-CFU doses. There were no fevers and there was one report of moderate diarrhea in 30 vaccinees; five additional vaccinees reported mild diarrhea. At the 10(5)-CFU dose, there were two reports of low-grade fevers and four reports of moderate diarrhea. The geometric means for immunoglobulin A (IgA) antibody-secreting cells (ASC) against lipopolysaccharide (LPS) were 30, 75, and 193 ASC per 10(6) peripheral blood mononuclear cells (PBMC) for the 10(3)-, 10(4)-, and 10(5)-CFU doses, respectively. The IgG means were 40, 46, and 135 ASC per 10(6) PBMC, respectively. The 10(4)-CFU dose of WRSS1 gave the best balance of safety and immunogenicity, since all vaccinees had a significant IgA ASC response and 73% had a response of more than 50 ASC. The anti-LPS seroconversion rate (threefold) for IgA was 60% and the IgG rate was 27% for the 10(4)-CFU cohort. Each vaccinee and a cohabitating household contact delivered daily perianal stool swabs for bacteriological culture. WRSS1 colonized vaccinees for a median of 5 days, and one individual excreted WRSS1 intermittently for 23 days. None of the 45 household contacts were colonized with WRSS1 after a cumulative 192 days of cohabitation with colonized vaccinees, suggesting that adventitious vaccine spread was not common in the community setting.

FIG. 1.

Isolation of WRSS1 from stool cultures of vaccinees or household contacts. The number of days positive for WRSS1 includes all days from the first day of vaccine culture until the last day of vaccine culture regardless of the number of positive or negative cultures between these two events. Data for each vaccinee-contact pair are aligned vertically.

FIG. 2.

Peak numbers of IgA and IgG ASC against S. sonnei LPS with the GMT for each dose of WRSS1. The solid line indicates 3 SD of the day 0 mean IgA or IgG ASC values for all volunteers; the dotted line indicates 10 ASC per 10⁶ PBMC; and the dashed line indicates 50 ASC per 10⁶ PBMC.

FIG. 3.

Rates of threefold ELISA anti-LPS seroconversion at day 14 for each dose of WRSS1.