Shigella flexneri 2a Strain CVD 1207, with Specific Deletions in virG , sen , set , and guaBA , Is Highly Attenuated in Humans

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Abstract
A phase 1 clinical trial was conducted among 35 healthy adult volunteers to evaluate the safety, immunogenicity, and shedding of different doses of CVD 1207, a live attenuated Shigella flexneri 2a vaccine candidate with specific deletion mutations in virG , sen , set , and guaBA . CVD 1207 retains the ability to invade epithelial cells but cannot effectively spread intercellularly after invasion (Δ virG ), does not produce enterotoxin (Δ sen and Δ set ), and has limited proliferation in vivo (Δ guaBA ). In a consecutive fashion, groups of three to seven subjects ingested a single oral dose of CVD 1207 at an inoculum of either 10 6 , 10 7 , 10 8 , 10 9 , or 10 10 CFU. CVD 1207 was remarkably well-tolerated at inocula as high as 10 8 CFU. In comparison, one of 12 subjects who received 10 9 CFU experienced mild diarrhea and another experienced a single episode of emesis. One of five subjects who received 10 10 CFU experienced watery diarrhea and emesis. All subjects who ingested doses of 10 8 to 10 10 CFU excreted the vaccine; in 23 of 25, the duration of excretion was ≤3 days. A dose-related, immunoglobulin A antibody-secreting cell (ASC) response to S. flexneri 2a O-specific lipopolysaccharide was seen, with geometric mean peak values of 6.1 to 35.2 ASCs/10 6 peripheral blood mononuclear cells (PBMC) among recipients of 10 7 to 10 10 CFU. The cytokine response to Shigella -specific antigens observed in volunteers' PBMC following vaccination suggested a Th1 pattern with stimulation of gamma interferon and absence of interleukin 4 (IL-4) or IL-5. CVD 1207 represents a Shigella live oral vaccine strain prepared from wild-type S. flexneri 2a by rational use of recombinant DNA technology that achieves a remarkable degree of attenuation compared with earlier recombinant strains, even when administered at high dosage.