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

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 (⌬virG), does not produce enterotoxin (⌬sen and ⌬set), and has limited proliferation in vivo (⌬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

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“…When volunteers ingested escalating single doses of up to 10 10 CFU of CVD 1207 (REF. 87), this live vaccine strain was remarkably well tolerated. No subjects manifested adverse reactions through the 10 8 CFU dosage level 87 , and even at 10 9 and 10 10 CFU only a few volunteers experienced mild diarrhoea 87 .…”

“…87), this live vaccine strain was remarkably well tolerated. No subjects manifested adverse reactions through the 10 8 CFU dosage level 87 , and even at 10 9 and 10 10 CFU only a few volunteers experienced mild diarrhoea 87 . The conclusion from the Phase I clinical trial of CVD 1207 was that the mutations definitively attenuated the 2457T parent strain, resulting in a vaccine that was well tolerated by North American volunteers at high dosage levels yet remained immunogenic.…”

“…These mutations include aroD and aroA (which encode enzymes in the aromatic amino-acid biosynthesis pathway; mutation makes mutants auxotrophic for substrates not found in sufficient concentration in mammalian tissues) 85,86 , virG 28, 87 , iuc (which encodes aerobactin) 28 , guaBA (which encodes enzymes involved in guanine-nucleotide biosynthesis) 87,88 , set (which encodes ShET1) and sen (which encodes ShET2) 87,88 .…”

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“…4B). Although the ⌬virG strain has been used as an attenuated live vaccine in several studies, including in clinical trials (14,21,(25)(26)(27), these findings suggested that bacteria with single mutation in the virG gene retain virulence in mice when inoculated with a large number of bacteria. Low dose (2 ϫ 10 7 CFU) infection of ⌬virG also caused significant body weight loss, to a maximum of 22.3 Ϯ 5.53% ( p Ͻ 0.05; n ϭ 10), compared with the saline-vaccinated mice.…”

“…These strains have been classified into two groups on the basis of the function of the mutated gene: 1) strains in which one or two genes in the metabolism have been inactivated, such as thyA, aroA, and aroD (15)(16)(17), and 2) strains harboring mutation of virG (icsA), a gene essential for cell-to-cell spreading, in addition to one of above gene mutations (18 -24). The ⌬virG strain has been widely used as an attenuated live vaccine strain or in combination with mutation in other gene(s) in several studies, including in clinical trials (14,21,(25)(26)(27). The vaccine strain, SC602, which has mutations in the virG gene and the aerobactin iuc locus, has proceeded to phase 2 trials in humans.…”