title: Safety, immunogenicity, and efficacy in monkeys and humans of invasive Escherichia coli K-12 hybrid vaccine candidates expressing Shigella flexneri 2a somatic antigen.
abstract: A live, oral Shigella vaccine, constructed by transfer of the 140-MDa invasiveness plasmid from Shigella flexneri 5 and the chromosomal genes encoding the group- and type-specific O antigen of S. flexneri 2a to Escherichia coli K-12, was tested in humans. Designated EcSf2a-1, this vaccine produced adverse reactions (fever, diarrhea, or dysentery) in 4 (31%) of 13 subjects who ingested a single dose of 1.0 x 10(9) CFU, while at better-tolerated doses (5.0 x 10(6) to 5.0 x 10(7) CFU), it provided no significant protection against challenge with S. flexneri 2a. A further-attenuated aroD mutant derivative, EcSf2a-2, was then tested. Rhesus monkeys that received EcSf2a-2 in three oral doses of ca. 1.5 x 10(11) CFU experienced no increase in gastrointestinal symptoms compared with a control group that received an E. coli K-12 placebo. Compared with controls, the vaccinated monkeys were protected against shigellosis after challenge with S. flexneri 2a (60% efficacy; P = 0.001). In humans, EcSf2a-2 was well tolerated at inocula ranging from 5.0 x 10(6) to 2.1 x 10(9) CFU. However, after a single dose of 2.5 x 10(9) CFU, 4 (17%) of 23 subjects experienced adverse reactions, including fever (3 subjects) and diarrhea (209 ml) (1 subject), and after a single dose of 1.8 x 10(10) CFU, 2 of 4 subjects developed dysentery. Recipients of three doses of 1.2 to 2.5 x 10(9) CFU had significant rises in serum antibody to lipopolysaccharide (61%) and invasiveness plasmid antigens (44%) and in gut-derived immunoglobulin A antibody-secreting cells specific for lipopolysaccharide (100%) and invasiveness plasmid antigens (60%). Despite its immunogenicity, the vaccine conferred only 36% protection against illness (fever, diarrhea, or dysentery) induced by experimental challenge (P = 0.17). These findings illustrate the use of an epithelial cell-invasive E. coli strain as a carrier for Shigella antigens. Future studies must explore dosing regimens that might optimize the protective effects of the vaccine while eliminating adverse clinical reactions.
authors.affiliation: Department of Pediatrics, University of Maryland School of Medicine, Baltimore 21201.
authors.forename: K L
authors.initials: KL
authors.lastname: Kotloff
authors.forename: D A
authors.initials: DA
authors.lastname: Herrington
authors.forename: T L
authors.initials: TL
authors.lastname: Hale
authors.forename: J W
authors.initials: JW
authors.lastname: Newland
authors.forename: L
authors.initials: L
authors.lastname: Van De Verg
authors.forename: J P
authors.initials: JP
authors.lastname: Cogan
authors.forename: P J
authors.initials: PJ
authors.lastname: Snoy
authors.forename: J C
authors.initials: JC
authors.lastname: Sadoff
authors.forename: S B
authors.initials: SB
authors.lastname: Formal
authors.forename: M M
authors.initials: MM
authors.lastname: Levine
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001428:Bacterial Vaccines / Q000276:immunology* / Q000633:toxicity; D004926:Escherichia coli / Q000276:immunology*; D006801:Humans; D007114:Immunization; D008253:Macaca mulatta; D012763:Shigella flexneri / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000276:immunology* / Q000633:toxicity
chemical_list: D000942:Antigens, Bacterial; D001428:Bacterial Vaccines; D014614:Vaccines, Synthetic