Kotloff K L, Herrington D A, Hale T L, Newland J W, Van De Verg L, Cogan J P, Snoy P J, Sadoff J C, Formal S B, Levine M M
Department of Pediatrics, University of Maryland School of Medicine, Baltimore 21201.
Infect Immun. 1992 Jun;60(6):2218-24. doi: 10.1128/iai.60.6.2218-2224.1992.
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.
一种活的口服志贺氏菌疫苗，是通过将弗氏志贺氏菌5型的140-MDa侵袭性质粒以及编码弗氏志贺氏菌2a群和型特异性O抗原的染色体基因转移至大肠杆菌K-12构建而成，并在人体中进行了测试。这种疫苗被命名为EcSf2a-1，在13名摄入单剂量1.0×10⁹CFU的受试者中，有4人（31%）出现了不良反应（发热、腹泻或痢疾），而在耐受性较好的剂量（5.0×10⁶至5.0×10⁷CFU）下，它对弗氏志贺氏菌2a的攻击没有提供显著的保护作用。随后测试了一种进一步减毒的aroD突变体衍生物EcSf2a-2。接受约1.5×10¹¹CFU三剂口服EcSf2a-2的恒河猴与接受大肠杆菌K-12安慰剂的对照组相比，胃肠道症状没有增加。与对照组相比，接种疫苗的猴子在受到弗氏志贺氏菌2a攻击后对志贺氏菌病具有抵抗力（60%的效力；P = 0.001）。在人体中，EcSf2a-2在5.0×10⁶至2.1×10⁹CFU的接种剂量范围内耐受性良好。然而，在单剂量2.5×10⁹CFU后，23名受试者中有4人（17%）出现了不良反应，包括发热（3人）和腹泻（209毫升）（1人），在单剂量1.8×10¹⁰CFU后，4名受试者中有2人出现痢疾。接受三剂1.2至2.5×10⁹CFU的受试者血清中针对脂多糖的抗体（61%）和侵袭性质粒抗原的抗体（44%）以及肠道来源的针对脂多糖（100%）和侵袭性质粒抗原（60%）的免疫球蛋白A抗体分泌细胞显著增加。尽管具有免疫原性，但该疫苗对实验性攻击诱导的疾病（发热、腹泻或痢疾）仅提供了36%的保护作用（P = 0.17）。这些发现说明了使用一种侵袭上皮细胞的大肠杆菌菌株作为志贺氏菌抗原载体的情况。未来的研究必须探索可能优化疫苗保护效果同时消除不良临床反应的给药方案。
