Shigella flexneri 2a strain CVD 1207, with specific deletions in virG, sen, set, and guaBA, is highly attenuated in humans
Shigella flexneri 2a strain CVD 1207, with specific deletions in virG, sen, set, and guaBA, is highly attenuated in humans
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DOI：
10.1128/iai.68.3.1034-1039.2000
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发表时间：
2000-03-01
影响因子：
3.1
通讯作者：
Levine, MM
中科院分区：
文献类型：
--
作者：
Kotloff, KL;Noriega, FR;Levine, MM
在35名健康成人志愿者中进行I期临床试验以评估不同剂量的CVD 1207的安全性、免疫原性和脱落，CVD 1207是在virG、sen、set和guaBA中具有特异性缺失突变的福氏2a志贺菌减毒活疫苗候选物，CVD 1207保留侵入上皮细胞的能力，但在侵入后不能有效地在细胞间扩散（Delta virG），不产生肠毒素（Delta sen和Delta set），并且在体内具有有限的增殖（Delta guaBA）。以连续的方式，三至七名受试者的组以10（6）、10（7）、10（8）、10（9）或10（10）CFU的接种物摄入单次口服剂量的CVD 1207。CVD 1207在高达10（8）CFU的接种物下耐受性非常好。相比之下，接受10（9）CFU的12名受试者中的一名经历了轻度腹泻，另一名经历了单次呕吐。接受10（10）CFU的5例受试者中有1例发生水样腹泻和呕吐，所有摄入10（8）至10（10）CFU剂量的受试者均排泄疫苗; 25例受试者中有23例排泄持续时间小于或等于3天。剂量相关的免疫球蛋白A抗体分泌细胞（ASC）对S。观察到福氏2a O特异性脂多糖，在10（7）至10（10）CFU的受体中，几何平均峰值为6.1至35.2 ASC/10（6）外周血单核细胞（PBMC），接种疫苗后，在志愿者PBMC中观察到的对志贺氏菌特异性抗原的细胞因子应答表明，在γ干扰素刺激和白细胞介素4（IL-4）缺乏的情况下，或IL-5。CVD 1207代表从野生型S.通过合理使用重组DNA技术，获得了与早期重组菌株相比显著程度的减毒，即使以高剂量给药。
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 (Delta virG), does not produce enterotoxin (Delta sen and Delta set), and has limited proliferation in vivo (Delta 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 less than or equal to 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.