Kotloff K L, Noriega F R, Samandari T, Sztein M B, Losonsky G A, Nataro J P, Picking W D, Barry E M, Levine M M
Division of Infectious Diseases, Department of Pediatrics, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Infect Immun. 2000 Mar;68(3):1034-9. doi: 10.1128/IAI.68.3.1034-1039.2000.
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 (DeltavirG), does not produce enterotoxin (Deltasen and Deltaset), and has limited proliferation in vivo (DeltaguaBA). 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.
在35名健康成年志愿者中进行了1期临床试验，以评估不同剂量的CVD 1207的安全性、免疫原性和排毒情况。CVD 1207是一种减毒活的福氏志贺菌2a疫苗候选株，在virG、sen、set和guaBA基因上有特定缺失突变。CVD 1207保留了侵袭上皮细胞的能力，但侵袭后不能有效地在细胞间扩散（DeltavirG），不产生肠毒素（Deltasen和Deltaset），并且在体内增殖受限（DeltaguaBA）。以连续的方式，每组三至七名受试者口服单剂量的CVD 1207，接种量分别为10(6)、10(7)、10(8)、10(9)或10(10) CFU。接种量高达10(8) CFU时，CVD 1207的耐受性非常好。相比之下，接受10(9) CFU的12名受试者中有1人出现轻度腹泻，另1人出现单次呕吐。接受10(10) CFU的5名受试者中有1人出现水样腹泻和呕吐。所有摄入10(8)至10(10) CFU剂量的受试者都排出了疫苗；25名受试者中有23名的排毒持续时间≤3天。观察到对福氏志贺菌2a O特异性脂多糖的剂量相关的免疫球蛋白A抗体分泌细胞（ASC）反应，在接受10(7)至10(10) CFU的受试者中，几何平均峰值为6.1至35.2个ASC/10(6)外周血单个核细胞（PBMC）。接种疫苗后在志愿者PBMC中观察到的对志贺菌特异性抗原的细胞因子反应提示为Th1模式，γ干扰素受到刺激，白细胞介素4（IL-4）或白细胞介素5（IL-5）缺乏。CVD 1207是一种通过合理使用重组DNA技术从野生型福氏志贺菌2a制备的志贺菌口服活疫苗株，与早期重组株相比，即使高剂量给药也能实现显著程度的减毒。
