Deletion in the Shigella enterotoxin genes further attenuates Shigella flexneri 2a bearing guanine auxotrophy in a phase 1 trial of CVD 1204 and CVD 1208
Deletion in the Shigella enterotoxin genes further attenuates Shigella flexneri 2a bearing guanine auxotrophy in a phase 1 trial of CVD 1204 and CVD 1208
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DOI：
10.1086/424680
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发表时间：
2004-11-15
影响因子：
6.4
通讯作者：
Levine, MM
中科院分区：
文献类型：
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作者：
Kotloff, KL;Pasetti, MF;Levine, MM
背景我们通过构建鸟嘌呤营养缺陷型谱系来创建活的减毒口服志贺菌疫苗，并进行双盲、安慰剂对照试验以确定（1）DeltaguaBA福氏志贺菌2a的减毒特征，其在鸟嘌呤核苷酸合成途径中具有缺失（CVD 1204）;（2）由分别编码志贺氏菌肠毒素（Shigella）1和2的set和sen基因的缺失赋予的额外减毒（CVD 1208）;和（3）这些构建体的相对免疫原性。住院志愿者接受单次口服剂量的CVD 1204、CVD 1208（10（7）、10（8）或10（9）cfu）或安慰剂。评价临床、免疫学和微生物学反应。CVD 1204的23名接受者中有8名发生反应原性，其特征为腹泻（30%）、发热（22%）和/或痢疾（17%），但CVD 1208的21名接受者中只有1名（5%）发生反应原性（短暂发热）（P = 0.02，Fisher精确检验）。通过抗体分泌细胞、血清或粪便抗体水平测量，抗脂多糖反应分别发生在67%、71%和100%的CVD 1204受体和86%、43%和100%的CVD 1208受体中，剂量分别为10（7）、10（8）和10（9）cfu。我们的结论是，1个或两个志贺菌是人类的毒力决定因素，其灭活，与DeltaguaBA相结合，导致耐受性良好和免疫原性的志贺菌疫苗候选人。
Background. We created a live, attenuated, oral Shigella vaccine by constructing a lineage of guanine auxotrophs and conducted a double-blind, placebo-controlled trial to ascertain ( 1) the attenuation profile of DeltaguaBA Shigella flexneri 2a, which harbors deletions in the guanine nucleotide synthesis pathway (CVD 1204); ( 2) additional attenuation conferred by deletions in set and sen genes encoding Shigella enterotoxins (ShETs) 1 and 2, respectively (CVD 1208); and ( 3) the relative immunogenicity of these constructs.Methods. Inpatient volunteers received a single oral dose of CVD 1204, CVD 1208 (10(7), 10(8), or 10(9) cfu), or placebo. Clinical, immunologic, and microbiologic responses were evaluated.Results. Reactogenicity occurred in 8 of 23 recipients of CVD 1204, characterized by diarrhea (30%), fever (22%), and/or dysentery (17%), but in only 1 (5%) of 21 recipients of CVD 1208 (brief fever) (P = .02, Fisher's exact test). Antilipopolysaccharide responses, as measured by antibody-secreting cell, serum, or fecal antibody levels, occurred in 67%, 71%, and 100% of recipients of CVD 1204 and in 86%, 43%, and 100% of recipients of CVD 1208 at doses of 10(7), 10(8), and 10(9) cfu, respectively.Conclusions. We conclude that 1 or both ShETs are virulence determinants in humans; their inactivation, in combination with DeltaguaBA, leads to a well-tolerated and immunogenic Shigella vaccine candidate.