Phase I trial of two candidate live oral salmonella enterica serovar paratyphi A

肠热病是由伤寒沙门氏菌和甲型或乙型副伤寒引起的一种临床综合征。 最近亚洲甲型副伤寒沙门氏菌(SPA)出现频率的增加和抗生素耐药性的出现 已经使治疗变得复杂，并对美国游客构成了风险。与伤寒沙门氏菌不同的是，没有疫苗可以预防 防止SPA，这是对美国食品来源的B类优先生物恐怖威胁。我们设计了两个SPA 通过删除Guaba染色体(编码两种酶)来候选口服活疫苗毒株 在远端从头合成嘌呤生物合成途径中)，还引入了c/px(编码 ATPase)或DPP(编码蛋白酶)，以分别产生菌株CVD1902和CVD1903。正在删除 GUBA一直是一种很有前途的减毒伤寒沙门氏菌的策略。在以下任一项中引入删除 Dpxp复合体的组件提供第二个独立的衰减性突变，将风险降至最低 理论上可以恢复野生型基因的重组，也可以加强保护 通过超表达鞭毛蛋白，一种既能诱导体液免疫又能诱导细胞免疫的保护性抗原 免疫反应。在DPP、DPx或clpXP中缺失的沙门氏菌降低了产生系统的能力 然而，由此产生的dpxp突变体仍然能够保护小鼠免受野生型挑战。 我们建议进行一项第一阶段试验，以评估升级的安全性、耐受性和免疫原性。 CVD1902和CVD1903的剂量(107、108和109CPU)。三个连续的队列(每个队列获得一个 14名年龄在18-45岁的健康受试者将被纳入心血管疾病研究 隔离病房20天，之后4次门诊就诊，6个月后电话联系。中的主题 每个队列将被随机(双盲)接受一次口服接种，接种CVD 1902(N=6) 或CVD1903(N=6)疫苗或安慰剂(N=2)。在他们180天的参与期间，受试者将密切关注 观察临床反应，并将捐赠一系列血液和粪便样本以检测定植情况 疫苗毒株，以确保该毒株被按方案抗生素消除，并评估 疫苗刺激相关的粘膜、体液和细胞免疫反应的能力。这个 将对结果进行分析，目的是选择耐受性良好的免疫原性疫苗株和 用于进一步临床开发的剂量。

Enteric fever is a clinical syndrome caused by Salmonella enterica serovar Typhi and Paratyphi A or B. Recent increases in the frequency of S. Paratyphi A (SPA) in Asia and emergence of antibiotic resistance have complicated treatment and posed a risk to U.S. travelers. In contrast to S. Typhi, there is no vaccine to prevent SPA, a category B priority bioterror threat to U.S. food sources. We have engineered two SPA candidate live oral vaccine strains by deleting the guaBA chromosomal locus (which encodes two enzymes in the distal de novo purine biosynthesis pathway) and also introducing deletions in either c/pX (encoding an ATPase) or dpP (encoding a protease), to create strains CVD 1902 and CVD 1903, respectively. Deleting guaBA has been a promising strategy for attenuating pathogenic S.Typhi. Introducing a deletion in either component of the dpXP complex provides a second, independent attenuating mutation to minimize the risk of a recombination that could theoretically restore the wild type genotype and may also enhance protection by hyper-expression of flagellar protein, a protective antigen that elicits both humoral and cell-mediated immune responses. Salmonella deleted in dpP, dpX, orclpXP have decreased ability to produce systemic infection yet the resultant dpXP mutants remain capable of protecting mice against wild type challenge. We propose to conduct a Phase 1 trial to evaluate the safety, tolerability, and immunogenicity of escalating dosages (107, 108, and 109 CPU) of CVD 1902 and CVD 1903. Three consecutive cohorts (each receiving a higher dosage of vaccine) of 14 healthy subjects 18-45 years of age will be admitted to the CVD Research Isolation Ward for 20 days followed by 4 outpatient visits and a telephone contact at 6 months. Subjects in each cohort will be randomized (double-blind) to receive a single oral inoculation with either CVD 1902 (N=6) or CVD 1903 (N=6) vaccine or placebo (N=2). During their 180-day participation, subjects will be closely observed for clinical response and will donate serial samples of blood and stool to detect colonization with the vaccine strain, to ensure that the strain was eliminated by per-protocol antibiotics, and to evaluate the ability of the vaccines to stimulate relevant mucosal, humoral, and cell-mediated immune responses. The results will be analyzed with the aim of selecting a well-tolerated and immunogenic vaccine strain and dosage for further clinical development.