A human hookworm vaccine is being developed to protect children against iron deficiency and anaemia associated with chronic infection with hookworms. aspartic protease-1 (-APR-1) and glutathione S-transferase-1 (-GST-1) are components of the blood digestion pathway critical to hookworm survival in the host. Recombinant -GST-1 and catalytically inactive -APR-1 (-APR-1[M74]) adsorbed to Alhydrogel were safe and immunogenic when delivered separately or co-administered to adults in phase 1 trials in non-endemic and endemic areas. We aimed to investigate the safety and immunogenicity of these antigens in healthy children in a hookworm-endemic area. This was a randomised, controlled, observer-blind, phase 1, dose-escalation trial, conducted in a clinical research centre, in 60 children aged six to ten years in Lambaréné, a hookworm-endemic region of Gabon. Healthy children (determined by clinical examination and safety laboratory testing) were randomised 4:1 to receive co-administered -GST-1 on Alhydrogel plus -APR-1(M74) on Alhydrogel and glucopyranosyl lipid A in aqueous formulation (GLA-AF), or co-administered ENGERIX-B hepatitis B vaccine (HBV) and saline placebo, injected into the deltoid of each arm. Allocation to vaccine groups was observer-masked. In each vaccine group, children were randomised 1:1 to receive intramuscular injections into each deltoid on two vaccine schedules, one at months 0, 2, and 4 or at months 0, 2, and 6. 10 μg, 30 μg, and 100 μg of each antigen were administered in the first, second, and third cohorts, respectively. The intention-to-treat population was used for safety analyses; while for immunogenicity analyses, the per-protocol population was used (children who received all scheduled vaccinations). The primary outcome was to evaluate the vaccines' safety and reactogenicity in healthy children aged between six and ten years. The secondary outcome was to measure antigen-specific serum IgG antibody levels at pre-vaccination and post-vaccination timepoints by qualified ELISAs. The trial is registered with , , and is completed. Between Jan 23 and Oct 3, 2017, 137 children were screened, of whom 76 were eligible for this trial. 60 children were recruited, and allocated to either 10 μg of the co-administered antigens (n=8 for each injection schedule), 30 μg (n=8 for each schedule), 100 μg (n=8 for each schedule), or HBV and placebo (n=6 for each schedule) in three sequential cohorts. Co-administration of the vaccines was well tolerated; the most frequent solicited adverse events were mild-to-moderate injection-site pain, observed in up to 12 (75%) of 16 participants per vaccine group, and mild headache (12 [25%] of 48) and fever (11 [23%] of 48). No vaccine-related serious adverse events were observed. Significant anti--APR-1(M74) and anti--GST-1 IgG levels were induced in a dose-dependent manner, with peaks seen 14 days after the third vaccinations, regardless of dose (for -APR-1[M74], geometric mean levels [GML]=2295·97 arbitrary units [AU] and 726·89 AU, while for -GST-1, GMLs=331·2 AU and 21·4 AU for the month 0, 2, and 6 and month 0, 2, and 4 schedules, respectively). The month 0, 2, and 6 schedule induced significantly higher IgG responses to both antigens (p=0·01 and p=0·04 for -APR-1[M74] and -GST-1, respectively). Co-administration of recombinant -APR-1(M74) and -GST-1 to school-aged Gabonese children was well tolerated and induced significant IgG responses. These results justify further evaluation of this antigen combination in proof-of-concept controlled-infection and efficacy studies in hookworm-endemic areas. European Union Seventh Framework Programme.

中文翻译：

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加蓬学龄儿童联合接种 Na-APR-1 和 Na-GST-1 钩虫疫苗的安全性和免疫原性：一项随机、对照、观察者盲法、第一阶段剂量递增试验

正在开发一种人类钩虫疫苗，以保护儿童免受与钩虫慢性感染相关的缺铁和贫血的影响。天冬氨酸蛋白酶-1 (-APR-1) 和谷胱甘肽 S-转移酶-1 (-GST-1) 是血液消化途径的组成部分，对钩虫在宿主体内的生存至关重要。在非流行区和流行区的 1 期试验中，吸附到 AlHydrogel 上的重组 -GST-1 和催化失活的 -APR-1 (-APR-1[M74]) 单独给药或共同给予成人时是安全的且具有免疫原性。我们的目的是研究这些抗原对钩虫流行地区健康儿童的安全性和免疫原性。这是一项随机、对照、观察者盲、第一阶段剂量递增试验，在加蓬钩虫流行区兰巴雷内的一个临床研究中心对 60 名 6 至 10 岁的儿童进行。健康儿童（通过临床检查和安全实验室测试确定）按 4:1 随机分配，接受 AlHydrogel 上的 -GST-1 加 AlHydrogel 上的 -APR-1(M74) 和吡喃葡萄糖基脂质 A 水性制剂 (GLA-AF) 联合给药，或同时注射 ENGERIX-B 乙型肝炎疫苗 (HBV) 和生理盐水安慰剂，注射到每只手臂的三角肌中。疫苗组的分配是被观察者掩盖的。在每个疫苗组中，儿童按 1:1 随机分配，按照两种疫苗计划接受三角肌肌内注射，一种是在第 0、2、4 个月，另一种是在第 0、2、6 个月。 10 μg、30 μg 和 100 μg分别在第一、第二和第三组中施用μg的每种抗原。使用意向治疗人群进行安全性分析；而对于免疫原性分析，则使用符合方案的人群（接受所有预定疫苗接种的儿童）。主要结果是评估疫苗对六至十岁健康儿童的安全性和反应原性。次要结果是通过合格的 ELISA 测量疫苗接种前和疫苗接种后时间点的抗原特异性血清 IgG 抗体水平。试验已在 、 、 注册，并已完成。 2017年1月23日至10月3日期间，共有137名儿童接受了筛查，其中76名儿童符合本次试验的条件。招募了 60 名儿童，并分配给 10 μg 共同施用的抗原（每个注射方案 n=8）、30 μg（每个方案 n=8）、100 μg（每个方案 n=8）或三个连续队列中的 HBV 和安慰剂（每个方案 n=6）。联合接种疫苗的耐受性良好；最常见的不良事件是轻度至中度注射部位疼痛，每个疫苗组 16 名参与者中多达 12 名（75%）观察到，以及轻度头痛（48 名参与者中 12 名 [25%]）和发烧（11 名参与者中观察到）。 23%]，共 48)。没有观察到与疫苗相关的严重不良事件。以剂量依赖性方式诱导显着的抗-APR-1(M74)和抗-GST-1 IgG水平，无论剂量如何，在第三次疫苗接种后14天出现峰值（对于-APR-1[M74] ,几何平均水平 [GML]=2295·97 任意单位 [AU] 和 726·89 AU，而对于 -GST-1，第 0、2、6 个月的 GML=331·2 AU 和 21·4 AU分别为 0、2 和 4 个计划）。第 0、2 和 6 个月的方案诱导了对两种抗原显着更高的 IgG 反应（-APR-1[M74] 和 -GST-1 分别为 p=0·01 和 p=0·04）。加蓬学龄儿童联合服用重组-APR-1(M74) 和-GST-1 耐受性良好，并诱导显着的 IgG 反应。这些结果证明在钩虫流行地区的概念验证控制感染和功效研究中进一步评估这种抗原组合是合理的。欧盟第七框架计划。