Université Paris Descartes, Sorbonne Paris cité, Paris, France; Inserm CIC 1417, Paris, France; Assistance Publique Hôpitaux de Paris, CIC Cochin-Pasteur, Paris, France.
University of Surrey, Guildford, United Kingdom.
EBioMedicine. 2017 Aug;22:164-172. doi: 10.1016/j.ebiom.2017.07.013. Epub 2017 Jul 15.
Approximately 164,000 deaths yearly are due to shigellosis, primarily in developing countries. Thus, a safe and affordable Shigella vaccine is an important public health priority. The GSK Vaccines Institute for Global Health (GVGH) developed a candidate Shigella sonnei vaccine (1790GAHB) using the Generalized Modules for Membrane Antigens (GMMA) technology. The paper reports results of 1790GAHB Phase 1 studies in healthy European adults.
To evaluate the safety and immunogenicity profiles of 1790GAHB, we performed two parallel, phase 1, observer-blind, randomized, placebo-controlled, dose escalation studies in France ("study 1") and the United Kingdom ("study 2") between February 2014 and April 2015 (ClinicalTrials.gov, number NCT02017899 and NCT02034500, respectively) in 18-45years old subjects (50 in study 1, 52 in study 2). Increasing doses of Alhydrogel adsorbed 1790, expressed by both O Antigen (OAg) and protein quantity, or placebo were given either by intramuscular route (0.059/1, 0.29/5, 1.5/25, 2.9/50, 5.9/100μg of OAg/μg of protein; study 1) or by intradermal (ID), intranasal (IN) or intramuscular (IM) route of immunization (0.0059/0.1, 0.059/1, 0.59/10μg ID, 0.29/5, 1.2/20, 4.8/80μg IN and 0.29/5μg IM, respectively; study 2). In absence of serologic correlates of protection for Shigella sonnei, vaccine induced immunogenicity was compared to anti-LPS antibody in a population naturally exposed to S. sonnei.
Vaccines were well tolerated in both studies and no death or vaccine related serious adverse events were reported. In study 1, doses ≥1.5/25μg elicited serum IgG median antibody greater than median level in convalescent subjects after the first dose. No vaccine group in study 2 achieved median antibody greater than the median convalescent antibody.
Intramuscularly administered Shigella sonnei GMMA vaccine is well tolerated, up to and including 5.9/100μg and induces antibody to the OAg of at least the same magnitude of those observed following natural exposure to the pathogen. Vaccine administered by ID or IN, although well tolerated, is poorly immunogenic at the doses delivered. The data support the use of the GMMA technology for the development of intramuscular multivalent Shigella vaccines.
每年约有 164000 人死于志贺氏菌病，主要在发展中国家。因此，安全且负担得起的志贺氏菌疫苗是一项重要的公共卫生重点。GSK 疫苗全球健康研究所（GVGH）使用广义膜抗原模块（GMMA）技术开发了一种候选的志贺氏菌血清型 1790GAHB 疫苗。本文报告了在健康的欧洲成年人中进行的 1790GAHB 一期研究结果。
为了评估 1790GAHB 的安全性和免疫原性特征，我们在法国（“研究 1”）和英国（“研究 2”）进行了两项平行的、一期、观察者盲、随机、安慰剂对照、剂量递增研究，研究对象为 18-45 岁的人群（研究 1 中为 50 人，研究 2 中为 52 人）。研究于 2014 年 2 月至 2015 年 4 月进行（ClinicalTrials.gov 编号分别为 NCT02017899 和 NCT02034500），用氢氧化铝凝胶吸附的 1790 以 O 抗原（OAg）和蛋白量表示的剂量递增，或安慰剂通过肌肉内途径（0.059/1、0.29/5、1.5/25、2.9/50、5.9/100μg OAg/μg 蛋白；研究 1）或皮内（ID）、鼻内（IN）或肌肉内（IM）途径免疫接种（0.0059/0.1、0.059/1、0.59/10μg ID、0.29/5、1.2/20、4.8/80μg IN 和 0.29/5μg IM，分别；研究 2）。由于缺乏针对血清型 1790 的志贺氏菌的血清学保护相关物，因此将疫苗诱导的免疫原性与自然暴露于血清型 1790 的人群中的 LPS 抗体进行了比较。
两项研究中疫苗均耐受良好，无死亡或与疫苗相关的严重不良事件报告。在研究 1 中，≥1.5/25μg 剂量组的血清 IgG 抗体中位数大于首次剂量后恢复期患者的中位数水平。研究 2 中无疫苗组的抗体中位数大于恢复期的中位数抗体。
肌肉内给予血清型 1790GAHB GMMA 疫苗具有良好的耐受性，最高可达 5.9/100μg，并诱导产生与自然感染病原体后观察到的至少相同大小的 OAg 抗体。虽然 ID 或 IN 给予的疫苗具有良好的耐受性，但在给予的剂量下免疫原性较差。这些数据支持使用 GMMA 技术开发肌肉内多价志贺氏菌疫苗。
