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首页> 外文期刊>EBioMedicine >Safety Profile and Immunologic Responses of a Novel Vaccine Against Shigella sonnei Administered Intramuscularly, Intradermally and Intranasally: Results From Two Parallel Randomized Phase 1 Clinical Studies in Healthy Adult Volunteers in Europe
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Safety Profile and Immunologic Responses of a Novel Vaccine Against Shigella sonnei Administered Intramuscularly, Intradermally and Intranasally: Results From Two Parallel Randomized Phase 1 Clinical Studies in Healthy Adult Volunteers in Europe

机译：肌肉注射，皮内注射和鼻内注射针对猪痢疾志贺菌的新型疫苗的安全性和免疫学应答：来自欧洲健康成人志愿者的两项平行随机第一阶段临床研究的结果

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Background: 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. Methods: 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, 5.9/100@mg of OAg/@mg of protein; study 1) or by intradermal (ID), intranasal (IN) or intramuscular (IM) route of immunization (0.0059/0.1, 0.059/1, 0.59/10@mg ID, 0.29/5, 1.2/20, 4.8/80@mg IN and 0.29/5@mg 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. Findings: Vaccines were well tolerated in both studies and no death or vaccine related serious adverse events were reported. In study 1, doses >=1.5/25@mg 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. Interpretation: Intramuscularly administered Shigella sonnei GMMA vaccine is well tolerated, up to and including 5.9/100@mg 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.
机译：背景：志贺菌病每年导致约164,000人死亡，主要在发展中国家。因此，安全和负担得起的志贺氏菌疫苗是重要的公共卫生重点。葛兰素史克全球健康疫苗研究​​所（GVGH）使用通用的膜抗原模块（GMMA）技术开发了一种候选痢疾志贺氏菌疫苗（1790GAHB）。该论文报告了在健康的欧洲成年人中进行的1790GAHB 1期研究的结果。方法：为了评估1790GAHB的安全性和免疫原性，我们在法国（``研究1''）和英国（``研究1''）进行了两个平行的1期观察者盲，随机，安慰剂对照的剂量递增研究。研究2''）在2014年2月至2015年4月之间（ClinicalTrials.gov，分别为NCT02017899和NCT02034500）在18-45岁的受试者中进行研究（研究1中有50个，研究2中52个）。通过肌内途径（0.059 / 1，0.29 / 5，1.5 / 25，2.9 / 50，5.9/100@mg的肌肉注射途径）来增加以O抗原（OAg）和蛋白质量表示的，被吸附的1790年Alhydrogel的剂量或安慰剂。 OAg / @ mg蛋白质;研究1）或通过皮内（ID），鼻内（IN）或肌内（IM）免疫途径（0.0059 / 0.1，0.059 / 1，0.59/10@mg ID，0.29 / 5，1.2 /20、4.8/80@mg IN和0.29/5@mg IM;研究2）。在没有针对血清志贺氏菌的保护的血清学相关性的情况下，将疫苗诱导的免疫原性与自然暴露于血清志贺氏菌的人群的抗LPS抗体进行了比较。调查结果：两项研究中疫苗的耐受性均良好，并且未报告死亡或疫苗相关的严重不良事件。在研究1中，剂量> =1.5/25@mg引起的血清IgG中值抗体在第一剂后的恢复期受试者中大于中位水平。研究2中没有疫苗组的中位抗体大于中位恢复期抗体。解释：肌内注射的志贺氏志贺氏菌GMMA疫苗耐受性良好，最高可达5.9/100@mg（含），并诱导的OAg抗体至少与自然暴露于病原体后所观察到的OAg大小相同。尽管耐受性良好，但通过ID或IN施用的疫苗在递送剂量下的免疫原性较差。数据支持使用GMMA技术开发肌内多价志贺氏菌疫苗。

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