Safety and immunogenicity of a candidate Middle East respiratory syndrome coronavirus viral-vectored vaccine: a dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial
Safety and immunogenicity of a candidate Middle East respiratory syndrome coronavirus viral-vectored vaccine: a dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial
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DOI：
10.1016/s1473-3099(20)30160-2
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发表时间：
2020-07-01
影响因子：
56.3
通讯作者：
Gilbert, Sarah
中科院分区：
文献类型：
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作者：
Folegatti, Pedro M.;Bittaye, Mustapha;Gilbert, Sarah
背景中东呼吸综合征冠状病毒(MERS-CoV)感染病例在沙特阿拉伯首次报告7年后在阿拉伯半岛持续上升。由于目前缺乏有效的对策，MERS冠状病毒对公共卫生安全构成重大风险。我们的目标是评估表达全长棘突表面糖蛋白ChAdOx1 MERS的候选猿腺病毒载体疫苗在人类中的安全性和免疫原性。方法这项剂量递增、开放标签、非随机、非对照的1期试验在英国牛津临床疫苗和热带医学中心进行，包括18-50岁的健康人，他们在接种前HIV抗体、乙肝表面抗原和丙型肝炎抗体呈阴性(女性尿路妊娠试验阴性)。参与者接受了三种不同剂量的ChAdOx1 MERS单次肌肉注射：低剂量组接受5×10(9)病毒颗粒，中剂量组接受2.5×10(10)病毒颗粒，高剂量组接受5？10 10病毒颗粒。主要目标是评估ChAdOx1 MERS的安全性和耐受性，通过疫苗接种后主动、主动和严重不良事件的发生来衡量。第二个目标是评估ChAdOx1 MERS的细胞和体液免疫原性，在接种疫苗后通过干扰素-伽马酶联免疫斑点、ELISA法和病毒中和试验来测量。参与者接受了长达12个月的跟踪调查。这项研究在ClinicalTrials.gov，NCT03399578上注册。2018年3月14日至8月15日，24名参与者参加了研究：6人被分配到低剂量组，9人被分配到中剂量组，9人被分配到高剂量组。所有参与者在6个月时都可以进行随访，但有5人(低剂量组1人，中剂量组1人，高剂量组3人)在12个月时失去了随访。单剂ChAdOx1 MERS在剂量高达5x10(10)个病毒颗粒时是安全的，12个月后没有报告与疫苗相关的严重不良反应。报告的一起严重不良事件被认为与ChAdOx1 MERS无关。124例患者中，92例(74%[95%可信区间66~81])为轻度不良反应，31例(25%[18~33])为中度不良反应，均为自律性不良反应。在接种疫苗后的28天内，被认为可能、可能或肯定与ChAdOx1 MERS有关的主动不良事件主要是轻微的，并在12个月的随访期内消失。中、重度不良事件发生率高剂量组显著高于中剂量组(相对危险度5 83[95%CI 2.11~17.42]，P
Background Cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection continue to rise in the Arabian Peninsula 7 years after it was first described in Saudi Arabia. MERS-CoV poses a significant risk to public health security because of an absence of currently available effective countermeasures. We aimed to assess the safety and immunogenicity of the candidate simian adenovirus-vectored vaccine expressing the full-length spike surface glycoprotein, ChAdOx1 MERS, in humans.Methods This dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial was done at the Centre for Clinical Vaccinology and Tropical Medicine (Oxford, UK) and included healthy people aged 18-50 years with negative pre-vaccination tests for HIV antibodies, hepatitis B surface antigen, and hepatitis C antibodies (and a negative urinary pregnancy test for women). Participants received a single intramuscular injection of ChAdOx1 MERS at three different doses: the low-dose group received 5 x 10(9) viral particles, the intermediate-dose group received 2.5 x 10(10) viral particles, and the high-dose group received 5 ? 10 10 viral particles. The primary objective was to assess safety and tolerability of ChAdOx1 MERS, measured by the occurrence of solicited, unsolicited, and serious adverse events after vaccination. The secondary objective was to assess the cellular and humoral immunogenicity of ChAdOx1 MERS, measured by interferon-gamma-linked enzyme-linked immunospot, ELISA, and virus neutralising assays after vaccination. Participants were followed up for up to 12 months. This study is registered with ClinicalTrials.gov, NCT03399578.Findings Between March 14 and Aug 15, 2018, 24 participants were enrolled: six were assigned to the low-dose group, nine to the intermediate-dose group, and nine to the high-dose group. All participants were available for follow-up at 6 months, but five (one in the low-dose group, one in the intermediate-dose group, and three in the high-dose group) were lost to follow-up at 12 months. A single dose of ChAdOx1 MERS was safe at doses up to 5 x 10(10) viral particles with no vaccine-related serious adverse events reported by 12 months. One serious adverse event reported was deemed to be not related to ChAdOx1 MERS. 92 (74% [95% CI 66-81]) of 124 solicited adverse events were mild, 31 (25% [18-33]) were moderate, and all were self-limiting. Unsolicited adverse events in the 28 days following vaccination considered to be possibly, probably, or definitely related to ChAdOx1 MERS were predominantly mild in nature and resolved within the follow-up period of 12 months. The proportion of moderate and severe adverse events was significantly higher in the high-dose group than in the intermediate-dose group (relative risk 5?83 [95% CI 2.11-17.42], p