WHO has identified Marburg virus as an emerging virus requiring urgent vaccine research and development, particularly due to its recent emergence in Ghana. We report results from a first-in-human clinical trial evaluating a replication-deficient recombinant chimpanzee adenovirus type 3 (cAd3)-vectored vaccine encoding a wild-type Marburg virus Angola glycoprotein (cAd3-Marburg) in healthy adults. We did a first-in-human, phase 1, open-label, dose-escalation trial of the cAd3-Marburg vaccine at the Walter Reed Army Institute of Research Clinical Trials Center in the USA. Healthy adults aged 18–50 years were assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 10 or 1 × 10 particle units (pu). Primary safety endpoints included reactogenicity assessed for the first 7 days and all adverse events assessed for 28 days after vaccination. Secondary immunogenicity endpoints were assessment of binding antibody responses and T-cell responses against the Marburg virus glycoprotein insert, and assessment of neutralising antibody responses against the cAd3 vector 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT03475056. Between Oct 9, 2018, and Jan 31, 2019, 40 healthy adults were enrolled and assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 10 pu (n=20) or 1 × 10 pu (n=20). The cAd3-Marburg vaccine was safe, well tolerated, and immunogenic. All enrolled participants received cAd3-Marburg vaccine, with 37 (93%) participants completing follow-up visits; two (5%) participants moved from the area and one (3%) was lost to follow-up. No serious adverse events related to vaccination occurred. Mild to moderate reactogenicity was observed after vaccination, with symptoms of injection site pain and tenderness (27 [68%] of 40 participants), malaise (18 [45%] of 40 participants), headache (17 [43%] of 40 participants), and myalgia (14 [35%] of 40 participants) most commonly reported. Glycoprotein-specific antibodies were induced in 38 (95%) of 40 participants 4 weeks after vaccination, with geometric mean titres of 421 [95% CI 209–846] in the 1 × 10 pu group and 545 [276–1078] in the 1 × 10 pu group, and remained significantly elevated at 48 weeks compared with baseline titres (39 [95% CI 13–119] in the 1 ×10 pu group and 27 [95–156] in the 1 ×10 pu group; both p<0·0001). T-cell responses to the glycoprotein insert and neutralising responses against the cAd3 vector were also increased at 4 weeks after vaccination. This first-in-human trial of this cAd3-Marburg vaccine showed the agent is safe and immunogenic, with a safety profile similar to previously tested cAd3-vectored filovirus vaccines. 95% of participants produced a glycoprotein-specific antibody response at 4 weeks after a single vaccination, which remained in 70% of participants at 48 weeks. These findings represent a crucial step in the development of a vaccine for emergency deployment against a re-emerging pathogen that has recently expanded its reach to new regions. National Institutes of Health.

中文翻译：

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黑猩猩腺病毒 3 型载体马尔堡病毒 (cAd3-Marburg) 疫苗在美国健康成年人中的安全性、耐受性和免疫原性：首次人体、第一阶段、开放标签、剂量递增试验


世卫组织已将马尔堡病毒确定为一种新出现的病毒，需要紧急研究和开发疫苗，特别是由于该病毒最近在加纳出现。我们报告了一项首次人体临床试验的结果，该试验在健康成人中评估了复制缺陷型重组黑猩猩腺病毒 3 型 (cAd3) 载体疫苗，该疫苗编码野生型马尔堡病毒安哥拉糖蛋白 (cAd3-Marburg)。我们在美国沃尔特里德陆军研究所临床试验中心对 cAd3-马尔堡疫苗进行了首次人体、第一阶段、开放标签、剂量递增试验。 18-50 岁的健康成年人被分配接受单剂量的 cAd3-马尔堡疫苗肌肉注射，剂量为 1 × 10 或 1 × 10 颗粒单位 (pu)。主要安全终点包括疫苗接种后前 7 天评估的反应原性和评估 28 天的所有不良事件。次要免疫原性终点是评估针对马尔堡病毒糖蛋白插入物的结合抗体反应和 T 细胞反应，以及评估疫苗接种后 4 周针对 cAd3 载体的中和抗体反应。本研究已在 ClinicalTrials.gov 注册，NCT03475056。 2018年10月9日至2019年1月31日期间，招募了40名健康成年人，并分配他们接受单剂量的cAd3-马尔堡疫苗肌肉注射，剂量为1 × 10 pu (n=20) 或 1 × 10 pu (n=20) ）。 cAd3-马尔堡疫苗安全、耐受性良好且具有免疫原性。所有入组参与者均接种了 cAd3-马尔堡疫苗，其中 37 名 (93%) 参与者完成了随访；两名 (5%) 参与者离开了该地区，一名 (3%) 失去了后续行动。没有发生与疫苗接种相关的严重不良事件。 接种疫苗后观察到轻度至中度反应原性，症状包括注射部位疼痛和压痛（40 名参与者中的 27 名 [68%]）、不适（40 名参与者中的 18 名 [45%]）、头痛（40 名参与者中的 17 名 [43%] ）和肌痛（40 名参与者中的 14 名 [35%]）最常报告。接种疫苗 4 周后，40 名参与者中有 38 名 (95%) 诱导产生了糖蛋白特异性抗体，1 × 10 pu 组的几何平均滴度为 421 [95% CI 209–846]，而 1 × 10 pu 组的几何平均滴度为 545 [276–1078]。 1 × 10 pu 组，与基线滴度相比，在 48 周时仍显着升高（1 × 10 pu 组中为 39 [95% CI 13–119]，1 ×10 pu 组中为 27 [95–156]；两者均p<0·0001）。疫苗接种后 4 周，T 细胞对糖蛋白插入物的反应和对 cAd3 载体的中和反应也有所增加。这种 cAd3-马尔堡疫苗的首次人体试验表明，该试剂是安全的且具有免疫原性，其安全性与之前测试的 cAd3 载体丝状病毒疫苗相似。 95% 的参与者在单次疫苗接种后 4 周产生了糖蛋白特异性抗体反应，而 70% 的参与者在 48 周时仍然存在这种抗体反应。这些发现代表了开发用于紧急部署针对重新出现的病原体的疫苗的关键一步，该病原体最近已将其影响范围扩大到新的地区。美国国立卫生研究院。