Walter Reed Army Institute of Research, Silver Spring, MD, USA; Department of Emergency Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Lancet. 2023 Jan 28;401(10373):294-302. doi: 10.1016/S0140-6736(22)02400-X.
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.
世界卫生组织已将马尔堡病毒确定为一种新出现的病毒，需要紧急开展疫苗研究和开发工作，尤其是因为该病毒最近在加纳出现。我们报告了在健康成年人中评估一种复制缺陷型重组黑猩猩腺病毒 3 型（cAd3）载体疫苗（编码野生型马尔堡病毒安哥拉糖蛋白的 cAd3-Marburg）的首次人体临床试验结果。
我们在美国沃尔特·里德陆军研究所临床试验中心进行了一项首次人体、1 期、开放性、剂量递增的 cAd3-Marburg 疫苗试验。18-50 岁的健康成年人被分配接受单次肌肉内剂量的 cAd3-Marburg 疫苗，剂量分别为 1×10 或 1×10 个病毒粒子单位（pu）。主要安全性终点包括接种后 7 天内的反应性和接种后 28 天内的所有不良事件。次要免疫原性终点包括评估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，以及评估接种后 4 周对 cAd3 载体的中和抗体反应。本研究在 ClinicalTrials.gov 上注册，编号为 NCT03475056。
在 2018 年 10 月 9 日至 2019 年 1 月 31 日期间，共招募了 40 名健康成年人，并分配接受单次肌肉内剂量的 cAd3-Marburg 疫苗，剂量分别为 1×10 pu（n=20）或 1×10 pu（n=20）。cAd3-Marburg 疫苗安全、耐受良好且具有免疫原性。所有入组的参与者都接受了 cAd3-Marburg 疫苗，其中 37 名（93%）参与者完成了随访；2 名（5%）参与者搬离了该地区，1 名（3%）参与者失访。没有与接种相关的严重不良事件发生。接种后观察到轻度至中度反应性，最常见的症状有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%）。接种后 4 周，38 名（95%）参与者诱导出糖蛋白特异性抗体，1×10 pu 组的几何平均滴度为 421（95%CI 209-846），1×10 pu 组的几何平均滴度为 545（276-1078），与基线滴度相比，在 48 周时仍显著升高（1×10 pu 组为 39（95%CI 13-119），1×10 pu 组为 27（95-156）；均 p<0·0001）。接种后 4 周，对糖蛋白插入物的 T 细胞反应和对 cAd3 载体的中和反应也有所增加。
这项首次人体 cAd3-Marburg 疫苗试验表明，该疫苗安全且具有免疫原性，其安全性与之前测试的其他 cAd3 载体丝状病毒疫苗相似。单次接种后 4 周，95%的参与者产生了糖蛋白特异性抗体反应，48 周时仍有 70%的参与者保持这种反应。这些发现代表着在开发针对新近出现的病原体的疫苗方面迈出了重要一步，该病原体最近已扩展到新的地区。
美国国立卫生研究院。
