对马尔堡病毒疫苗非人类灵长类动物研究和人体临床试验的系统评价。
Systematic review of Marburg virus vaccine nonhuman primate studies and human clinical trials.
机构信息
Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Walter Reed Army Institute of Research, Silver Spring, MD, USA.
出版信息
Vaccine. 2021 Jan 8;39(2):202-208. doi: 10.1016/j.vaccine.2020.11.042. Epub 2020 Dec 9.
BACKGROUND
Recent deadly outbreaks of Marburg virus underscore the need for an effective vaccine. A summary of the latest research is needed for this WHO priority pathogen. This systematic review aimed to determine progress towards a vaccine for Marburg virus.
METHODS
Article search criteria were developed to query PubMed for peer-reviewed articles from 1990 through 2019 on Marburg virus vaccine clinical trials in humans and pre-clinical studies in non-human primates (NHP). Abstracts were reviewed by two authors. Relevant articles were reviewed in full. Discrepancies were resolved by a third author. Data abstracted included year, author, title, vaccine construct, number of subjects, efficacy, and demographics. Assessment for risk of bias was performed using the Syrcle tool for animal studies, and the Cochrane Collaboration risk of bias tool for human studies.
RESULTS
101 articles were identified; 27 were related to Marburg vaccines. After full text review, 21 articles were selected. 215 human subjects were in three phase 1 clinical trials, and 203 NHP in 18 studies. Vaccine constructs were DNA plasmids, recombinant vesicular stomatitis virus (VSV) vectors, adenovirus vectors, virus-like particles (VLP), among others. Two human phase 1 studies of DNA vaccines had 4 adverse effects requiring vaccine discontinuation among 128 participants and 31-80% immunogenicity. In NHP challenge studies, 100% survival was seen in 6 VSV vectored vaccines, 2 DNA vaccines, 2 VLP vaccines, and in 1 adenoviral vectored vaccine.
CONCLUSION
In human trials, two Marburg DNA vaccines provided either low immunogenicity or a failure to elicit durable immunity. A variety of NHP candidate Marburg vaccines demonstrated favorable survival and immunogenicity parameters, to include VSV, VLP, and adenoviral vectored vaccines. Elevated binding antibodies appeared to be consistently associated with protection across the NHP challenge studies. Further human trials are needed to advance vaccines to limit the spread of this highly lethal virus.
背景
马尔堡病毒最近的致命爆发突显了对有效疫苗的需求。这是世卫组织优先病原体，需要对最新研究进行总结。本系统评价旨在确定针对马尔堡病毒疫苗的研究进展。
方法
为查询 1990 年至 2019 年期间在人类中进行的马尔堡病毒疫苗临床试验和非人类灵长类动物（NHP）中的临床前研究的同行评审文章，制定了文章搜索标准。两位作者对摘要进行了审查。对相关文章进行了全面审查。分歧由第三位作者解决。提取的数据包括年份、作者、标题、疫苗构建体、受试者数量、疗效和人口统计学。使用 Syrcle 工具对动物研究进行风险评估，使用 Cochrane 协作风险偏倚工具对人类研究进行风险评估。
结果
共确定了 101 篇文章，其中 27 篇与马尔堡疫苗有关。在对全文进行审查后，选择了 21 篇文章。在三项 I 期临床试验中，有 215 名人类受试者，在 18 项研究中有 203 只 NHP。疫苗构建体包括 DNA 质粒、重组水疱性口炎病毒（VSV）载体、腺病毒载体、病毒样颗粒（VLP）等。两项人类 I 期 DNA 疫苗研究中，在 128 名参与者中，有 4 名因出现不良反应而停止接种疫苗，免疫原性为 31-80%。在 NHP 挑战研究中，6 种 VSV 载体疫苗、2 种 DNA 疫苗、2 种 VLP 疫苗和 1 种腺病毒载体疫苗的 100%存活。
结论
在人类试验中，两种马尔堡 DNA 疫苗要么免疫原性低，要么未能引起持久免疫力。多种 NHP 候选马尔堡疫苗表现出良好的存活和免疫原性参数，包括 VSV、VLP 和腺病毒载体疫苗。在整个 NHP 挑战研究中，高结合抗体似乎始终与保护相关。需要进一步的人类试验来推进疫苗的研发，以限制这种高致命病毒的传播。
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