埃博拉病毒疫苗最新研究进展

埃博拉病毒(Ebola virus,EBOV)是引起人类和非人灵长类动物严重出血热的最危险病原体之一,1976年首次得到报道.2014年撒哈拉以南非洲暴发的EBOV病的病死率高达90％.研究表明EBOV灭活疫苗无效,但多个新型EBOV候选疫苗已在临床前试验中显示有效,其中部分已进入临床试验.这些新型疫苗包括病毒载体疫苗、病毒样颗粒疫苗和核酸疫苗.此文对EBOV疫苗的研究进展做一综述.     

埃博拉病毒疫苗研究进展

埃博拉出血热是埃博拉病毒(Ebola virus,EBOV)引起的人类和非人灵长类动物急性出血性传染病,目前尚无治疗药物和疫苗获得批准.科研人员正在进行EBOV疫苗的研发,包括病毒样颗粒疫苗、DNA疫苗和病毒载体疫苗等.虽然这些疫苗的免疫机制各不相同,但部分疫苗在非人灵长类动物中能有效对抗EBOV,提示有望成功研制出EBOV疫苗.     

抗埃博拉病毒药物研究近期动态

对抗埃博拉病毒新药的近期研究成果以及业界提出或可用于治疗埃博拉出血热的已上市药物进行总结归纳,旨在为抗埃博拉病毒药物的进一步开发及埃博拉出血热治疗方案的探索提供参考。     

埃博拉病毒 一级恐惧

令世界医学界闻之色变的非洲神秘病毒“埃博拉”再度在乌干达现身。这种令感染者七窍流血，心肝肺俱烂的可怕病毒到10月初引起国际卫生组织警惕时，已呈大规模传染之势。     

中医谈埃博拉

编者按:2014年,埃博拉病毒肆虐西非数国,甚至使远离非洲大陆的美欧亚各国也深感危机。其实早在几千年前,"埃博拉"就已经存在,但直至1976年才真正发现埃博拉具有强致病性,虽然此前也曾几度流行,但疫情尚不严重。此次埃博拉疫情规模及严重程度为历史罕见。世界各国纷纷积极应对疫情,但西医的治疗手段及成效并不尽如人意。就在众人对埃博拉几乎束手无策之时,有人提出,     

干扰埃博拉病毒繁殖突破性进展

美国波士顿大学医学院“全国潜在传染病实验室”专家托马斯·盖斯伯特领导一个团队,选取2组恒河猕猴应用这种试验性药物。美国研究者利用微粒状基因物质干扰埃博拉病毒繁殖的研究取得突破性进展。实验室研究表明,感染埃博拉病毒的恒河猕猴接受一种试验性药物治疗后死亡率降低。     

日本科学家成功去除埃博拉病毒毒性有望制成疫苗

东京大学医学科学研究所的科研小组在《美国科学院院报》上发表了一项研究成果：该研究小组成功地通过基因无毒化操作，使导致埃博拉出血热的埃博拉病毒只在特殊的实验用人工细胞中繁殖。埃博拉病毒感染后死亡率高达50％～90％，目前尚无预防疫苗与治疗药物。研究小组从埃博拉病毒拥有的8个基因中只去除了病毒繁殖必需的“VP30”基因，从而制成了无毒病毒。该无毒病毒仅在注人了“VP30”基因的猴子细胞中进行繁殖，在普通细胞中既不繁殖也不发挥毒性。除此之外，该病毒的外观及性质与原来的埃博拉病毒并无任何区别，     

埃博拉病毒入侵：尚有多远？

与具有高传染性的埃博拉患者密切接触的医护人员,仍是埃博拉病毒感染的高发人群。目前全球已有450名医务工作者感染埃博拉病毒,其中244人死亡。在这场可能发生的＂埃博拉战争＂面前,我国医务人员该如何做好预控工作,保护好自身和广大就医者？     

人体埃博拉疫苗试验凸显时代需求

最近第一个人体埃博拉疫苗试验拉开序幕，无疑凸显了人们对这种疾病的关注，人们都意识到这种疾病不再是和自己无关紧要的也不是偶然的，而是潜在的全球性的。     

Development of a broad-spectrum antiviral with activity against Ebola virus

We report herein the identification of a small molecule therapeutic, FGI-106, which displays potent and broad-spectrum inhibition of lethal viral hemorrhagic fevers pathogens, including Ebola, Rift Valley and Dengue Fever viruses, in cell-based assays. Using mouse models of Ebola virus, we further demonstrate that FGI-106 can protect animals from an otherwise lethal infection when used either in a prophylactic or therapeutic setting. A single treatment, administered 1 day after infection, is sufficient to protect animals from lethal Ebola virus challenge. Cell-based assays also identified inhibitory activity against divergent virus families, which supports a hypothesis that FGI-106 interferes with a common pathway utilized by different viruses. These findings suggest FGI-106 may provide an opportunity for targeting viral diseases.     

Implications of Toll-like receptors in Ebola infection

Introduction: The potential roles of toll-like receptors (TLRs) in immunopathogenesis of Ebola virus disease should be unraveled to provoke possible prophylactic or therapeutic implications of TLRs for EVD.

Areas covered: The Ebola virus (EBOV) infection virtually paralyses all the main mechanisms responsible for induction of type I interferon (IFN-I) response. To summarize, EBOV infection interferes with: a) the TIR-domain-containing adapter-inducing interferon-β (TRIF) pathway that is mediated by TLR3 and TLR4 signaling; b) the interferon regulatory factor 7 (IRF7) pathway that is stimulated by TLR7 and TLR9; c) the intracellular signaling that is induced by retinoic acid-inducible gene 1 (RIG-I)-like receptors (RLRs); and d) the autocrine/paracrine feedback loop that is mediated by the IFN-stimulated gene factor 3 (ISGF3) complex. Upon infection with EBOV infection, TLR4 plays a key role in production of proinflammatory mediators.

Expert opinion: It is theoretically possible that use of TLRs 3, 4, 7, and 9 agonists would be beneficial to improve the IFN-I response, despite their systemic side effects. Also, antagonist of TLR4 can be utilized to prevent production of proinflammatory cytokines. Additionally, it is highly recommended to design future investigations aimed at determining if the utilization of IFN-I would be beneficial for prophylactic/therapeutic programs of Ebola.     

Improving attrition rates in Ebola virus drug discovery

Introduction: The Ebola 2014/2015 outbreak has had devastating effects on the people living in West Africa. The spread of the disease in endemic countries and the potential introduction of sporadic cases in other continents points out the global health threat of Ebola virus disease (EVD). Despite the urgent need for treating EVD, there are no approved treatments. Given the lack of treatments available, alternative therapeutic strategies have had to be used.

Areas covered: This article summarizes the unregistered therapeutics that were used to treat patients during the Ebola 2014/2015 outbreak, in addition to approaches used for the selection of candidate drugs. The article also proposes potential theoretical criterion for use in virtual screening of molecular libraries for candidate Ebola drugs.

Expert opinion: In the absence of approved therapeutics for EVD, experimental drugs have had to be used. The repurposing of approved drugs for the treatment of EVD, as an alternative therapeutic strategy, has also been suggested. Screening in vitro- and in silico-approved drugs revealed several promising candidates but further testing is required to test their efficacy. All these therapeutic approaches are, however, only short-term solutions and there is still an urgent need for the development of specific drugs for the current and future outbreaks.     

埃博拉病毒病的治疗及新药研究进展

埃博拉病毒是世界上最具威胁的病原体之一,2013年12月始于西非几内亚的埃博拉病毒病（Ebola virus disease,EVD）疫情,成为有记载以来最严重的一次暴发。由于对疫情的估计不足以及缺乏有效的治疗药物,本次疫情的防治效果并不乐观。美国FDA紧急批准了未经系统研究的ZMapp和TKM-Ebola用于埃博拉病毒病的治疗,但限于未知的疗效、安全性和产能的不足,意义有限。本文综述了现有的治疗埃博拉病毒病的方法以及新药的最新研究进展,方便相关人员了解此方面的信息。     

Nonclinical safety assessment of repeated administration and biodistribution of ChAd3-EBO-Z Ebola candidate vaccine

ChAd3-EBO-Z is an investigational adenovirus-based vaccine for the prevention of Ebola virus disease. Two nonclinical studies were performed to evaluate the biodistribution, local tolerance and potential local and systemic toxic effects of this vaccine. In the biodistribution study, rats received a single intramuscular injection of either ChAd3-EBO-Z or saline. Enlargement of the draining lymph nodes, starting on day 2, was noticed in ChAd3-EBO-Z-treated rats, indicating that an immune response had taken place. Viral DNA was mainly found at the injection sites and in the draining lymph nodes, from where it progressively disappeared during the observation period, while it was found only transiently and occasionally in other organs. In the repeated-dose toxicity study, either ChAd3-EBO-Z or saline was administered intramuscularly to rabbits on two occasions with a 2-week interval. General health status, rectal temperature, local tolerance, ophthalmology, hematology, coagulation and blood chemistry parameters were monitored. Macroscopic and microscopic evaluations were performed. Treatment-related changes included a transient increase in neutrophil count, C-reactive protein and fibrinogen levels, and a transient decrease in platelet count. As expected, microscopic observations 3 days after the second injection were related to the elicited inflammatory reaction, and these inflammatory responses had almost completely disappeared 29 days after the second immunization. In conclusion, the vaccine was locally and systemically well-tolerated and the viral vector was partially or totally cleared from the organs where it disseminated, supporting the clinical development of the vaccine.     

Development of experimental and early investigational drugs for the treatment of Ebola virus infections

Introduction: Ebola virus (EBOV) causes severe hemorrhagic fever in humans, and due to the aggressive nature of infection it has been difficult to develop effective medical countermeasures. Total casualties from past outbreaks numbered fewer than 1500 cases, but EBOV unexpectedly emerged from Guinea in late 2013 and infected over 25,000 people in nine countries spanning Africa, Europe and North America. Concern among the public and authorities helped spark an unprecedented push to fast-track experimental drugs for clinical use.

Areas covered: The authors provide a historical timeline of the progress in developing a licensed post-exposure EBOV drug for use in humans. Furthermore, they summarize and discuss the published data with different in light of their potential to play a role during outbreak times.

Expert opinion: Monoclonal antibody-based therapy is able to reverse advanced EBOV disease, but the outbreak of an antigenically divergent filovirus would require the reformulation and possibly redevelopment of the most promising candidates. Immunocompetent small animal models have not yet been developed for screening drugs against other filoviruses aside from Ravn and Marburg virus, and thus the number of prophylactic and therapeutic candidates lag behind that of EBOV. There is an urgent need for the proactive development of drugs against other neglected pathogens before the next major outbreak.