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.     

埃博拉出血热的临床特征与防治进展

埃博拉出血热（ EHF）是由埃博拉病毒（ EBOV）引起的急性出血性传染病。 EHF在非洲多次发生较大规模流行。2014年主要流行于西部非洲的几内亚、塞拉利昂、利比里亚等多个国家。主要经接触患者的血液、分泌物和排泄物等传播。临床主要特征为急性发热,伴肌痛、出血、皮疹,以及肝脏、肾脏损害。严重病例可发生低血容量性休克、多器官功能障碍综合征（ MODS）或多器官功能衰竭（ MOF）。病死率达50％～90％。电镜法检测病毒或病毒分离、病毒抗原检测、基因检测是确诊的依据。预防措施包括控制传染源、切断传播途径、保护易感者。早期诊断及时隔离EHF患者对控制传染源十分重要。接触者须严格执行防护措施。 EHF预防性疫苗研究尚在进行中。目前采取综合治疗原则,主要包括支持与对症处理,控制出血,防治低血容量休克、急性呼吸窘迫综合征（ ARDS）、弥散性血管内凝血（ DIC）和MOF等。干扰素（ IFN）、EBOV单克隆抗体、恢复期血清治疗等均在探索中。     

炭疽、Ebola病毒、马尔堡病毒以及委内瑞拉马脑炎病毒的单独和联合DNA疫苗的比较

作者首先构建了炭疽杆菌保护性抗原( PA)、Ebola病毒 ( EBOV)、Marburg病毒( MARV)和委内瑞拉马脑炎病毒 ( VEEV)DNA疫苗。并用基因枪在 0、4、8和 2 1周对新西兰白兔免疫 2 0 μg炭疽 PA DNA疫苗 ;而对照动物则在 0、4、8和 1 2周肌肉注射0 .5ml人用吸附炭疽疫苗 ( AVA)或同剂量非重组质粒 ;在 2 4周时皮下注射有毒力的热激活炭疽芽孢进行攻击。用 EBOV包膜糖蛋白 ( GP)或核壳蛋白 ( NP) DNA疫苗对 6～ 8周的 BAL B/c小鼠进行接种 ,再用 EBOV的小鼠适应株攻击。在 MARV的研究中 ,使用钴辐射过的纯化 MARV Ravn或 Mu…     

丝状病毒疫苗的现状与挑战

能保护人类防御高致死性马尔堡和埃博拉病毒的疫苗尚未问世,但它们的载体疫苗已在非人灵长类动物模型中取得成功.载体疫苗在人体内的安全性及先存的抗载体免疫力问题是其获批的关键障碍.尽管马尔堡和埃博拉病毒疫苗防御作用的免疫机制还不十分明确,但非人灵长类动物研究显示,防御马尔堡和埃博拉病毒是可能的,疫苗有望在不久的将来获准用于人类.     

疾病综述：埃博拉出血热

埃博拉出血热是一种严重的出血性疾病,由某一种埃博拉病毒（EBOV）感染引起,其对赤道非洲地区的公共健康构成了很大威胁。对埃博拉病毒的分类、传播方式、致病机制、风险因子、流行病学、诊断、预防、治疗、新药研发管线及治疗靶标进行综述。     

现行新型冠状病毒疫苗的临床试验进展

为有效预防新型冠状病毒的感染及控制病毒的传播,疫苗的研制迫在眉睫.截至2020年9月28日,WHO公布现有40项新型冠状病毒疫苗临床试验正在进行,疫苗类型包括灭活疫苗、病毒载体疫苗、DNA疫苗和mRNA疫苗等,每类疫苗都有其优缺点.其中新型冠状病毒灭活疫苗、黑猩猩腺病毒载体疫苗和5型腺病毒载体疫苗等7款候选疫苗在Ⅰ/Ⅱ...     

炭疽、Ebola病毒、马尔堡病毒以及委内瑞拉马脑炎病毒的单独和联合DNA疫苗的比较

作者首先构建了炭疽杆菌保护性抗原(PA)、Ebola病毒(EBOV)、Marburg病毒(MARV)和委内瑞拉马脑炎病毒(VEEV)DNA疫苗。并用基因枪在0、4、8和21周对新西兰白兔免疫20μg炭疽PADNA疫苗；而对照动物则在0、4、8和12周肌肉注射0．5ml人用吸附炭疽疫苗(AVA)或同剂量非重组质粒；在24周时皮下注射有毒力的热激活炭疽芽孢进行攻击。     

生物防御用DNA疫苗

近年的生物防御疫苗研究集中于DNA疫苗.DNA疫苗对人以及环境相对安全、经济,并且多价联合DNA疫苗还可以提供多重保护,因此有良好的研发前景和潜在的实用价值,但也存在免疫原性不强和接种方式有待改进等问题.此文就炭疽杆菌、埃博拉病毒、马尔堡病毒、猴痘病毒、天花病毒和委内瑞拉马脑炎病毒等几种被美国NIH和CDC列为重要生物...     

疫苗增强性疾病风险探讨

目的 对疫苗增强性风险进行探讨,为新型冠状病毒疫苗上市后安全性监测提供参考.方法 通过检索、整理国内外关于病毒类疫苗与疫苗增强性疾病的研究成果,关注新型冠状病毒疫苗潜在的安全性问题.结果与结论 2020年新型冠状病毒引发的疫情蔓延全球,由于目前尚无针对新型冠状病毒的特效治疗药物,新型冠状病毒疫苗的研发己成为全球关注的热...     

正在研发的病毒疫苗

疫苗接种是预防人类病毒性传染病的最有效措施.病毒疫苗可以预防或缓解个体的疾病严重性,也可以阻断和减少病毒传播给其他易感人群.在过去的50年中,预防天花、脊髓灰质炎、麻疹、乙型肝炎的疫苗已经为人类健康作出了重要贡献.对病毒学和免疫学基础研究的发展为人类在21世纪征服病毒性疾病提供了美好前景.目前对于HIV、呼吸道合胞病毒、HCV等严重威胁人类健康的病毒还需要更多的基础研究.本文介绍即将用于临床或即将上市的病毒疫苗.这些疫苗包括抗RNA病毒减毒活疫苗--轮状病毒疫苗和流感疫苗;人乳头瘤病毒和水痘-带状疱疹病毒疫苗,这些DNA病毒可以建立持续感染,导致较高的发病率和死亡率.尽管在美国仅流感疫苗得到批准,但在随后几年里必将有一些新型疫苗问世.因此,有必要对这些病毒疫苗的研究进展作一总结.     

Could the Ebola virus matrix protein VP40 be a drug target?

Filoviruses are filamentous lipid-enveloped viruses and include Ebola (EBOV) and Marburg, which are morphologically identical but antigenically distinct. These viruses can be very deadly with outbreaks of EBOV having clinical fatality as high as 90%. In 2012 there were two separate Ebola outbreaks in the Democratic Republic of Congo and Uganda that resulted in 25 and 4 fatalities, respectively. The lack of preventive vaccines and FDA-approved therapeutics has struck fear that the EBOV could become a pandemic threat. The Ebola genome encodes only seven genes, which mediate the entry, replication, and egress of the virus from the host cell. The EBOV matrix protein is VP40, which is found localized under the lipid envelope of the virus where it bridges the viral lipid envelope and nucleocapsid. VP40 is effectively a peripheral protein that mediates the plasma membrane binding and budding of the virus prior to egress. A number of studies have demonstrated specific deletions or mutations of VP40 to abrogate viral egress but to date pharmacological inhibition of VP40 has not been demonstrated. This editorial highlights VP40, which is the most abundantly expressed protein of the virus and discusses VP40 as a potential therapeutic target.     

Current issues in the development of a vaccine to prevent human immunodeficiency virus: insights from the society of infectious diseases pharmacists

Infection with the human immunodeficiency virus (HIV) continues to affect millions of people worldwide. Preventive measures have done little to slow the transmission of the virus. Discovery of an effective vaccine to prevent HIV could have a tremendous impact on this global pandemic. However, the complex interactions between HIV and the host immune system have limited the progress in vaccine development. Traditional vaccination strategies have shown little promise. Currently, subunit vaccines, DNA vaccines, recombinant vector vaccines, and prime-boost strategies are being evaluated in clinical trials. Although many breakthroughs have been made in HIV vaccine research, only three candidate HIV vaccines have been studied in phase III clinical trials. The current strategies being investigated in the development of preventive HIV vaccines are reviewed.     

Vaccine development for an imminent pandemic: why we should worry, what we must do

The avian H5N1 virus continues to evolve and poses an imminent pandemic threat. Pandemic vaccine development, however, has progressed slowly. For it to succeed, it must be based on a public health perspective that reflects the arithmetic of pandemic vaccine demand, especially by countries without vaccine companies. Clinical trials of H5N1 vaccines have been discouraging, and we must understand why the H5N1 virus is so poorly immunogenic. Antigen-sparing pandemic vaccines will be required, and future trials must identify the most effective adjuvant and determine whether whole virus vaccines will be needed. Problems related to intellectual property and concerns about several regulatory issues must be resolved. Public funding for clinical trials must be provided and firm leadership and coordination exercised by national and international (WHO) public health officials. Vaccination for an imminent pandemic requires a global perspective not only for vaccine development but also for vaccine production and distribution.     

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.     

Toxicological safety evaluation of DNA plasmid vaccines against HIV-1, Ebola, Severe Acute Respiratory Syndrome, or West Nile virus is similar despite differing plasmid backbones or gene-inserts.

The Vaccine Research Center has developed a number of vaccine candidates for different diseases/infectious agents (HIV-1, Severe Acute Respiratory Syndrome virus, West Nile virus, and Ebola virus, plus a plasmid cytokine adjuvant-IL-2/Ig) based on a DNA plasmid vaccine platform. To support the clinical development of each of these vaccine candidates, preclinical studies were performed to screen for potential toxicities (intrinsic and immunotoxicities). All treatment-related toxicities identified in these repeated-dose toxicology studies have been confined primarily to the sites of injection and seem to be the result of both the delivery method (as they are seen in both control and treated animals) and the intended immune response to the vaccine (as they occur with greater frequency and severity in treated animals). Reactogenicity at the site of injection is generally seen to be reversible as the frequency and severity diminished between doses and between the immediate and recovery termination time points. This observation also correlated with the biodistribution data reported in the companion article (Sheets et al., 2006), in which DNA plasmid vaccine was shown to remain at the site of injection, rather than biodistributing widely, and to clear over time. The results of these safety studies have been submitted to the Food and Drug Administration to support the safety of initiating clinical studies with these and related DNA plasmid vaccines. Thus far, standard repeated-dose toxicology studies have not identified any target organs for toxicity (other than the injection site) for our DNA plasmid vaccines at doses up to 8 mg per immunization, regardless of disease indication (i.e., expressed gene-insert) and despite differences (strengths) in the promoters used to drive this expression. As clinical data accumulate with these products, it will be possible to retrospectively compare the safety profiles of the products in the clinic to the results of the repeated-dose toxicology studies, in order to determine the utility of such toxicology studies for signaling potential immunotoxicities or intrinsic toxicities from DNA vaccines. These data build on the biodistribution studies performed (see companion article, Sheets et al., 2006) to demonstrate the safety and suitability for investigational human use of DNA plasmid vaccine candidates for a variety of infectious disease prevention indications.     

呼吸道合胞病毒疫苗及疫苗研究和开发新方法

呼吸道合胞病毒(respiratory syncytial virus,RSV)是造成婴幼儿、老年人、免疫抑制者等免疫功能低下的人群呼吸道感染的最常见原因之一.RSV是一种单股负链RNA病毒,研究和开发RSV疫苗已有40多年的历史.最初儿童接种福尔马林灭活疫苗后再次感染RSV会出现病情加重的情况;减毒活疫苗在遗传稳定性上存在问题;以纯化的F蛋白和G蛋白研制的部分亚单位疫苗已进入临床试验阶段,尚存在一些需要解决的问题.某些DNA疫苗在动物模型上表现出良好的免疫原性,但由于生物安全的问题,DNA疫苗的应用前景尚不清楚.目前应用反向遗传学技术研制新的BSV疫苗已显示良好的应用前景.     

基于神经氨酸酶的流感疫苗研究进展

当前广泛使用的季节性流感疫苗的主要抗原成分包括2个重要的流感病毒表面糖蛋白,血凝素和神经氨酸酶(neuraminidase,NA).研究表明NA抑制性抗体虽然不能防止流感病毒感染,但能有效抑制病毒扩散,因此基于NA设计的疫苗开始受到重视.NA的相对保守性也使此类疫苗有潜力成为广谱流感疫苗.目前基于NA的多种形式流感疫苗,包括DNA疫苗、病毒样颗粒疫苗、重组载体疫苗、重组亚单位疫苗以及联合其他流感病毒蛋白的疫苗等,在动物模型中均表现出诱导交叉保护的能力.此文综述了近年来发表的有关基于NA的流感病毒疫苗的研究.     

Advances in respiratory syncytial virus vaccine development

Respiratory syncytial virus (RSV) is the most important causative agent of respiratory tract infections. Young children with chronic lung or congenital heart disease are at increased risk for severe disease. Intensive research into a candidate vaccine has yielded live attenuated vaccines and subunit vaccines, which have been studied in humans. Although immunogenic, occurrence of upper respiratory tract infection symptoms with live attenuated vaccine prohibits evaluation in young infants. Subunit vaccines include purified F protein (PFP-1 and -2) and BBG2Na. PFP vaccines are effective in seropositive children, but also induce upper respiratory symptoms. BBG2Na was being investigated in phase III clinical trials, however, further development has now been discontinued. This review discusses recent advances in RSV vaccine development.     

Repurposing of berbamine hydrochloride to inhibit Ebola virus by targeting viral glycoprotein

Ebola virus (EBOV) infection leads to staggeringly high mortality rate. Effective and low-cost treatments are urgently needed to control frequent EBOV outbreaks in Africa. In this study, we report that a natural compound called berbamine hydrochloride strongly inhibits EBOV replication in vitro and in vivo. Our work further showed that berbamine hydrochloride acts by directly binding to the cleaved EBOV glycoprotein (GPcl), disrupting GPcl interaction with viral receptor Niemann-Pick C1, thus blocking the fusion of viral and cellular membranes. Our data support the probability of developing anti-EBOV small molecule drugs by targeting viral GPcl. More importantly, since berbamine hydrochloride has been used in clinic to treat leukopenia, it holds great promise of being quickly repurposed as an anti-EBOV drug.     

Dose-response relationship of DNA and recombinant fowlpox virus prime-boost HIV vaccines: implications for future trials

Estimating effective doses of novel HIV vaccines is challenging. Dose-response analyses of DNA and fowlpox virus HIV vaccines showed that 1 mg of DNA vaccine and 5 x 10(7)pfu of fowlpox virus booster was immunogenic in macaques. However, this dose was poorly immunogenic in humans. When adjusted for body surface area, the human dose studied was equivalent to a poorly immunogenic lower dose in monkeys. These data provide a rationale for guiding dosing in future trials of HIV vaccine technologies.