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Professors Deming Zhou/Lihe Zhang research group creates flu vaccine from live virus using ‘revolutionary’ approach, the researchers reported in Science


 Engineered Flu Virus a Replicative Dud, but Stays Live 

Developing a live vaccine is a tricky balancing act. But it can become more of a sure thing if the vaccine developer puts a thumb on the scales. That’s one way to describe the approach taken by Peking University researchers. They decided to tweak the influenza A virus genetically so that it would not only remain fully capable of activating the immune system, but would also be incapable of replicating in healthy cells.
The secret? Well, that’s the proverbial thumb, which in this case is a cell line that makes use of an expanded genetic code. In cells of this line, viruses could replicate, but only in the presence of an unnatural amino acid.
Details appeared December 2 in the journal Science, in an article entitled, “Generation of Influenza A Viruses as Live but Replication-Incompetent Virus Vaccines.” It described how the Peking University researchers, led by Demin Zhou, Ph.D., contrived a virus that could generate only in genetically tweaked cells, but not in healthy cells.
In a proof-of-principle study, we expanded the genetic code of the genome of influenza A virus via a transgenic cell line containing orthogonal translation machinery,” wrote the paper’s authors. “This generated premature termination codon (PTC)–harboring viruses that exerted full infectivity but were replication-incompetent in conventional cells.”
The authors described how genome-wide optimization of the sites for incorporation of multiple PTCs resulted in highly reproductive and genetically stable progeny viruses in transgenic cells. This approach may become more widely used for generating live virus vaccines adapted to other viruses.
In mice, administering the modified, infected cells in the form of a vaccine offered full protection against influenza. The new vaccine was found to offer an antibody response comparable to an existing live-virus vaccine, and a second dose further increased antibody titers by a factor of six to eight. Similar beneficial effects were seen when the virus vaccine was tested against several different strains of influenza and tested in guinea pigs and ferrets.
These types of virus vaccines can be potentially adapted to almost any virus, the authors say, as long as their genome could be manipulated and packaged in a cell line.
From: http://www.genengnews.com/gen-news-highlights/engineered-flu-virus-a-replicative-dud-but-stays-live/81253494
 
New way to tame a virus
A live, genetically modified flu virus can infect animals and trigger a strong immune response, but cannot multiply in its host's cells. Such modified viruses could one day be used to improve on current vaccines.
Vaccines made of live viruses elicit stronger protective immune responses than inactivated vaccines, but, because they can replicate, have the potential to cause disease. To overcome this, Demin Zhou and his colleagues at Peking University in Beijing genetically altered the influenza A virus so that it could be produced efficiently by special transgenic cells, but could not replicate in normal cells or in infected animals. When compared with a commercially available inactivated flu vaccine, the modified virus stimulated stronger immune reactions in mice, ferrets and guinea pigs. Mice given the new vaccine and then infected with the unmodified flu virus survived, whereas all unvaccinated mice died.
From: http://www.nature.com/nature/journal/v540/n7632/full/540172c.html
 
北大药学院周德敏/张礼和课题组在病毒疫苗领域取得重大突破,
相关成果发表在《Science》杂志上
 
122日国际顶级期刊《Science》发表了北京大学周德敏/张礼和课题组的突破性研究进展,题为Generation of Influenza A Viruses as Live but Replication-Incompetent Virus Vaccines”。鉴于该成果在预防和治疗病毒性传染病方面的重大医学价值和社会意义,全球最大的科技新闻工作站SciPak将该发现作为亮点,于美国东部时间121日下午2:00向全球媒体发布。随即新华社、纽约时报、华尔街日报、加拿大广播公司和香港南华早报等媒体相继跟进,对这一重大发现进行了专题报道。Nature杂志也对此突破性进展给与了高度评价,认为周德敏及其北京大学同仁们建立的方法将被广泛用来制备更高效的病毒疫苗。
流感、艾滋病、SARS和埃博拉出血热等致命性传染病及其周期性爆发,时刻危害着人类健康和社会稳定,其幕后黑手是结构多样、功能复杂且变异快速的病毒,而疫苗是预防病毒感染的有效手段。当前临床使用的疫苗或因病毒灭活致免疫原性和安全性差,或因制备工艺复杂而不通用,或因病毒突变致免疫逃逸失效,从而使人们往往谈病毒色变。周德敏/张礼和课题组在国家创新药物专项、基金委和国家973计划的支持下,以流感病毒为模型,发明了人工控制病毒复制从而将病毒直接转化为疫苗的技术,即在保留病毒完整结构和感染力的情况下,仅突变病毒基因组的一个三联码,使流感病毒由致命性传染源变为了预防性疫苗,再突变三个以上三联码,病毒由预防性疫苗变为治疗病毒感染的药物,并且随着三联码数目的增加而药效增强。这一四两拨千斤技术不仅使疫苗研发不再复杂,而且摆脱了对病毒生物学知识获得的依,并适用于几乎所有病毒。这一发现颠覆了病毒疫苗研发的理念,成就了活病毒疫苗的重大突破。
周德敏教授和张礼和院士来自于北京大学药学院天然药物及仿生药物国家重点实验室,五年直博生司龙龙和徐欢为该论文的共同第一作者。
Si L., Xu H., Zhou X., Zhang Z., Tian Z., Zhang B., Niu Z., Yao T., Wang Y., Li S., Zhang C., Fu G., Xiao S., Xia Q., Zhang L., and Zhou D*Science, Dec 2, 2016, aah5869.
 
相关链接: http://science.sciencemag.org/content/354/6316/1170?from=singlemessage
 
相关点评
 
我科学家发明病毒转化疫苗新技术
 
光明日报北京121日电(记者田雅婷通讯员付东红)记者1日从北京大学医学部获悉,北京大学药学院天然药物及仿生药物国家重点实验室主任周德敏、张礼和院士课题组,发明了人工控制病毒复制从而将病毒直接转化为疫苗的新技术,该课题组的《制备复制缺陷的活流感病毒疫苗》的论文,已在国际顶级期刊《科学》上发表。
据周德敏介绍,流感、艾滋病、非典和埃博拉出血热等致命性传染病,其幕后黑手是结构多样、功能复杂且变异快速的病毒,而疫苗是预防病毒感染的有效手段。但是,目前临床使用的疫苗,或因病毒灭活致免疫原性和安全性差,或因 制备工艺复杂而不通用,还有些则因病毒突变致免疫逃逸失效。正因这样,人们往往谈病毒色变。在国家创新药物专项、基金委和国家973”计划的支持下,周德敏、张礼和课题组以流感病毒为模型,发明了这项新技术,即在保留病毒完整结构和感染力的情况下,仅突变病毒基因组的一个三联码,使流感病毒由致命性传染源变为预防性疫苗,再突变三个以上三联码,病毒由预防性疫苗变为治疗病毒感染的药物。不仅如此,随着三联码数目的增加,药效会进一步增强。
我们研发的疫苗是活病毒疫苗,保留了野生流感病毒完全的感染力,只是将它感染人体后,在细胞内复制和生产新病毒的能力剔除掉。周德敏解释说,通过这种方式,既保留了病毒感染人体引发的全部免疫原性,又使其对人体的毒性被控制住。周德敏强调,这是一种通用方法,可以做几乎所有致命性病毒的疫苗及治疗性生物技术药物。
《光明日报》(20161202 06)

 
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