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标题: 转移贴：How To Improve Vaccines To Trigger T Cell As Well As Antibody Res... [打印本页]

作者: rojjer 时间: 2015-6-9 11:24
标题: 转移贴：How To Improve Vaccines To Trigger T Cell As Well As Antibody Res...
原贴由rojjer发表于 2009-9-21 2009/9/21 21-9-2009 21/9/2009 10:01

今日看到ScienceDaily 上一则短报“How To Improve Vaccines To Trigger T Cell As Well As Antibody Response？”
我想对于从事疫苗研究的朋友应该有所启发。特拿出来供大家分享，也希望在本版由此展开对如何提高疫苗免疫原性、优化疫苗设计的讨论。
讨论内容：您所知道的增强疫苗免疫原性的策略？

作者: rojjer 时间: 2015-6-9 11:24
How To Improve Vaccines To Trigger T Cell As Well As Antibody Response
ScienceDaily (Sep. 18, 2009)

Killed or disabled viruses have proven safe and effective for vaccinating billions worldwide against smallpox, polio, measles, influenza and many other diseases.
But killed or severely "attenuated" vaccines, which are safer than "live" vaccines, have been largely unsuccessful for many non-viral diseases, including illnesses like tuberculosis and malaria.

A new study by researchers from the University of California, Berkeley, and Berkeley-based Aduro BioTech provides clues why killed and severely attenuated vaccines don't always work. It also suggests ways to engineer an attenuated vaccine to make it as potent as a live vaccine but as safe as a killed vaccine.

"It's not only that these killed or attenuated vaccines can't immunize, it's that they also suppress immunity," said co-author Daniel Portnoy, UC Berkeley professor of molecular and cell biology and of public health. "What this says is that the immune system knows the difference between a live bug that's virulent and a dead one that is harmless."

The study, which appears in the Sept. 4 online edition of the journal PLoS Pathogens, suggests that for killed or severely attenuated non-viral vaccines to work – and for viral vaccines to work better – it's necessary to make the microbes act as if they're alive.

"In general, killed vaccines have not lived up to the potency of live vaccines, and our finding might partially explain this observation," said co-author Dirk Brockstedt, director of research and development at Aduro. "The finding is really key for us to develop a strategy to select new bacterial strains that induce the right kind of immune response."

The findings support a new hypothesis about how the innate immune system distinguishes pathogenic from non-pathogenic microbes, proposed by Portnoy, UC Berkeley colleague Russell Vance, assistant professor of molecular and cell biology, and Ralph Isberg of Tufts University in the July 23 issue of the journal Cell Host & Microbe. They argue that it's not only how a pathogen looks that determines how the immune system responds, but also how it acts – where it goes in the cell, what pathways it interferes with, and how disruptive it is.

"There are a series of different things that pathogens have to do in order to be pathogenic, so it makes sense for the immune system to try to detect these common patterns," Vance said. "We know already that there are surveillance pathways in the cytosol that seem to respond specifically to pathogens and not to non-pathogens."

The findings are most important for creating effective vaccines against pathogens – bacteria, parasites and viruses – that live and hide inside cells. While some pathogens, such as viruses, can be knocked back when they exit one cell to infect another – hence the effectiveness of some antiviral vaccines – other intracellular pathogens never completely leave the cell.

A vaccine against these intracellular pathogens would need to induce a so-called cellular or T cell response that is not effectively induced by current available vaccines, Brockstedt said.

A delicate balance

The body's immune system is a complex interplay of activation and suppression that operates to keep the body in a balanced state with no inflammation until it's needed, Portnoy said. The first line of defense against invading pathogens is the innate immune system, which deploys when the body recognizes characteristics of viruses and microbes that are common enough that they have been programmed into our genes and are with us from birth.

The more sophisticated system, however, is the acquired or adaptive immune system, which kicks in after the innate immune response. It recognizes unique aspects of pathogens – the proteins and sugars that they sport and generates antibodies to latch onto and target them for destruction. It also mobilizes T cells to attack the invaders or, more importantly, infected cells.

Listeria generates one of the strongest immune responses of any intracellular pathogen, which makes it a promising vehicle to deliver antigens that will immunize against a range of illnesses, from cancer to HIV. Portnoy has studied Listeria bacteria for 22 years to understand why it is so immunogenic, and how Listeria can be used as a vaccine without itself inflaming the immune system and causing disease.

Based on their and other experiments, Portnoy and Vance argue that the immune system looks at more than the microbe's coat, but also at how the microbe behaves. Listeria bacteria, for example, enter macrophage cells by luring these cells to engulf them. Once inside the phagosome, or stomach, of the macrophage, the bacteria secrete proteins that punch holes in the phagosome that allow the bacteria to spread throughout the guts of the cell, the cytosol.

It has been known for decades that killed Listeria vaccines don't provide protective immunity. It was believed that failure to reach the cytosol was the major reason. In earlier experiments, Portnoy and others found that mutant strains of Listeria that are not able to break out of the phagasome fail to stimulate an immune response. The current study shows why.

Killed Listeria suppress immune system

Portnoy, Brockstedt, Keith S. Bahjat of the Earle A. Chiles Research Institute in Portland, Ore., and Nicole Meyer-Morse of UC Berkeley's Department of Molecular and Cell Biology injected mice with a mixture of attenuated, but live, bacteria that stimulate a good immune response and dead bacteria that produce no response. They found that the cells' response to this mixture was less than if the researchers had injected only the effective vaccine.

"You would think, 'Why wouldn't the immunogenic strain still immunize?' But by having the non-immunogenic strain, it suppressed immunity," Portnoy said.

The implication, the researchers argue, is that the innate immune system monitors behavior as well as the antigens on the surface of invaders to know how aggressively to respond. The initial response of the innate immune system determines the level of response of the acquired immune system.

"You need to have an innate response to get adaptive responses to occur properly," Vance said. "For example, a killed virus might stimulate certain kinds of innate signals that lead to good antibody production, but might not generate the right response to properly activate T cells."

"Potentially, if we could figure out what kinds of responses are the ones that are really best at inducing immunization, this could have a lot of importance for how we design vaccines in the future," Vance added.

New vaccines for cancer, salmonella, anthrax

Portnoy's work has already led to two promising Listeria-based vaccines. Aduro's predecessor, Anza Therapeutics, collaborated with Portnoy to produce live, attenuated Listeria vaccines against cancer and hepatitis C that have been evaluated for safety in Phase I clinical trials. Aduro is continuing this line of work but is also developing what it calls a killed, but metabolically active (KBMA), form of Listeria to serve as a vaccine vector for a range of infectious diseases.

KBMA retains the ability to break out of the cell's stomach into the cell's cytosol, just like live Listeria, but, unlike live Listeria, it is unable to grow, said Portnoy. The KBMA strategy has also been extended to salmonella bacteria and, most recently, to anthrax, as reported by Portnoy and Aduro colleagues in the April 2009 issue of the journal Infection and Immunity.

But Portnoy has hopes that Listeria can do even better. His lab is currently searching for mutant strains of Listeria that can mimic the behavior of live bacteria even when killed or attenuated.

"The field has moved so rapidly that we now have the opportunity to make designer vaccines that can be used for many different applications," Portnoy said, noting that he has engineered Listeria to express foreign genes, turn on various immune pathways, and even pop or not pop. "We can make Listeria dance the salsa."

"The whole battle with vaccines is that you want them to be completely immunogenic and completely avirulent and safe, which today is a disconnect," Portnoy said. "We would like to enable this, so that we can have a completely safe and fully immunogenic vaccine. That is what everyone wants."

Authors of the PLoS Pathogens paper include Portnoy, Brockstedt, Bahjat and Meyer-Morse, in addition to Edward E. Lemmens and Thomas W. Dubensky, formerly of Anza Therapeutics, and Jessica A. Shugart of the Providence Cancer Center in Portland.

The work was funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

作者: rojjer 时间: 2015-6-9 11:25
mimisikai再生
可能说的不对也不好欢迎拍砖
免疫原性上来说得归根到疫苗设计的最初就像某抗原中几个点突变蛋白构象就由β片层变成了a螺旋，直接导致中和抗原提高很多倍，但是这样的例子要有多少工作多少运气才能实现呢

现在的疫苗有人喜欢用佐剂用免疫途径来提高免疫效果
实际上呢不管是什么佐剂也好什么途径（皮内皮下电穿孔基因枪）效果能提供多少？5倍？10倍都是很困难的！效果达不到数量级上的变化，能说明其有效？
我觉得一个疫苗走到靠这些边边角角的辅佐措施来提高免疫效果，应该说这样的疫苗就是失败的！
好了牢骚发完了大家来拍砖吧。

作者: rojjer 时间: 2015-6-9 11:25
lianghuang1983
使用融合蛋白算不算呢？
有报道使用Albumin binding protein的融合抗原能提高小鼠的免疫反应。
详见The serum albumin binding region of streptococcal protein G potentiates the immunogenicty of the G130-230 RSV-A protein. VACCINE,1999

作者: rojjer 时间: 2015-6-9 11:26
rojjer
确实近年来疫苗的主要研究中，在注重疫苗候选抗原选择和设计的同时（如将某些信号截去，表位串联等等），又出现了一些新的研究方向，如疫苗的递送系统（病毒载体、脂质体包裹、VLP、DNA疫苗的基因枪以及靶向策略等）和佐剂方面。关于佐剂方面，mimisikai再生所言诚恳极，这些结果都是体现在研究论文中，当然如果应用于临床能达到5倍？10倍的话当然是万事大吉。个人觉得新型佐剂的研究还是非常有必要的，从各大疫苗公司的专利佐剂来看（AS03、MF59、AF03），配合其新型佐剂的疫苗确实占有了很多的份额，甚至佐剂的作用已经不仅仅局限于节省抗原用量，(AS03 adjuvanted pre-pandemic H5N1 vaccine: single dose primary vaccination with clade 1 vaccine strain leads to strong immune responsiveness to clade 2 strain booster vaccination, 交叉保护 )，最近看到说是《柳叶刀》杂志批评美国关于甲型H1N1 流感疫苗不加佐剂的决定，尽管美国的季节性流感疫苗都是无佐剂疫苗，但是对于H1N1这样的应急事件，在当前生产能力严重不足的情况下，合适的佐剂还是能发挥不小的作用。
今天因为帮老板查点资料，翻了一下十几期的vaccine杂志，三个问题比较突出，其一就是一些细胞因子相关佐剂和靶向APC表面标志的文章很多，其二，DNA疫苗大批涌现，其三，中国作者小占份额，压力很大呀。呵呵

作者: rojjer 时间: 2015-6-9 11:26
mimisikai

rojjer说的我也看到部分。只是DNA疫苗是挺火，啥都上DNA疫苗，但是这种免疫方式注定其免疫原性较差，不能有效的激活免疫系统。佐剂是个好东西，但是如果苗本身就打不起来免疫反应，或者说很低，就想通过佐剂把他提升到很高？我觉得不可能。
我不知道有没有这样的疫苗啊，就算本身不行，通过佐剂+免疫途径就搞到很高，那也太神奇了，期望能见识一下，哈哈

作者: rojjer 时间: 2015-6-9 11:27
半拉木匠
呵呵大连金港安迪做到了，，，好像犯法了。。。。。加点东西呗

作者: rojjer 时间: 2015-6-9 11:27
半拉木匠
开玩笑喽，在此收回楼上的话，再不刺激金刚安迪的事情了，抱歉。。。。。
国外的添加剂增强免疫圆形的方法好像已经获得认可，国内无临床数据，流调时间好像非常非常的长。。。。

作者: rojjer 时间: 2015-6-9 11:28
lianghuang1983
弱问：DNA疫苗是指佐剂中添加DNA（如国内某厂所为），还是抗原即是DNA？

作者: rojjer 时间: 2015-6-9 11:28
rojjer
9# lianghuang1983
推荐：http://bbs.virology.com.cn/viewthread.php?tid=1827

作者: rojjer 时间: 2015-6-9 11:29
pipi302
感觉国内对佐剂的应用还是比较的保守，多认为免疫原性不够好才考虑应用佐剂来提高。一个铝佐剂应用了好多年，关于佐剂的研发涉及的也较少。
佐剂提高免疫原性，减少单位抗原成份的应用，降低副反应，减少生产成本优势还是一大把的，关键是免疫机制的基础研究和新型疫苗佐剂的开发！

作者: rojjer 时间: 2015-6-9 11:29
giggle334
这个讨论的方式不错顶起来哦

作者: rojjer 时间: 2015-6-9 11:30
hxq78316
学习了！

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