【讨论帖】疫苗研发的新思路 - 经验共享

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标题:【讨论帖】疫苗研发的新思路

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发表于 2014-8-6 18:11 资料个人空间短消息加为好友

小中大

相关疾病：
疟疾传染病肺结核糖尿病脑型疟疾感染疾病
等了这么久,终于有网友提到了疟疾疫苗!
我在疟疾领域,和我的一些同事一样,每年长期在欠发达的热带国家现场开展疟疾项目(期待回国呀),我自然对疟疾疫苗很关注.
先来说说freecell推荐的"The end of the beginning: Vaccines for the next 25 years". 谢谢推荐,拜读了. 我曾查询到这篇论文,但没有机会看到全文. 但是浏览完后,对这篇评论文章很失望.评价两个字---"垃圾"(对不起).
疟疾现在仍作为全球三大传染病之一(HIV;肺结核),当然,现实中受疟疾折磨的都是落后的国家,连中国海南岛也不常见了.作者通篇都未有提及疟疾的字眼.哦,作者更关注理论上潜在的威胁,而忽视现实的疾患:1918西班牙流感H1N1重出江湖(或者重组出新的HxNy),oh, SARS东山在起, oh,美国在世界上打来打去,大家都得小心Bioterrorism呀. 况且,疟疾疫苗今年取得了重大的进展(当然,该文发表在前,但是,这个进展是持续的,其积极的苗头已经显现.).作者来自英语世界,不存在科技语言和文献的障碍,如果不是作者有意的忽视疟疾,那么就是疟疾在他的疾病谱中,不占有位置. 作者通篇讨论疾病的都是所谓的当前热点.文中作者表达了"with a call for superhuman action for us to reach out far way from science into policymakers and decision and finance people." 套用作者自己的逻辑,以彼矛攻彼盾,如何? 印度(或者中国)将目光瞄准月球,而对大量的HIV,TB,糖尿病等等都视而不见,又如何? 作者自己本人就有视野的盲区,如何能达到最大善意的影响政治家/金融家而促进人类的健康?
感谢maoadai提到了RTS,S疫苗. 在08年12月8日,新英格兰医学杂志发表了2篇RTS,S疫苗II期临床试验的文章,同时配以一片评论文章. 采用新的佐剂后,该疫苗的保护效果达到了60%(具体有几个数据,对于恶性疟感染的保护效果,对于恶性疟发病的保护效果,可以去察看全文.) 试验表明疫苗安全,且其中一个试验表明其可以与婴幼儿的常规疫苗接种联合使用,这将大大简化该疟疾疫苗的使用.这是疟疾疫苗的重大进展. 这些数据支持由葛兰素史克联合盖茨基金开发的这个疫苗在09年初在非洲7个国家11个地点,共16000婴幼儿的III期临床试验. 这是目前为止, 唯一一个开发到这个阶段的疟疾疫苗. NEJM的文章一发表, 立刻引起了国际媒体的关注. 纽约时报发表社论,高度评价了这个进展,给与盖次基金应得的赞许. Wall Street Journal,卫报和经济学人等都有文章介绍这个进展. 这个上市前最终的III期临床试验预计费用为1亿美金. 关于III期临床的成功率,我看到有专家的意见是50-50.
60%的保护效果,相对于其他很多疫苗,都是有差距的, 但是,及时是不完全的保护效果,依然可以挽救很多非洲儿童的生命. 这也是很多专家的意见.
对于佐剂:
该两项II期临床试验采用了新的佐剂,其中一个特别设计以提高免疫反应的佐剂,它产生的抗体是另外一个的10倍; 两者的保护效果都高于先前发表在lancet的30%的保护效果.
maoadai也提到了减毒子孢子疫苗.就有这么一家纽约的生物公司,专门研发这个疫苗. 我前面推荐的文章中,对这个公司也进行了介绍. 解剖蚊子,取其子孢子,用Gammar射线处理后, 该子孢子可以完成入侵肝细胞的过程, 且能在肝细胞短暂存活,但是它不会产生裂殖子释放入血液.所有的过程都符合FDA的规范. 该公司也从盖茨基金获得了millions的基金以开发.NIAID的头头,感染性疾病的专家Fauci对其这个公司也有很积极的评价. 如果RTS,S疫苗最终能如期在2012年上市,那么我相信, 这家公司开发的减毒子孢子疫苗其保护效果会更好.
(让我表达一下对盖茨的敬意！呵呵)
不过,疟疾疫苗还有其他的靶点,除了瞄准子孢子过程;还有红细胞期的滋养体(rings/trophs);还有瞄准配子体期望阻止传播的疫苗.
我认同freecell推荐的文章中,作者认为当前的疫苗基本都是做出来的,而不是设计出来的.
关于HIV疫苗, Fauci 08年下半年Stupid在NEJM上发表了了一片评论文章,承认当前HIV疫苗研究的困境,认为应该寻找新的途径和思路.推荐给大家浏览.

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发表于 2014-8-6 18:11 资料个人空间短消息加为好友

小中大

人类迄今使用的大多数疫苗为灭活或减毒病毒疫苗，但是目前还没有人完全理解一种有效疫苗的免疫学机制。

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Re:【讨论】免疫学发展史上产生的诺贝尔生理学与医学奖

出于安全性的考虑，主流领域几乎完全回避灭活或减毒HIV病毒疫苗的研究，因此，HIV疫苗研究迄今为止还面临着与HIV被发现时同样的挑战，其根本原因在于我们对免疫现象的理解仍然存在相当的局限性。
2008年10月3-5日在德国纽伦堡举办的2nd World Conference on Magic Bullets (Ehrlich II) 上有很多Presentation涉及疫苗的研究。
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发表于 2014-8-6 18:12 资料个人空间短消息加为好友

小中大

相关疾病：
疟疾寄生虫病
寄生虫的疫苗开发似乎比较难哦.
为什么? 虫体太大, 特异性抗体和T细胞能不能搞定啊?
个人认为, 疾病的控制策略应该很多种,或者说,疾病的控制应该是采取综合措施和因病而异.
对付那些传播性能很高,也就是说,通过空气尘埃,飞鸟,人之间近距离接触,污染的用具和食品等进行的,病毒病,疫苗是很成功的. 一些细菌病也是如此.
但是,对于像疟疾,血吸虫等寄生虫病,我认为,环境治理措施应该有效得多.包扩其中间宿主的控制,和药物治疗. 这也是为什么疟疾和血吸虫在我国得以控制的原因.当然,高效疫苗开发也应该是我们努力的方向.
maoadai 和gofrom2004战友说的很好, 让我们学到了许多东西.
目前疫苗开发研究热潮中,似乎把寄生虫给忘记了.这是非常不明智的,国家应该投入一定的比例来做. 防患于未然,何况,我国好象血吸虫在洞庭湖又重现了哦!
期待更多虫子疫苗方面的研究讨论.
学习中............

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发表于 2014-8-6 18:12 资料个人空间短消息加为好友

小中大

一篇评述：
Vaccines: Predicting immunity
Nature Reviews Immunology 9, 4 (January 2009) | doi:10.1038/nri2478
Two recent studies have used systems biology approaches to identify early gene 'signatures' induced in humans vaccinated with the attenuated yellow fever vaccine YF17D that correlate with, and in some cases predict, the subsequent adaptive immune response.
YF17D, which is one of the most effective vaccines generated so far, is thought to mediate long-lasting protection by inducing neutralizing antibodies, although cytotoxic T-cell responses might also be important. However, a detailed understanding of the early immune response that is induced by YF17D which leads to protection from yellow fever is lacking. The two studies described here used high-throughput technologies, combined with computational modelling in one study, to identify early gene signatures that were induced by YF17D vaccination.
Both studies analysed total peripheral-blood mononuclear cells from different cohorts of human volunteers (who had not been previously vaccinated with YF17D) at various time points following vaccination. Early (3 and 7 days post-vaccination) effects on gene expression were determined by transcriptional profiling and analysed using several bioinformatics approaches. Many of the genes that were regulated early are involved in the innate immune response, including genes that are associated with Toll-like receptor signalling, the interferon pathway, the antiviral response, the complement pathway and the inflammasome. By visualizing these gene networks, a group of transcription factors, including interferon-regulatory factor 7, signal transducer and activator of transcription 1 and ETS2, could be identified as key regulators of the early immune response to the YF17D vaccine. In addition, Gaucher et al. showed that YF17D triggers the proliferation and expansion of several immune-cell types (such as macrophages, dendritic cells, natural killer cells and lymphocytes). Together, these data highlight the broad range of innate immune effector mechanisms that are induced by YF17D vaccination.
Although this vaccine is highly effective, the magnitude of the CD8+ T-cell responses and antibody titres varied greatly between individuals, but Gaucher et al. found that the T-cell response was of broad epitope specificity and persistent. Querec et al. sought to determine gene signatures that would correlate with and predict the variations in the adaptive immune response; however, none of the genes that had been identified by their transcriptional profiling analyses significantly correlated with the magnitude of the adaptive immune response. Using additional bioinformatics approaches, the authors identified a gene signature that did correlate with the magnitude of antigen-specific CD8+ T-cell responses and antibody titres.
To evaluate the actual predictive capacity of this signature, they determined whether the gene signature could predict the magnitude of the CD8+ T-cell or B-cell response in individuals from a second YF17D vaccine trial. They found that several signatures for CD8+ T-cell responses from the first trial were predictive with up to 90% accuracy in the second trial and vice versa. EIF2AK4, which has an important role in the integrated stress response, was repeatedly represented in most of the predictive signatures that were generated, which suggests that this gene could have a central role in mediating the YF17D-induced CD8+ T-cell response. Consistent with this, YF17D triggered the integrated stress response in human cells in vitro. In addition, the authors identified a distinct early gene signature that included TNFRSF17 (a receptor for B-cell-activating factor) that predicted the neutralizing antibody titres as late as 90 days following vaccination.
So, these studies provide a detailed description of the transcriptional profile that is induced early after YF17D vaccination and highlight the complexity of the response that is required for the induction of long-lasting immune protection. In addition, the magnitude of a protective immune response to YF17D can be predicted early after vaccination using systems biology approaches. These approaches could help to identify early correlates of protection for multiple vaccine candidates and new mechanisms by which vaccines generate protective immune responses.

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发表于 2014-8-6 18:16 资料个人空间短消息加为好友

小中大

Nature Reviews Immunology 9, 28-38 (January 2009) | doi:10.1038/nri2451
Harnessing invariant NKT cells in vaccination strategies
To optimize vaccination strategies, it is important to use protocols that can 'jump-start' immune responses by harnessing cells of the innate immune system to assist the expansion of antigen-specific B and T cells. In this Review, we discuss the evidence indicating that invariant natural killer T (iNKT) cells can positively modulate dendritic cells and B cells, and that their pharmacological activation in the presence of antigenic proteins can enhance antigen-specific B- and T-cell responses. In addition, we describe structural and kinetic analyses that assist in the design of optimal iNKT-cell agonists that could be used in the clinical setting as vaccine adjuvants.

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发表于 2014-8-6 18:16 资料个人空间短消息加为好友

小中大

好贴，寄生虫和真菌疫苗需要多多研究，尤其是一些肉用动物必须用高毒的“三致”药物才能有效治疗的这些微生物疾病。

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发表于 2014-8-6 18:17 资料个人空间短消息加为好友

小中大

从生产线上看疫苗开发：
我是兽药生产企业的研发着，每次看到关于基因疫苗，感觉无法真正在我们的车间里生产。
主要问题就是成本高。
目前有一种DNA免疫增强剂，是美国动物保健品公司研发主管推荐我们在佐剂开发中添加的成分，20kb左右，但如果大规模合成这个2mg左右需要2000左右人名币，折合到每头份疫苗中约1头猪7块钱，现在市场上疫苗几乎还没有7块1头份的呢。所以说根本无法实现。
另外个人意见：DNA 序列特异性高，这比病原的血清型还要复杂，所以说对疾病的预防特异性达不到要求。

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发表于 2014-8-6 18:18 资料个人空间短消息加为好友

小中大

亮助先生是善于思考的同志：病毒和机体的关系本身就是哲学问题，处处充满了辩证的思想的......
我的观点：
1：DNA疫苗和各种亚单位疫苗....都是骗人的！新型佐剂的研究...！哈哈！就像寻找“长生不老药”一样可笑！
2. 我们现有的病毒学与免疫学理论，也就是对病毒和机体的关系本身了解了那么一点点......，还等着免疫学的重大新理论！！！！？盲人摸象！耳朵是啥样你还没摸全呢！就喊着要发现“大象的新品种”！！！
3. 各种新型疫苗（多肽疫苗，载体疫苗，DNA疫苗等）至少在未来50年，甚至更长时间，将长期停留在理论研究或者实验室水平上！！！。
4. “绝对安全而又高效的疫苗”我认为在理论上是不存在的！要高效就不会安全！这是生命的基本法则！！
5. 疫苗的研发方向应是“全病原体活疫苗”！把我们的分子与基因工程技术用在全病原体活疫苗吧！专家们教授们！给我们的儿子剩些钱吧！去！去海选“全病原体活疫苗”吧！至于它为什么高效，留给我们的儿子去研究吧！
言辞过激了！为长话短说！

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发表于 2014-8-6 18:18 资料个人空间短消息加为好友

小中大

Recent attempts for improved influenza vaccines.
Influenza virus’ high rate of mutation is a major obstacle in designing an effective, universal influenza vaccine. Every year, new strains of virus emerge and the seasonal vaccine must be freshly prepared using circulating strains. The WHO’s Global Influenza Surveillance Network monitor and inform governing authorities of the emerging influenza viruses so new vaccines can be produced before the influenza season starts. In addition to the need to prepare seasonal influenza vaccines annually, the imminent threat of a pandemic influenza, especially with the H5N1 avian strain, has facilitated research into universal means to control this mutative virus, using antibodies that can neutralize or a vaccine that can protect against different influenza strains.
Michael Deem and colleagues at Rice University (TX, USA) have used a novel computational method to predict the efficacy of influenza vaccines. Mutations in the virus genes were given numerical scores and the scientists could then estimate whether a vaccine may be effective against divergent viral strains.
“For seasonal influenza, we validated our model against observational data compiled by the World Health Organization’s Global Influenza Surveillance Network,” said Deem. “We also ran tests against bird flu data. We found that multiple-component bird flu vaccines appeared to be helpful in controlling the simultaneous multiple introduction of bird flu strains.”
“Oftentimes, bird flu seems to emerge with multiple strains, and something similar can happen with newly released or evolved strains of seasonal flu as well,” explained Deem. The scientists hope that their new computational approach can help predict the necessity and efficacy of a multiple-component vaccine should multiple influenza strains emerge at the same time.
Screening for antibodies that are able to neutralize divergent strains of influenza virus is another approach in tackling the virus’ high mutation rate. Such antibodies will be useful in passive immunization, as well as in designing new vaccines that can elicit antibodies with similar neutralizing ability. In a recent study published in Science online ahead of print, Ekiert et al. from the Scripps Research Institute (CA, USA) identified CR6261, a human antibody that could neutralize both H1N1 (responsible for the 1918 influenza pandemic) and H5N1 (fear to cause the next pandemic) viruses. The authors wrote: ‘CR6261 recognizes a highly conserved helical region in the membrane-proximal stem of HA1/HA2 [the viral hemagglutinin]. The antibody neutralizes the virus by blocking conformational rearrangements associated with membrane fusion. The CR6261 epitope identified here should accelerate the design and implementation of improved vaccines that can elicit CR6261-like antibodies, as well as antibody-based therapies for the treatment of influenza.’
In another study published in the March issue of Nature Structural and Molecular Biology, Sui et al. from Harvard Medical School (MA, USA) screened an antibody phage-display library and identified ten antibodies that could neutralize all group 1 influenza viruses, including H1N1 and H5N1. The researchers were also able to demonstrate that each of these antibodies neutralized the virus ‘by inserting its heavy chain into a conserved pocket in the stem region [of the viral hemagglutinin], thus preventing membrane fusion.’ They appeared to work by the same mechanism, which was similar to that described by Ekiert et al. In summary, conserved regions in the stem section of influenza virus hemagglutinin may serve as a good antigen candidate for future vaccine design, and antibodies that bind these regions may be able to neutralize divergent viral strains, thus they may be used as therapeutics in an emergency where vaccines cannot be used.
Sources: Ekiert DC, Bhabha G, Elsliger MA et al. Antibody recognition of a highly conserved influenza virus epitope. Science 324(5924), 246–251 (2009); Sui J, Hwang WC, Perez S et al. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat. Struct. Mol. Biol. 16(3), 265–273 (2009); Rice University, TX,

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发表于 2014-8-6 18:18 资料个人空间短消息加为好友

小中大

Application of pharmacogenomics to vaccines
Pharmacogenomics
May 2009, Vol. 10, No. 5, Pages 837-852
内容提要
▪ The application of the science of pharmacogenomics and pharmacogenetics to vaccines has led to a new science of vaccinomics.
▪ Twin studies offer an ideal system for understanding the genetic contribution to variation in the immune response to vaccines, and for identification of SNPs.
▪ The activation and/or suppression of specific immune response pathway genes associated with response to vaccines provide a basis for the theory of the immune response gene network.
▪ HLA gene polymorphisms are important contributors to human immune responses to prophylactic vaccines.
▪ Genetic variants in immune response genes have important associations with immune responses to measles–mumps–rubella, influenza, HIV, hepatitis B vaccine and smallpox vaccines.
▪ A number of polymorphisms in SLAM, CD46, cytokine, cytokine receptor and TLR genes have been discovered that are associated with variations in both humoral and cellular immune responses to the measles–mumps–rubella vaccine.
▪ It may be feasible to design new personalized vaccines based on complex interactions of host genetic, environmental and other factors that control immune responses to vaccines.
▪ An emerging field associated with vaccinomics is the area of genetically determined vaccine-associated adverse events and atypical immune responses – collectively called adversomics.
▪ At the current time, cost is a major obstacle to vaccinomics and personalized vaccinology approach.
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What is vaccinomics?
The development of the field of pharmacogenomics (associations of whole genomes and drug or vaccine response) and pharmacogenetics (associations of individual genes and drug or vaccine response) has provided both the science base and clinical outcomes that together increasingly allow for the practice of individualized drug therapy. The application of this same science when applied to vaccines we have labeled ‘vaccinomics’ [1]. Thus, just as we now recognize that a variety of drugs, such as antidepressant and antihypertensive medications, may require different dosing based on individual genetic differences and result in different side-effect profiles, resulting in variations in therapeutic effect based on genetically-based individual variations; we have now begun to recognize similar attributes in terms of vaccine indications, dosing, side effects and outcomes. As one clinician noted, ‘…vaccines licensed in the USA are safe and effective. However, not every vaccine is equally safe or equally effective in every person’ [2].
As discussed later in this paper, we have done extensive work identifying associations between immune response gene polymorphisms and variations in immune responses to several prophylactic live viral vaccines [3–13]. Such phenotype/genotype data, in combination with high throughput genetic sequencing and bioinformatics, we believe will accelerate the field of vaccinomics and personalized vaccinology. In turn, the growth of this area of inquiry will increasingly allow us to understand and predict immune responses to vaccines, adverse events to vaccines and accelerate new vaccine development. Such research is a logical extension of what physicians now do – tailor any intervention to the unique characteristics of the patient before them. For example, patients with renal failure or who are immunocompromised may get a hepatitis B antigen dose two- to four-times the usual dose in order to improve the chances of seroconversion and protection. Similarly, an HLA-extended haplotype that is associated with nonresponse to this vaccine has been defined [14]. Multiple repeat dosing may seroconvert such identified individuals [15]. Thus, such findings result in changes in clinical care, such as requiring higher doses, alternative vaccines, and accelerated or enhanced schedules. Vaccinomics will also chart new courses for novel vaccine development. It will drive novel scientific approaches and solutions to vaccine nonresponse, such as new vaccine adjuvants and peptide cocktail vaccines based on HLA supertype and other approaches.
How does vaccinomics inform vaccine development & vaccine science?
It is clear that the ability to respond to the threat of infectious disease depends on the ability of the host to mount an effective defense against an invading pathogen. However, for this to occur, a variety of biologic systems must be activated by the host, eventually resulting in the activation and secretion of cytokines, antibodies, chemokines and immune effector cells. In turn, for these events to take place, a variety of genes must be activated or suppressed and their products transcribed and their proteins translated, modified, expressed and secreted. In this regard, we have previously discussed the theory of the ‘immune response gene network’ whereby it is clear that the interactive and iterative activation and suppression of specific pathway genes must occur in a choreographed fashion in order for a coherent immune response to result after recognition of a pathogen [11]. Genes involved in virus binding and cell entry, antigen recognition, processing and presentation, immune effector cell function and immunoregulation are all necessary for a coordinated attack against an invading pathogen. Our work with the measles–mumps–rubella (MMR) vaccine, for example, has illustrated significant associations between class I and II HLA, cytokine, cytokine receptor, signaling lymphocyte activation molecule (SLAM) and CD46, and other immune response gene polymorphisms, humoral immune responses (IgG enzyme-linked immunosorbent assay [ELISA] and neutralizing antibody levels) and markers of cell-mediated immune responses (lymphoproliferative assays, cytokine secretion, enzyme-linked immunosorbent spot [ELISPOT] assays, and so on) [3,5,7–9,16–19]. In addition, we have advanced such work by expanding the scientific NIH data-sharing database to include microarray data, and more recently, transcriptomics data at increasingly remarkable levels of sensitivity [20].

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