相关疾病：
流行性感冒
龙博士提出这个TOPIC， 不管是在国内还是在国外，都是疫苗领域中的科研工作者最为关心和最想解决的事情。但往往令人失望的就是，没有任何一种疫苗是UNIVERSAL的，或没有人能保证对任何一种传染病能100%PROTECTION。包括对于流感病毒来说，这段时间有很多关于M2 UNIVERSAL VACCINE AGAINST INFLUENZA A VIRUS的文章，对我们人的应用前景，我看看可能不会比全病毒灭活疫苗能好到哪里去，对我们兽医来说，我想可能没有人会用这样的UNIVERSAL VACCINE。
就我的认识来说，免疫学的经典理论可能还要长期指导传统疫苗或现在新型疫苗的设计和发展。譬如，多少年之前，对于HIV 的防制，一窝蜂的认为体液免疫最好，美国的多少大牛们因为支持了这个观点，而获得的很多GRANT，但事情是瞬息万变的，现在在美国，好像细胞免疫站了上风了，先前那些认为能够诱导很好的NEUTRALIZED ANTIBODY， 就能预防HIV/AIDS的人现在也没有底气反驳了。但是真的抗原能诱导T 或B 细胞产生免疫反应，就一定能很好地预防HIV？可能谁也不敢这么说。防控某一种疾病，疫苗应该是最有效的手段之一，但也是受到很多因素的影响，就像上面的一些朋友说的，免疫原性，免疫途径和方式，抗原递呈，佐剂等等。
怎么办呢？我们都希望利用最先在的技术手段，集所有优点于一种疫苗上，行吗？我看也不可靠，什么东西都有个此消彼长的功能，就行药物上的配伍禁忌。就我知道的而言，一个PI在流感的疫苗上试了所以市面上很多的佐剂，像什么TB, MF95, CpG, Flegalin,等等，左后也搞不清楚那个更好，反而把自己弄糊涂了，有的刺激体液免疫，有的刺激细胞免疫。呵呵。
说了这么多，我的观点是，我们还是要立足免疫学理论，做好疫苗诱导免疫反应的具体机理。然后有针对性的设计疫苗。我现在挺感兴趣的包括：1. 现在一些PIs 做的关于T and B memory机理方面的东东。这些对疫苗的免疫原性，途径以及持续期都会有指导性的作用。
2，抗原递呈。上面的朋友也提到的DC在抗原递呈过程中的作用，direct presentation and cross presentation, 那个发挥主要作用，就我看得文章，我还不知道，但可能也有科学家已经解决了。3. mucosal immune or innate immune that are old topics I do not want to talk here. 4. Treg, 有点热门，但不在我现在的研究范围内，知道甚少。
这些纯粹纸上谈兵，欢迎畅所欲言。 我也很有兴趣看到更多的关于疫苗工艺化的帖子，那也是疫苗应用的重要一个环节。作者: ALALA 时间: 2014-8-6 17:45
共享1篇综述：
European Journal of Pharmaceutical Sciences
Opportunities and challenges in vaccine delivery.作者: free 时间: 2014-8-6 18:03
Bull Acad Natl Med. 2008 Mar;192(3):511-8; discussion 518-9
New vaccination strategies
Pasteur put vaccination on an empiric and experimental basis during the 1880s, and vaccine development proceeded slowly until the second World War. During this period live vaccines against bacterial and viral diseases were developed by attenuation through passage in animals and killed microbes were inactivated without destroying their immunogenicity. Moreover, knowledge of bacterial toxins and polysaccharides permitted the development of new vaccines for several epidemic diseases. At the beginning of the third century of vaccination, classical methods are still providing new vaccines, but molecular biology and genetic engineering have begun to influence vaccine development. In addition, for the first time basic immunology is contributing to the domain of vaccinology. Thus, the current trends in vaccine development are as follows: reassortment of segmented genomes, attenuated strains recombined with genes from pathogens, vectors carrying foreign genes, replication-defective particles, DNA plasmids, and reverse vaccinology, among others. Also, new methods of vaccine delivery besides injection will be used and new adjuvants will be added to vaccines in order to stimulate specific responses. The future of vaccination is promising.作者: free 时间: 2014-8-6 18:03
推荐：Next Generation Vaccines 福布斯一年前的文章07年12月。
cuturl('http://www.sanaria.com/pdf/Forbes%20Wolfe%20Emer%20Tech%2012.07.pdf') （在其PDF的第3页Next Generation Vaccines，共2页的内容。）
该文讨论了 抗原的选择，佐剂的研制和delivery system 这疫苗研究领域的 三驾马车，都是从实战角度讨论的哦，都有具体的在研的商业例子。然后终于介绍了商业疫苗领域的那几颗立在大大的蛋糕之上极为鲜艳的“草莓”：Wyeth's Prevnar（$2 billion
in annual sales） and Merck's Gardasil（HPV疫苗。$235 million in sales in 2006 and is
projected to reach $1.6 billion by 2009.）不过，接下来引用的一个数据正好足够说明了对未来的不可预测性。它引用了Lehman Brothers的数据；这家盛名的金融公司竟然在今年倒闭了！仅仅一年就成为历史了！它也讨论了HIV疫苗临床试验的失败，这对于HIV疫苗研究实在是个很大的打击呀。不过，它还是对其它疫苗保持了乐观。最后列举了几个有可能近期有突破的疾病（其实包括太多了）。
最突入我眼球的其实是那么多的dollar，又是million又是billion。哈哈。 这种商业/技术分析，也可以做到这么专业，实在让我们看到差距呀。作者: TNT 时间: 2014-8-6 18:06
的确, 抗原的选择,佐剂的研制和delivery system 是疫苗研究领域的三驾马车.
其中, 抗原应该是核心部分.
抗原的选择,构建和修饰等等.
这里一篇文章, 提供一个对抗原进行修饰的思路.
"Deceptive imprinting and immune refocusing in vaccine design "
地址:
cuturl('http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TD4-4TN5GDC-4&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=259921bd152dc4a1659c9509b4ffb1b8')
其实,这个理论已经提出10多年了,但是,他们似乎并没有取得重大的突破性进展.
个人认为理论很好,问题关键是没有联合其他技术理论进行综合研究.
"去掉容易突变的而且是无效的抗原表位, 突出保守的,具有能诱导中和效价的表位."
作者1999年的文章: Deceptive Imprinting: Insights into Mechanisms of
Immune Evasion and Vaccine Development.
(文章大于1MBb, 还请教斑竹如何上传? 感兴趣的战友可以GOOGLE查题目看摘要,或P我要全文.)作者: orangecake 时间: 2014-8-6 18:07
相关疾病：
感染
阻止性条件反射=免疫?
从那只喜欢与人交往的加拿大白鲸联想到。
The Scientist网络杂志。
cuturl('http://www.the-scientist.com/news/display/55262/')
Saving Luna
What can science learn from one lonely killer whale?
让人类对它进行一些故意的轻微攻击，疼痛，但不致伤，更不致命。
这样就可以提醒他：人类会造成疼痛，离得远一点才好。于是拯救了他。否则这类鲸又会被拖船螺旋桨弄伤弄
死。
人体免疫，如天花接种，也是先拿小的感染/伤害刺激人体。让它知道，这些微生物虽然"看"起来挺可爱，但却
是有害的，
人体和白鲸一样，犯的致命错误是：把掠夺者看作可爱的，可以一起玩的同伴。
人，不接触真实的老鼠、狮子、老虎的话，会觉得他们挺可爱。 作者: dragonkilly 时间: 2014-8-6 18:08
疫苗以后的目标不仅仅是预防疾病，治疗疾病同样有前途。
治疗性疫苗的作用对象则为曾经感染的病原体,天然结构的病原体蛋白一般难于诱导机体产生特异性免疫应答。因此,治疗性疫苗必须经过分子设计,重新构建,以获得与原天然病原体蛋白结构类似,但又不同的新的免疫分子。治疗性疫苗旨在打破机体的免疫耐受,提高机体特异性免疫应答。
怎样打破免疫耐受是治疗性疫苗研究的关键。
另外，佐剂的使用和开发确实也有意义，比如粘膜免疫佐剂的开发，说不定以后可以有“疫苗吧”或者“疫苗霜”。
植物疫苗,如：土豆疫苗，西红柿疫苗。
哈哈，疫苗“钱”景广阔，同志们仍需努力！作者: toy 时间: 2014-8-6 18:08
Experts: AIDS Vaccine Research Has "Lost Its Way"
BOSTON--Two prominent researchers have bluntly assessed the depressing state of AIDS vaccine research and have urged the U.S. National Institutes of Health (NIH) to correct its course.
In back-to-back plenary talks at the 15th Conference on Retroviruses and Opportunistic Infections today, Ronald Desrosiers, director of the New England Primate Research Center in nearby Southborough, said he thought that NIH--the world's largest funder of AIDS vaccine research--had "lost its way," spending too much money on developing and testing products and not enough on basic research. Virologist Neal Nathanson, a professor emeritus at the University of Pennsylvania who formerly headed NIH's Office of AIDS Research, echoed Desrosiers's plea that more money go toward risky, innovative studies.
The trigger for the unusually harsh public critiques of the field came last fall, when an AIDS vaccine that many considered the best prospect in development bombed in large clinical trials (Science, 16 November 2007, p. 1048). Recapping that failure, Desrosiers, who tests AIDS vaccines in monkeys, went so far as to contend that a useful vaccine is not even on the horizon. "None of the products in the pipeline stand any chance of being effective," asserted Desrosiers, because the field is hampered by many unknowns, such as an understanding of which immune responses a vaccine must elicit. "We need to do a much better job of bringing to clinical testing only products that show significant promise."
Clinical studies receive about one-third of the nearly $600 million that NIH spends on AIDS vaccine research a year, most of it coming from the National Institute of Allergy and Infectious Diseases (NIAID). In January, Desrosiers and 13 other researchers privately wrote NIAID Director Anthony Fauci about their concerns that the field was adrift. "The letter was a good outside tweak about something that I was already thinking," Fauci told Science at the meeting here. Fauci said NIAID plans to hold a daylong AIDS vaccine "summit" on 25 March to explore how to move forward. It will be open to the public and webcast. "The real issue is the balance that we want between discovery research and development," said Fauci. "We need to take a time out."作者: memory 时间: 2014-8-6 18:10
就疟疾疫苗的研究来谈谈我自己的看法。
现在的疟疾疫苗主要来说有两种，一种就是减毒子孢子，另外就是筛选的抗原合成的人工疫苗。减毒子孢子无疑是最为有效的疫苗，但是由于传播媒介蚊的影响，使其不可能大量的生产。另外就是人工合成疫苗，现在做的最远的就是RTS-S，是以子孢子CSP为主要抗原的一个亚单位疫苗，但是现在临床试验证实一方面人群的接种效率不高，只有40%左右，另一方面其抗体的维持时间过短。
所以在我看来，疫苗的研究，特别是对于胞内寄生的病原体来说还有很远的路要走。第一，合理的有效的抗原的筛选，筛选的抗原不仅仅是在某个时期高度表达的，最关键的我觉得应该是对病原体性状改变及其重要，并且在遗传上相对稳定的抗原。比如疟原虫的CSP，各个虫种，甚至株之间都有很大的遗传多样性，不可能说每个虫种，种株都去设计一个疫苗吧。第二，病原体免疫逃避的机制仍待深入的探讨。病原体从其诞生到现在，和人的斗争经过了N代，所以它也已经能够很好的适应人体的环境，那么找到病原体逃避人体免疫的方式，甚至其重要的调控的基因……it will be an striking discovery。第三，如何维持有效疫苗在人体的滴度，不需要更多次的频繁的接种。
所以说，机制的研究在目前看来，还是许多病原体疫苗研究方向最为迫切的问题，同时，相关的免疫知识的完善和进步也是尤为重要的。作者: xueyouzhang 时间: 2014-8-6 18:11
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.作者: xue258 时间: 2014-8-6 18:11
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.作者: ALALA 时间: 2014-8-6 18:16
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.作者: hyuu 时间: 2014-8-6 18:16
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,作者: ALALA 时间: 2014-8-6 18:18
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].作者: ALALA 时间: 2014-8-6 18:19
The next evolution in understanding such data will be in analyzing and better understanding such issues as gene family pathways, epigenetic modifications and complementation. For example, we have developed protocols whereby ex vivo infection of human peripheral blood mononuclear cell (PBMC) cultures and the application of mass spectrometry tools have allowed us to identify naturally processed and presented pathogen-derived peptides – the very entity responsible for pathogen-induced adaptive immune responses [21]. Coupled with a growing body of data regarding pathogen-derived peptide promiscuity and HLA supertypes, such data will lead to identification of peptides capable of stimulating humoral and recall immunity [21–23]. A repertoire of such peptides (peptide cocktail) may permit the design and development of new vaccines for particular subpopulations [24]. For example, certain polymorphisms in the SLAM (CDw150) receptor for live measles vaccine virus are associated with poor humoral immune responses [7]. Since both vaccine and wild-type measles virus strains infect host cells via the interaction of the measles virus hemagglutinin protein with the V-domain of the SLAM receptor, SNPs in the SLAM gene are significantly associated with variations in immune responses to measles vaccine. Microarray experiments demonstrate gene-expression patterns (13 upregulated and 206 downregulated genes) in PBMCs from children with acute measles and children in the convalescent phase, which were consistent with the prolonged alteration of lymphocyte responses to measles [25]. It may well be possible to design new vaccines for use in individuals who suffer from variant cell-based receptors for viral recognition and do not respond well to current vaccines. Investigators may develop new vaccine models that do not depend upon such receptors or develop new vaccines that effectively allow vaccine virus to bind to a range of receptor polymorphic areas [26,27].
The goal of pharmacogenomics and vaccinomics is to identify genetic variants that predict adverse responses to vaccines, predict aberrant immune responses, contribute to personalized therapy and that predict susceptibility to diseases and response to vaccines [28]. Vaccinomics may also be useful in the development and use of existing and novel vaccine adjuvants and stimulants. For example, specific polymorphisms of the TLR3 gene are associated with significantly diminished humoral and cell-mediated immune responses to the measles vaccine [8]. Understanding the mechanism by which such polymorphisms diminish innate and other immune responses may offer a critical insight into designing work around the limitations imposed by such polymorphisms – either by developing new adjuvants that utilize other receptors, or by the addition of stimulant molecules that can potentiate or augment the immune response.
Similarly, complement components are key factors of the innate and adaptive immune response against pathogens. Without a fully functioning complement system normal immune response, lymph node organization and B-cell maturation, differentiation, responsiveness and tolerance is adversely affected [29]. Products from the cleavage of complement or component proteins can bind to cell-surface receptors to influence inflammation [30], T-cell immunity [31] and B-cell response [32]. These receptors are known as regulators of complement activation (RCA) and are a family of common receptors present on most cells [33]. It has been demonstrated that any deficiencies in C4, C2 or C3 proteins can lead to a weakened antibody response to bacterial infections [34]. For example, targets for complement components C4b and C3b on both Neisseria meningitidis and Neisseria gonorrhoeae have been described [35]. Most genes of the complement system are polymorphic, with the C4 molecule having over 35 identified variants [36]. While it has been demonstrated that complement genes play a critical role in the immune response to influenza [37,38], rubella [39] and other viral infections, there have been no studies to date investigating how complement gene polymorphisms may affect immune response to viral infections and/or viral vaccines.
Another area of importance is genetically determined vaccine-associated adverse events, which we have called ‘adversomics’. Scarce data are available regarding the immunogenetics of adverse vaccine responses. Black et al. recognized differing and more severe adverse events to receipt of the measles vaccine in Amazon Basin Indians compared with other groups – suggesting a possible genetic contribution [40]. More recently, Vestergaard et al. demonstrated an association between receipt of the MMR vaccine and subsequent febrile reactions and febrile seizures [41], providing a logical genetic basis for increased susceptibility to adverse events to live viral vaccines. Very recently, debate has arisen over the hypothesis that live viral vaccines could in some fashion exacerbate pre-existing genetically-coded problems such as mitochondrial or metabolic defects, for example, inborn errors of amino acid and organic acid metabolism, lipid metabolism, carbohydrate metabolism and of purine and pyrimidine metabolism [2,42]. Mitochondrial disorders in particular are estimated to occur at an incidence of 1 in 4000–5000 births [43]. If knowledge of such disorders were to be identified as important in predicting vaccine-induced immune responses or adverse events, screening for such genetic defects or polymorphisms might become more commonplace. In an analogous manner, the routine screening for such disorders among all live children born in the USA, represents personalized and predictive medicine, particularly to the extent that findings of concern would result in different specific vaccine recommendations.作者: ALALA 时间: 2014-8-6 18:19
Concerns over more severe vaccine-related side effects, such as neurotropic and viseotropic reactions to yellow fever vaccine, encephalitis-related reactions to smallpox vaccine, Guillain-Barré reactions temporally occurring with vaccination and others, warrant further investigation for the potential of identifying genetic predictors of risk [44–47]. With the availability of high-throughput sequencing and large patient databases that allow identification of serious adverse events related to immunization, such studies are increasingly feasible. Such studies would be further enhanced by reliable and stable funding mechanisms for broader population-based studies of adverse events for other commonly administered vaccines.
Specific examples of prophylactic vaccines
▪ Twin studies
Twin studies provide opportunities to explore genetic contribution to vaccine response and to identify specific gene polymorphisms. This benefit occurs for two reasons. First, a number of nongenetic factors may influence antibody levels (and cellular immune responses) following vaccination, including the presence of maternal antibodies [48], race [49], differences in vaccine storage, handling and administration [50,51], and concurrent illness at the time of vaccine administration [52–54]. However, twins who are raised together are highly likely to share these and other factors (such as exposure to viral diseases) that may influence measures of vaccine immunity. In addition, twins are also highly likely to be vaccinated at the same time with the same lot of vaccine, which has been stored and administered under the same conditions. They are also matched on age, exposure to older and younger siblings, and on overall family environment. Therefore, twin studies provide an ideal way to control for shared environmental factors. Second, monozygotic (MZ) twins share all of their genes, while dizygotic (DZ) twins share half their parents’ genes. Therefore, differences in immune responses within MZ twin pairs can be attributed to differential environmental exposures and chance variation, while differences in immune responses within DZ twins can be attributed to differential environmental exposures, chance variation and genetic differences.
Investigators have used twin studies to estimate the genetic and environmental contributions to a variety of different diseases, including determining the genetic contribution to variation in total immunoglobulin levels and specific IgG antibody levels to pneumococcal capsular polysaccharides [55,56]. Recent studies have observed a high heritability of 77% (95% CI: 63–85) for antibody response to hepatitis B vaccine in 207 Gambian twin pairs aged 5 months [57]. Heritabilities for antibody responses to oral polio, tetanus and diphtheria vaccines were 60% (95% CI: 43–73), 44% (95% CI: 16–70) and 49% (95% CI: 17–77), respectively [57]. In addition, significant heritability was also observed for IFN-γ and IL-13 cytokine immune responses to tetanus, pertussis and several Bacillus Calmette–Guérin (BCG) vaccine antigens, ranging between 39 and 65% [57]. Another study among 147 DZ and 43 MZ Gambian twin pairs showed that the IgG antibody response to Haemophilus influenzae type b (Hib) vaccine is highly heritable among Gambian infants. Heritability of antibody responses to Hib conjugate vaccine was estimated to be 51% (95% CI: 32–66), indicating a significant genetic contribution to the variation of antibody response to the polysaccharide antigen of Hib [58].
Since twin studies provide an ideal method for quantifying the magnitude of genetic contributions to the variability in vaccine-induced immunity, determining the proportion of variation attributable to specific genes in healthy individuals following live attenuated MMR vaccination was investigated. The Mayo Vaccine Research Group (MN, USA) conducted a twin study to determine the magnitude of genetic influence on variability in circulating antibody levels to measles, mumps and rubella viruses [59,60]. A total of 100 twin pairs (45 MZ and 55 DZ) residing in Minnesota were recruited and information regarding demographic characteristics, vaccine history and exposure to or occurrence of any vaccine-preventable diseases collected. Blood samples were collected from each child and viral-specific IgG antibody levels were quantified by ELISA. The genetic variance and heritability of the IgG levels were examined using analysis of variance techniques. It was found that the heritability was 88.5% for measles (95% one-sided CI: 52.4), 38.8% for mumps (95% one-sided CI: 1.6) and 45.7% for rubella (95% one-sided CI: 4.9). These data demonstrate that genetic influences play a substantial role in antibody levels following measles vaccination, and a somewhat lesser role in the antibody levels following mumps and rubella vaccination. Others have commented that ‘Knowledge that a trait of interest has high heritability can support a study that proposes to investigate the genetic determinants of that trait’ [61]. It is important to note that the unique genetic and environmental characteristics of different individuals and vaccines demand a clear understanding of the role of critical aspects of vaccine pharmacogenomics [11,62].
The pathways by which protective humoral and cellular immune responses develop to live viral vaccines is a multistep process: the vaccine virus (such as measles) must first be recognized by its cellular receptors (SLAM and CD46) and also activate toll-like receptors (TLRs) or other innate sensors, triggering innate immune responses. After antigen presentation by HLA molecules, cytokine and cytokine receptor gene activation occurs, along with signaling molecules, resulting in secretion of cytokines as intercellular messengers to stimulate Th1 and Th2 immune responses [63–65]. Individual variations within any of these relevant genes could effect gene transcription, regulation or expression, and thereby influence immune responses or the propensity to an adverse reaction to the vaccine antigen. Below we will give specific examples of genetic associations with immune responses to live viral vaccines.
▪ MMR vaccine
As discussed above, we have performed and reported a twins study of measles vaccine immunogenicity. This study demonstrated that antibody levels to measles vaccine have a very high heritability of 88.5% [59,60]. Informed by advances in basic immunology on the role of the HLA complex in immune recognition and response, a series of immunogenetic studies designed to answer questions on the role of HLA in vaccine immune responses was performed.
The HLA proteins play an essential role in generating an immune response against pathogens. Generally, the class I A, B and C alleles bind and present peptides to CD8+ T lymphocytes, while the class II DR, DQ and DP alleles bind and present peptides to CD4+ T cells. The peptide-binding clefts of the HLA molecules contain highly polymorphic clusters of amino acids that act to control or restrict the spectrum of peptides capable of being bound and presented by a given HLA molecule. A single HLA molecule is able to bind self- and pathogen-derived peptides that share common amino acid motifs [66,67]. Differences in HLA-binding affinities may result in decreased binding of specific pathogen-derived peptides and inefficient peptide presentation to T lymphocytes [68–70]. Inefficient peptide presentation may, in turn, result in decreased T-cell activation and cytolytic function, decreased cytokine production and decreased B-cell production of pathogen-specific antibodies.作者: ALALA 时间: 2014-8-6 18:19
We have reported a number of findings in relation to measles, mumps and rubella vaccine antigens and HLA genetics [9,17,71–73]. Recent reviews of these population-based clinical studies have revealed a number of findings of interest. Specific class I and class II HLA alleles are associated with variations in antibody levels after a single dose of measles vaccine [3–5]. In particular, class II DRB1*03, DQA1*0201 and the class I B8, B13 and B44 alleles are associated with lower levels of measles antibodies in healthy schoolchildren. In the case of HLA homozygosity it was also demonstrated that overall lack of variation in the HLA alleles is associated with decreased measles-specific antibody levels following a single dose of vaccine, with increasing risks of vaccine nonresponse with increasing homozygosity [16]. The role of HLA molecules in vaccine-induced immune responses after two doses of MMR vaccine was also examined [6,9,17]. Little verification was found that either homozygosity at specific HLA loci or overall homozygosity had any disadvantage in terms of measles-specific cytokine immune responses, such as IFN-γ, IL-2, IL-4, IL-10 and IL-12p40, following two doses of measles vaccine, suggesting that at some level genetic restriction could be overcome by higher or repeated doses of vaccine [73]. In addition, associations between HLA haplotypes and HLA supertypes and MMR vaccine-specific humoral and cellular immune responses following two doses of MMR vaccine were investigated [23,74]. The haplotypes with the strongest evidence for association with lower measles-induced antibodies were DRB1*07–DQB1*02–DPB1*02 and DRB1*07–DQB1*03–DPB1*04. Haplotype A*26–Cw*12-B*38 was significantly associated with higher antibody levels and higher lymphocyte proliferation and response to the mumps vaccine [74]. Among our study subjects, the supertypes B44 and B58 were strongly associated with lower measles vaccine-specific antibody levels. In contrast, the most common B7 supertype was associated with higher measles vaccine antibody response. For the mumps vaccine, it was found that the HLA-DQB1*0303 allele was associated with lower mumps-specific antibody titers and the B62 supertype was suggestive of an association with mumps-specific higher lymphoproliferation after the MMR vaccine [9,23]. Further, alleles of the DRB1, DQA1 and DQB1 loci were associated with significant variations in lymphoproliferative immune responses to mumps vaccine [9]. It was also demonstrated that HLA-A (*2402 and *6801) alleles were associated with lower vaccine-induced IFN-γ secretion levels in response to rubella virus antigens [19]. Associations were further observed between measles (IFN-γ and IL-4) and rubella (IFN-γ and IL-10) specific cytokine responses and class I and class II HLA gene polymorphisms [19,75–77]. Class I HLA-A (*0101, *3101), HLA-C (*0303, *0501), and class II HLA-DRB1 (*0301, *1501) and HLA-DQB1 (*0201, *0303 and *0602) alleles were significantly associated with variations in measles-virus-induced in vitro IFN-γ secretion [75,76]. These studies demonstrated that both humoral (antibody) and cellular (lymphoproliferation and secreted cytokines) immune responses to MMR vaccine are clearly influenced by polymorphisms of the HLA genes.
HLA gene polymorphisms may also be related to variations in cytokine production following measles immunization through variations in T-cell activation; however, variation in the cytokine genes themselves may also directly affect cytokine secretion after antigen stimulation [10]. It is also possible that other immune response genes or other currently unknown genes may also influence vaccine immunity more strongly than the HLA genes. In this regard, polymorphisms in cytokine and cytokine receptor genes may also contribute to variations in vaccine immune response [78]. SNPs that are associated with differences in cytokine secretion levels could also influence vaccine-induced immune responses [18]. For example, the presence of minor allele T for intronic SNP rs2201584 within the IL12RB2 gene and the presence of minor allele A of the rs373889 within the IL12RB1 gene were strongly associated with an allele dose-related decrease in antibody titer and lymphoproliferation, respectively, after two doses of mumps viral vaccine [9]. More recent preliminary data demonstrate that specific SNPs in the IL10 and IL12RB2 genes are associated with low antibody and low cell-mediated immune responses to the measles vaccine, while SNPs in the IL2 gene are associated with high antibody and cellular immune responses to measles [18]. The same IL2 promoter SNP (rs2069762) identified in our study was also found to be associated with the responder phenotype following hepatitis B virus (HBV) vaccination [79]. Significant associations were also found between IL4R gene polymorphisms and levels of measles-specific secreted IL-4 (major alleles for four SNPs were associated with lower levels of IL-4) [18], indicating that cytokine and cytokine receptor gene polymorphisms may be significant factors in the development of vaccine immunity.
We also examined gene polymorphisms in the two known genes that code for the measles virus receptors – SLAM and membrane cofactor protein – CD46. Both SLAM and CD46 are known to play a role in measles virus binding and entry into the host cell, as well as in cell tropism and pathogenesis. Our study demonstrates that increased representation of minor alleles for rs3796504 and rs164288 in the SLAM gene were associated with a significant allele dose-related decrease in measles-specific antibodies [7]. The SNP rs3796504 leads to an amino acid change of threonine to proline at position 333 of the SLAM gene, and may change the conformation of the SLAM receptor, making it unsuitable for binding to the measles virus hemagglutinin protein. Within the CD46 gene, the minor allele C for intronic SNP (rs11118580) was associated with an allele-dose related decrease in measles-specific antibodies [7]. Although the mechanism is unclear, intronic SNP rs11118580 may also play a critical role in the regulation of gene transcription. Thus, variations in measles vaccine-induced antibody levels may be influenced by polymorphisms in the genes for the SLAM and CD46 measles virus receptors.
Discovery of genetic variation (e.g., immunogenetic profiling) in a population is important for understanding its role in vaccine-induced immunity [26]. In this regard, polymorphisms of the TLR genes involved in innate immune responses have also been demonstrated to influence the susceptibility to infection and immune responses to pathogens. For example, Heer et al. have shown that TLR signaling is not required for anti-influenza effector T-cell responses, but through both direct and indirect ways it orchestrates anti-influenza B-cell responses [80]. It has been reported that laboratory adapted and vaccine strains of measles virus, including the Edmonston vaccine strain, induce TLR3 in human dendritic cells, which may be associated with protective immunity against measles via enhanced IFN-β secretion [81]. This suggests that measles virus-induced expression of TLR3 may be a sign of augmented IFN production that plays an important role in host defense to viral infection. Specific SNPs in the coding and regulatory regions of the TLR3 (and associated intracellular signaling molecule MyD88) were also associated with variations in antibody and cellular immune responses to measles vaccine, suggesting that TLR signaling may be required for antimeasles T- and B-cell immune responses [8,10]. However, more work in this area is required in order to understand how immune responses to vaccines can be impaired by SNPs within the genes encoding TLRs.作者: ALALA 时间: 2014-8-6 18:20
▪ Influenza vaccine
Influenza is a single-stranded RNA virus that causes substantial morbidity and mortality. Influenza vaccines prevent disease in 80% of healthy subjects [82] Therefore, it is important to investigate the effect of immune response gene polymorphisms on humoral (and cellular) immune responses following influenza immunization [83]. While a variety of genes and gene pathways are involved in whole influenza virus immunity, it is essential to understand gene polymophisms that may be involved with generating an immune response to the influenza hemagglutinin (H) and neuraminidase (N) transmembrane glycoproteins, as these proteins form the sole influenza virus-derived components of inactivated influenza vaccine. Serum antibody titers, measured by a hemagglutination inhibition assay, are believed to be a reliable correlate of immunity to influenza viruses [84]. Associations between HLA gene polymorphisms and influenza A virus H1- and H3-specific hemagglutination inhibition antibody titers in healthy subjects who received trivalent influenza vaccine, containing A/H1N1 New Caledonia/20/99, A/H3N2 California/7/2004 and B/Shanghai/361/2002 influenza virus antigens were examined. HLA-A*1101 (p = 0.0001) and A*6801 (p = 0.09) alleles (global p-value for HLA-A locus 0.007) were associated with higher median levels of influenza H1 vaccine-induced antibodies [12]. Gelder et al. demonstrated an increased frequency of HLA-DRB1*0701 and a decreased frequency of HLA-DQB1*0603–9/14 in individuals who were nonresponders to the influenza subunit vaccine [85]. Significant associations between both H1- and H3-specific antibody immune responses and polymorphisms of cytokine and cytokine receptor genes (such as IL1R1, IL2RA, IL6, IL10RA, IL12B and other genes) were also identified, suggesting that SNPs present in HLA, cytokine and cytokine receptor genes may influence humoral responseMoon following seasonal influenza vaccination [12]. Further examination of the role of immune response gene polymorphisms and variations in influenza vaccine-induced immunity is warranted, particularly given the public health impact of both seasonal and pandemic influenza.
▪ HIV vaccine
Variations within the host’s genome may contribute substantially to the individual immune response to vaccination and susceptibility to infectious diseases. For example, evidence demonstrates that class I HLA-B*35 and B*08 alleles are associated with faster HIV type 1 (HIV-1) disease progression, and homozygosity at class I loci confers a significant risk of accelerated infection [86,87]. A study of canarypox vector-based HIV (vCP1433) vaccine (ALVAC)-HIV-1 recombinant canarypox vaccines showed that the HLA-B*27 and B*57 (the two alleles best known for an association with slower disease progression) were associated with earlier and positive CD8+ cytotoxic T lymphocyte responses to Gag and Env viral proteins [88]. However, homozygosity at class I loci, although conferring an unfavorable prognosis following natural HIV-1 infection, showed no such disadvantage for ALVAC-HIV-1 vaccine response [88]. For class II, associations with the DRB1*1300–DQB1*0603 haplotype and transporter gene products (TAP2 Ala665) and progression of HIV-1 infection have been also reported [89]. There appears to be a strong association between polymorphisms in the CCR5 chemokine receptor gene, located on the short arm of chromosome 3 and HIV-1 infection [90]. Caucasian individuals homozygous for a deletion of CCR5 (CCR5-Δ32), which encodes the cell entry co-receptor for HIV, appear to be at lower risk of acquiring HIV/AIDS [91]. Likewise, genetic studies of HIV demonstrate that the presence of the most frequent TLR8 polymorphism, TLR8 A1G (rs3764880), confers a significantly protective effect against disease progression [92]. Recently, de la Torre et al. demonstrated the contribution of five polymorphisms in the vitamin D receptor (VDR) gene to HIV-1 susceptibility among Spanish HIV-infected patients [93]. Specifically, haplotypes for VDR (SNPs rs11568820, rs4516035, rs10735810, rs1544410 and rs17878969) polymorphisms revealed important associations with protection against HIV-1 infection (OR: 0.4; 95% CI: 0.22–0.72; p = 0.0025).
▪ HBV vaccine
Hepatitis B vaccination of twin pairs is a valuable model with which to study the importance of host-genetic factors for the immune response to HBV antigens. The vaccine licensed throughout much of the world consists of recombinant hepatitis B surface antigen (HBsAg) and alum and induces protective antibodies (>10 IU/ml) in 95% of vaccinees following three doses. Hohler et al. studied 96 DZ and 95 MZ twin pairs and demonstrated that genetic factors have a significant effect on the immune response to the HBsAg vaccination [94]. In this study more than 60% of the observed variability in anti-HBsAg immune responses was attributed to genetic factors. The heritability of the HBsAg vaccine response accounted for by the HLA-DRB1 locus (such as DRB1*01, DRB1*11 and DRB1*15) was estimated to be 0.25, leaving the remaining heritability of 0.36 to other gene loci, suggesting that approximately 40% of the genetic contribution to HBsAg response is affected by HLA genes and approximately 60% by non-HLA genes [94]. This study suggests that while genes encoded within the HLA complex are important for the immune response to HBsAg, more than half the heritability is determined outside of this complex, with strong evidence that other immune response genes (complement factor C4A, IL2, IL4 and IL12Black Eye are also important determinants of nonresponsiveness to HBV vaccination [95,79]. In addition, increased antibody levels and lymphoproliferative immune responses to HBV vaccination were found to be influenced by polymorphisms within the IL1β gene [96].
Several HLA association studies have demonstrated that the DRB1*03 and/or DRB1*07 alleles confer a higher possibility of HBV vaccine failure [97,98]. Further, analyses of genotyping data from 164 North American adolescents vaccinated with recombinant HBV vaccine demonstrated that the HLA-DRB1*07 allele (relative odds [RO]: 5.18; p < 0.0001) was associated with nonresponse to full-dose vaccination [79]. However, when HBsAg-specific T-cell responses following HBsAg vaccination were compared ex vivo in 24 MZ and three DZ twin pairs, it appeared that the DRB1 alleles associated with vaccine failure (such as DRB1*0301 and *0701), were able to competently present HBsAg-derived peptides [99]. This argues that HLA-DRB1 allelic associations with HBV-specific immune response are not caused by differences in peptide binding or by a change in the ELISPOT Th1 (IFN-γ)/Th2 (IL-10) profile. The authors suggested that the defect in nonresponse to the HBV vaccine may be on the side of the T-helper cells and not on the side of the antigen-presenting cells [99].作者: ALALA 时间: 2014-8-6 18:20
▪ Smallpox vaccine
Immunity to smallpox is an important issue for public health and vaccine development. In this regard, genetics play a critical role in the host immune response variation to smallpox vaccination within a population. The variability of humoral and cellular immune responses modulated by HLA and other genes is a significant factor in the development of a protective effect of smallpox vaccine (or live vaccinia virus). We tested whether associations exist between individual HLA alleles and vaccinia virus-specific humoral (neutralizing antibody) and cellular (IFN-γ-ELISPOT) responses in a group of healthy individuals (n = 1076; age: 18–40 years) who received one dose of smallpox vaccine (Dryvax™Wink. Significant associations were found between class II HLA-DQB1*0302 (p = 0.003) and DQB1*0604 (p = 0.03) alleles and higher vaccinia-induced neutralizing antibody levels (global p-value 0.01). A striking finding was an association of several class I HLA alleles with vaccinia-specific cellular responses. The global tests revealed associations between vaccinia-induced IFN-γ responses and HLA-B and -C loci (p < 0.001 and 0.03, respectively). Specifically, HLA-B*1501 (p = 0.006), B*3508 (p = 0.02), B*4901 (p = 0.04), B*5701 (p = 0.04), B*5802 (p = 0.05), C*0303 (p = 0.01) and C*0704 (p = 0.02) alleles were significantly associated with higher cellular responses to vaccinia virus. In contrast, HLA-B*3701 (p = 0.03), B*4001 (p = 0.03), B*5301 (p = 0.04), B*5601 (p = 0.03), C*0102 (p = 0.03), C*0702 (p = 0.04) and C*0801 (p = 0.01) alleles were significantly associated with lower IFN-γ responses to the smallpox vaccine [100]. These preliminary data suggest that both humoral and cellular immune responses to smallpox vaccine are, in part, genetically restricted by HLA genes.
Associations between smallpox vaccine-induced immunity and SNPs in cytokine and cytokine receptor genes were also studied. A variety of statistically significant associations between SNPs in the cytokine and cytokine receptor genes, in some cases associated with an allele–dose relationship, were found. For example, the minor variant for rs1035130 in the IL18R1 gene was associated with higher (p = 0.0002) vaccinia-specific antibody titers, while the heterozygous variant for rs2230052 in the IL12A gene was associated with lower levels of neutralizing antibodies (p = 0.03). The minor allele of rs2229113 in the IL10RA gene was found to be associated with a dose-related increase in IFN-γ responses (p = 0.03). Furthermore, two SNPs (rs1495963 and rs3024679) in the IL4R gene were associated with a dose-related decrease in IFN-γ production (p ≤ 0.05) [101]. These preliminary data suggest that SNPs in cytokine/cytokine receptor genes may influence immune response following smallpox vaccine. Other genes in the region may also contribute to the genetic control of this immune response. Our group is currently conducting extensive genome-wide association studies of immune responses to the smallpox vaccine.
Severe complications due to the smallpox (live vaccinia virus) vaccine have been reported [102]. The licensed vaccinia vaccine against smallpox (Dryvax) is associated with rare severe side effects, including encephalitis and myopericarditis [47,103]. Common adverse events, such as fever after vaccination, have been observed in 13–15% of newly vaccinated individuals [104,105]. Stanley et al. examined associations between the development of fever (≥37.7°C) and SNPs in 19 candidate genes among 346 individuals assessed for clinical responses to smallpox vaccine [105]. Fever following smallpox vaccination was found to be associated with specific haplotypes in the IL1 gene complex on chromosome 2 and with haplotypes within the IL18 gene on chromosome 11. A specific haplotype in the IL4 gene was significant for reduced risk for the development of fever after smallpox vaccination among vaccinia-naive subjects [105].
Recent papers have confirmed the association between receipt of the Dryvax vaccine and the development of myopericarditis [47,103,106]. It would be clinically important to determine if the individuals who developed myopericarditis after smallpox vaccination carry the IL1, IL18 or other haplotypes. It is conceivable that IL1, IL4 or IL18 gene polymorphisms may also be influencing the development of more common adverse events, such as fever and febrile seizures, after MMR immunization in children [41,107]. Further exploration of the role of specific gene polymorphisms in adverse reactions to vaccines is crucial to our understanding of immune responses to vaccines and to preventing serious adverse events. We are confident that similar immunogenetic work on other vaccines (such as anthrax, yellow fever, avian influenza and so on) will be pursued in the near future.
The above data illustrate the clinical utility in regards to vaccinomics information. If we understood that a polymorphism in the TLR ‘x’ gene led to poor or absent immune response, and we knew the prevalence of that polymorphism, perhaps we could design a specific adjuvant that could overcome the genetic defect coded for by that particular polymorphism and direct the immune response in a favorable manner. For example, CpG oligonucleotide, which stimulates TLR9, was used as an adjuvant with the HBV vaccine to activate innate immune responses to the standard alum formulation of HBV vaccine in healthy adults [108]. Vandenbroeck et al. state that ‘alterations in the expression levels of cytokines typically accompany aberrant immune activation … and demonstrate that cytokine gene association studies (of polymorphisms) are instrumental in identifying these disease states … such findings will ultimately lead to novel therapeutic strategies’ [109]. Large-scale population-based immunogenetic studies will further inform us regarding molecular mechanisms of protective vaccine immunity and provide important clues in the development of novel vaccines. The data discussed above from numerous human studies demonstrate the genetic basis for interindividual variation in immune responses to viral vaccines in genetically heterozygous populations.
What’s next? The developing field of personalized vaccinology
In many ways the era of personalized vaccines has already begun [110]. For example, the rationale behind and utilization of personalized vaccinology in cancer vaccines is increasingly clear and a benchmark in this regard [111,112]. In particular, in the field of cancer vaccines, much thought and progress has been demonstrated with the concept of personalized peptide vaccines [112].
Of particular interest to the personalized peptide vaccines concept is the peptide-based vaccine approach of identification of specific naturally processed pathogen-derived antigenic peptides. Targeting pathogenic T lymphocytes via vaccines consisting of synthetic peptides representing T- and B-cell epitopes is an interesting tactic since peptide-based approaches offer multiple advantages over whole-protein immunization strategies, including ease of manufacture, lower cost and the lack of a requirement for maintaining a cold chain [113–115]. Furthermore, identifying immunogenic peptides that would be restricted by numerous HLA alleles (promiscuous peptides) is one of the critical aspects to designing successful peptide-based vaccines that are useful among populations. 作者: ALALA 时间: 2014-8-6 18:21
An increasing number of articles, editorials and scientific efforts are being directed toward personalized medicine [116–118]. These efforts will affect everything in medicine, and vaccines are no exception [110,111]. At a minimum, we predict that the role of genomics in the field of vaccinology will serve to elucidate new mechanisms and biologic pathways in understanding vaccine-induced immune responses and adverse responses, as well as provide new insights into vaccine development [119]. With high-throughput, low-cost genetic sequencing, large-scale phenotype/genotype databases, and bioinformatics; personalized vaccinology at the subpopulation and the individual level will occur. Of most value early in the development of this field will be associations with major or even dominant impacts (e.g., the SNP or allele that imparts a clinically impactful high relative risk ratio for poor response or adverse effect, or conversely protection from adverse events [120,121]. Such work will provide studies useful in clinical decision-making at the individual level. As sophistication increases, the ability to detect meaningful associations through the contributions of multiple genes will be discernible and potentially clinically useful. Finally, the ability to understand and predict the effect of the presence/absence and interactions of the entire genome or heritable non-DNA encoded differences (epigenetics, complementation and so on) may prove the most useful in understanding an individual patient’s benefit or risk in receiving a specific vaccine [122,123]. In such a scenario, the finding of a particular SNP that confers a very high risk of a major adverse event to a vaccine, may be outweighed or mitigated by the simultaneous finding of other specific SNPs that confer protection against such a side effect. In this manner, the totality of the genetic risk or protective effects could be assessed and integrated with other aspects of a patient’s personalized profile in regards to receiving a vaccine. Of course, to be useful we again caution that determining such a genetic profile will need to be inexpensive, easy to interpret and easy for physicians to understand and synthesize as clinical data. Thus, we see the following broad steps as necessary for the development of personalized vaccinology. If carried out such steps are likely to rapidly accelerate advances in the science and improve our ability to advise our patients on an individual (as opposed to a population level) level [124]. Without a coordinated approach, advances in the science are likely to be slow, uneven, disjointed, and less predictable and useful. ▪ Better designed gene-association studies are critical to advancing the science. Much has been written regarding this, but briefly such studies should be powered to detect scientifically and clinically meaningful associations [125–131];
▪ Studies should examine clinically meaningful end points. Studies designed to detect risks of vaccinia-associated encephalopathy are more important than studies defining the risk of transient, low grade and spontaneously resolving local or systemic side effects such as fever;
▪ Studies should be designed to maximize the amount of genetic information derived. Initial studies of a small number of gene candidates are likely to be less promising than either genome-wide association studies or large candidate gene set studies for example, but may be appropriate as initial exploratory studies;
▪ Once initial genotype:phenotype association studies are completed and candidate SNPs or alleles identified, follow-up validation studies are critical to confirming true associations and to determining if such associations are also found in other ethnic/racial groups;
▪ The costs for such studies are currently high. Because of this, we applaud the NIH’s efforts at directing funding toward such studies and in developing public databases that will allow other investigators access to study results and protocols so that results can be duplicated in other settings. It would be helpful, if possible, to develop biobanks of DNA material under study protocols so that studies could later be performed of vaccine immune response genotype:phenotype associations in as expeditious and inexpensive a manner as possible. By analogy, we need a ‘Framingham study’ [132] approach in order to develop clinically meaningful information;
▪ We must develop genetic tests that are reliable and reproducible, of low cost, for use in clinical settings, rapid, and are accompanied by sophisticated analytic tools in bioinformatics, informed by increasingly sophisticated understanding of genetics, immunology and immunogenetics.
Conclusion
The field of vaccinomics, adversomics and personalized vaccinology represents the evolution of new fields of study with new scientific possibilities informed by new paradigms and discoveries in immunology, genetics and bioinformatics. Growth in this field will be driven not only by scientific reasons, but also by consumer demands for increasingly safe and risk-free medical treatment, prevention and the desire to understand and prevent serious and severe vaccine adverse events. In turn, we believe that vaccinomics and an increasingly personalized vaccine approach will lead to new and better directed vaccine development – including the development of niche vaccines for those persons who are susceptible to serious or chronic outcomes from a given infectious disease and who are unlikely to, or have not, responded with protective immune responses to standard vaccines.
The finding that approximately 90% of the variation in measles vaccine immune response is explainable genetically provides but one insight into the importance of the field of vaccinomics. Understanding and defining associations between important immune response gene polymorphisms and subsequent immune response can aid in not only designing new vaccines, but also in developing new concepts that lead to a better understanding of viral vaccine-induced immune response variability in all human vaccines. In addition, such understandings may well allow us to predict who will not respond to a vaccine (and hence shouldn’t receive the vaccine) or who is likely to suffer a serious adverse effect from a given vaccine. Thus, the broader development of vaccinomics data can be used to make individualized decisions regarding vaccine practice.
Nonetheless, as we have previously pointed out, difficulties remain in the study and application of the immunogenetics and immunogenomics of vaccine-induced immune responses [11]. First and foremost, the science base needed is still developing. We have yet to identify genotype:phenotype associations that would reliably call for variations in vaccinations (e.g., one more or one less dose, higher or lower concentration, or other changes in schedule). In addition, for the most part we do not yet have alternative vaccines to use to address poor immunogenetic responses (e.g., peptide cocktails and cytokine adjuvanted vaccines). The complexity and extensive polymorphic nature of immune response genes will require improved and increasingly powerful bioinformatic approaches in order to inexpensively acquire, display and understand complex genetic information. Further complexity results from issues of multigenic and gene–gene interactions and response effects such as complementation and heritable epigenetic modifications. Once initial data are available, validation studies in broader and more diverse subpopulations will need to be done in order to better understand the significance of gene-specific polymorphisms and to sort true-positive from spurious false-positive associations [133]. A recent editorial succinctly states that ‘use of genetic risk information to guide intervention must be justified by data demonstrating improved outcomes, reduced costs, or both’ [117]. We would endorse such a statement.作者: ALALA 时间: 2014-8-6 18:21
Second, to proceed with a program of personalized vaccines, the economics of the genotype:phenotype associations and the alternative interventions would need to lend themselves favorably to adjust vaccination. Vaccination succeeds currently as a population-level public health measure because it is cost-effective and that cost–effectiveness is driven by the universal application of a one-dose-fits-all model. We would need a situation with personalized vaccines that similarly saved costs. To illustrate, imagine a vaccine usually given in three doses at a cost of US$100 a dose. Let us assume a genetic association with complete penetrance that would permit us to give only two doses to a subgroup of individuals to get the same level of protection. With two doses, we would save US$100 for each of those individuals. Assume the genetic association occurs in the population at a rate of 10%. Identification of such individuals requires testing all in the population. As long as the test costs less than US$10 an individual, the new program would break even. For the program to save money, the test would need to be cheaper. To save an average of US$5, the test would need to cost only US$5. Third, such testing in practice would need a high diagnostic accuracy in order to base clinical decisions on the result.
In general, while substantial difficulties need to be solved, we nonetheless believe that the vaccinomics era of personalized predictive vaccinology [11,110] is coming and that this will eventually allow clinicians to predict the likelihood of a significant adverse event to a specific vaccine [105], develop novel vaccines in a directed, nonempiric manner, predict the necessity for a given vaccine as well as the dose and number of doses of a given vaccine needed to produce the desired immunologic outcome, and identify approaches to vaccination for individuals and groups (based on age, gender, race and other) based on genetic predilections to vaccine response and reactivity. As stated by one investigator ‘just as pharmacogenetics has suggested ways of designing drugs to minimize population variability, understanding mechanisms of immunogenetic variation may lead to new vaccines designed specifically to minimize immunogenetically based vaccine failure’ [134].
At the current time, a major barrier to vaccinomics and personalized vaccinology remains the cost. For the widespread application of personalized vaccinology, much data remains to be developed, genetic sequencing costs must be inexpensive and rapidly obtained with high-throughput sequencers, and increasingly more sophisticated and less labor-intensive bioinformatic approaches will need to be developed and validated. All these issues continue to experience substantial scientific and public interest, with regular new discoveries. Hence we believe that the future of vaccinology is bright indeed, and the era of empiric vaccine development, and a strict one-size-fits-all public health approach to vaccine delivery will diminish, with adoption instead of a philosophy of the best vaccine solution for each individual or subgroup of individuals. How fast and whether public health paradigms of vaccination against infectious diseases will evolve is unknown, but critical to the public’s health, particularly in an era of consumer concern over safety, is the growing realization in healthcare policy that prevention is cheaper than treatment, and ultimately this will successfully drive advances in vaccine sciences to the benefit of all. In this regard, comprehensive and stable funding for childhood and adult immunization programs is critical to protecting the citizenry and national security.
Future perspective
Associations between HLA and other immune response gene polymorphisms, as well as innate and adaptive immune responses to vaccines are presently the best illustration of vaccine pharmacogenomics and pharmacogenetics (collectively called vaccinomics). To date, a number of immune response gene polymorphisms have been described that are associated with variations in vaccine-induced immune responses in genetically heterogeneous populations. This information, in combination with individual high-throughput genetic sequencing and bioinformatics will accelerate the field of vaccinomics and individualized vaccinology. Genetic sequencing approaches are critical for recognizing regulatory components of genes that are important in understanding immune responses following vaccination. Analysis of potential transcriptomic biomarkers for vaccine immune responses is another important technique informing the development of the next generation of prophylactic vaccines. Epigenetic aspects of heritable changes in gene-expression patterns in the absence of DNA sequence modifications of vaccine-related immune response genes will also be defined. Over the next decade, the role of immunogenetics relevant to personalized vaccines will also be further developed. We believe that the future of personalized medicine is such that with the appropriate enabling technology, one will be able to predict the likelihood of vaccine response, of numbers of doses need to achieve protection and the likelihood of serious adverse events due to vaccination. At the same time, additional immune response genes that influence variations in vaccine response will also be discovered, providing strategies for new immunotherapy approaches, novel vaccines and vaccine adjuvants. Prospective vaccine population-based studies should center on comprehensive genetic sequencing and epigenetic (DNA methylation, histone modifications) studies and on the mechanisms by which genetic polymorphisms and/or epigenetic modifications regulate gene expression and influence immune responses to vaccine antigens作者: ALALA 时间: 2014-8-6 18:22
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Influenza vaccine market dynamics
The market for seasonal influenza vaccines, sized at US$2.8 billion in 2008–2009 across the seven major markets (United States, Japan, France, Germany, Italy, Spain and UK), has had a strong compound annual growth rate of 12.6% since 2005–2006 (Ref. 1). In recent years, the sector has benefited considerably from an increase in disease awareness and funding, triggered by the threat of an influenza pandemic. However, owing to increasing competition and market commoditization, maintaining this strong growth momentum will be a key challenge in the future. The cautious stance of regulators towards new technologies inhibits successful product differentiation, particularly in the crucial US market. Improved vaccines for the elderly, alongside faster and more flexible manufacturing technologies, are the key unmet needs.
Challenges of the market
The influenza vaccines market is a challenging sector for several reasons. Besides requiring annual updates, seasonal influenza vaccines have to be produced and shipped within a short time frame of 6 months. Manufacturing delays and reduced output can result in losses of revenue and market share. Additionally, the demand for seasonal influenza vaccines is variable and often unpredictable, being influenced by factors such as the weather, the timing and severity of the influenza season, vaccine availability and public awareness of vaccination. These factors make production planning difficult. The pandemic influenza vaccines business is even more unpredictable and depends almost exclusively on government stockpiling and supply contracts.
A re-emerging focus for vaccine players
Historically, the influenza vaccine landscape has undergone marked fluctuations, particularly in the United States. The country remains the single largest market for seasonal influenza vaccines, accounting for 40% of overall sales across the seven major markets in 2008–2009 (Ref. 1). In the 1970s, at least ten US firms were marketing seasonal influenza vaccines. As a consequence of stricter FDA regulations and poor returns on investment compared with other pharmaceutical sectors, only three companies remained in the market in 2002: Wyeth, Aventis Pasteur (now Sanofi Pasteur) and PowderJect (now Novartis). In 2003, Wyeth ceased production of its own vaccines to concentrate on marketing MedImmune's (now part of AstraZeneca) FluMist, but decided to leave the flu space altogether in 2004.
Two factors prompted a change in US policy: the emerging threat of a pandemic caused by the H5N1 avian influenza strain since 2004 and a perceived vaccine supply shortage in 2004–2005 following disruptions at Chiron's (previously PowderJect's) manufacturing facility. The US government subsequently began to invest heavily into establishing US-based influenza vaccine production capacity, aiming to decrease the country's dependence on vaccine imports from few, mostly European, manufacturers. Furthermore, the US provided an additional growth stimulus by sequentially expanding recommendations on seasonal influenza vaccination to include more than 85% of the country's population by 2009 (Ref. 2). This combination of 'push' and 'pull' incentives transformed the sector's commercial potential, attracting numerous vaccine developers to build and expand their influenza portfolios in the United States. Following the market entry of GlaxoSmithKline (GSK) in 2005 and CSL in 2007, the number of vaccine suppliers for the US market has increased to five in 2009, with Sanofi Pasteur as the market leader (Fig. 1).
However, as the demand for seasonal influenza vaccination in the general population has failed to meet the expectations of suppliers, oversupply of these vaccines in the United States has become a growing problem during the past influenza seasons (Fig. 2).
This has triggered a growing commoditization of influenza vaccines. Prices, which increased from below $2 per dose in the late 1990s to $12 per dose at the peak of the business in 2007, have fallen over the past 2 years to reach a new low of $8.60 on average in 2009 (Ref. 3). To reverse this price decline, reduce the commodity nature of influenza immunizations and improve their market shares, vaccine developers are turning to new technologies that could offer product differentiation.
Developments in adjuvant technology作者: ALALA 时间: 2014-8-6 21:10
One key area of interest is an enhancement of vaccine immunogenicity through adjuvants. The key advantage in the influenza sector is a reduction in the amount of antigen required for protective immunization. This so-called dose-sparing effect helps to increase the number of available vaccine doses. This is particularly important in a pandemic, when the supply, limited by manufacturing capacity, cannot meet the demand. Another advantage of adjuvanted vaccines is their potential for improved immunogenicity in the elderly, which is a key unmet need. Novartis and GSK are currently furthest advanced in developing these technologies for influenza. Both companies have already received European approval to make products using their oil-in-water-based emulsions MF59 and AS03, respectively. By contrast, gaining US approval for adjuvanted vaccines has proven difficult, with the FDA adopting a conservative position, presumably owing to a lack of data on the long-term safety profile of novel adjuvants. The current influenza A (H1N1) pandemic has rejuvenated interest in adjuvanted influenza vaccines, with several governments investing into large adjuvant stockpiles. Clinical studies investigating potential benefits of various adjuvanted pandemic influenza A (H1N1) vaccines were initiated. However, clinical trials of non-adjuvanted H1N1 vaccines have now demonstrated sufficient immune responses, indicating that at least in the early stages of vaccination against H1N1, adjuvants will not play a part in the US.
Improving manufacturing techniques
A further opportunity for product differentiation is the influenza vaccine manufacturing process. With the exception of Novartis's Madin–Darby canine kidney (MDCK) cell-based vaccine Optaflu, which gained European Union approval in 2007, all marketed seasonal influenza vaccines are still manufactured in chicken eggs. This process is not only lengthy and inflexible, but would also be unsuitable in the event of an avian influenza pandemic. To provide faster and more flexible alternatives, numerous companies are developing alternative production systems. Besides Novartis, Baxter is the only other player to have gained European approval for a cell-based influenza vaccine — its mock-up pandemic vaccine Celvapan, which is manufactured in Vero cells (a kidney epithelial cell line derived from African green monkeys). During the current pandemic, both companies are set to gain substantial commercial windfalls from using this faster production technology for H1N1 vaccine production. Smaller players, including Protein Sciences and Novavax, are developing production systems in insect cells based on the baculovirus system. Other strategies in earlier stages of development include the use of bacterial and plant expression systems.
Outlook
The current influenza A (H1N1) pandemic has boosted vaccine stockpiling contracts. Established manufacturers, particularly Novartis and GSK, are likely to draw the largest commercial benefit. Besides its direct impact on pandemic vaccine sales, H1N1 will also influence the future development of the seasonal influenza vaccines market. We think that the most likely outcome for future sales development will be a transient boost triggered by the current pandemic. Seasonal influenza vaccine uptake will increase considerably over the next two influenza seasons, with sales figures rising to $4 billion by 2010–2011 across the seven major markets. Once the pandemic has passed, however, we expect a period of stagnation caused by declining seasonal vaccination coverage in most population groups (Fig. 3). By 2018–2019, the seasonal influenza vaccine market size could reach $5 billion across the seven major markets, driven by further extensions of vaccination recommendations1. Sanofi Pasteur, which was market leader in 2008 with global influenza vaccine sales exceeding $1 billion5, will maintain its top position; however, we think that GSK and Novartis will increase their share owing to their competitiveness in new technologies such as adjuvants and cell-based manufacturing.作者: hold住 时间: 2014-8-6 21:18
