全球艾滋病研究几年前曾遭受过一次重创。在临床试验中，研究人员为3000名受试者注射了当时被寄予厚望的HIV疫苗――默克疫苗，但试验结果却出人意料地糟糕：没有一个人获得了对HIV的抵抗力。更糟糕的是，这种疫苗反而会使部分受试者更容易感染HIV。
在很大程度上，默克疫苗的失败是因为研究人员尚不知道如何制造出完美的疫苗。事实上，很多疫苗的成功都存在侥幸成分。当年的科学家对免疫系统和病原体相关知识所知不多，不懈努力加上运气，碰巧发现了可使人体产生抵抗力的疫苗。但更多的时候，试验结果常常令人失望。
还有更快捷高效的方法吗？如果能在临床试验前就预知疫苗对人体的效用会如何？理论上，如果想让一种疫苗诱发出强烈的保护性免疫反应，我们首先要做的，就是清晰了解在这一过程中必定要发生的每一种免疫反应。然后，科学家把这些信息纳入一个系统性的特征图谱里，通过对比，从中选出接近理想状况的疫苗配方。接下来，他们就通过一些规模小、周期短的临床试验改进这些候选配方，直到找出最佳配方。通过比较它们的生物学特性与理想特性，科学家就能在相当短的时间内知晓，一种疫苗是否具有较大的成功几率。
在今天的系统生物学领域，很多科学家正在组建这样的研究团队，而且已经踏出了第一步。以艾滋病研究为例，我们目前已开始更细致地研究，如果要使一个人对HIV产生抵抗力，需要激发哪些免疫反应。
追查败因
默克公司研制的HIV疫苗为什么会遭遇滑铁卢？要知道，这种疫苗曾被认为非常有希望成功，而这次失败宣判了它的死刑，震惊了整个艾滋病研究领域。
默克疫苗并不是首个接受测试的HIV疫苗。在以往的临床试验中，科学家主要是想用疫苗引发有效的抗体反应，以便在HIV在人体内站稳脚跟之前将它们除掉。
默克疫苗采用了另一种研究方法：激活适应性免疫系统中的杀伤性T细胞。理论上，注射了这种疫苗后，任何人感染了HIV，都能无限期地把病毒抑制在静止状态。在灵长类动物中进行的初步试验强烈暗示，这种疫苗也能使人体对HIV产生一定的抵抗力。
出人意料的是，默克疫苗未能奏效。尽管成功诱导出了T细胞反应，而且这种反应在75%的受试者中，也能准确向HIV感染细胞发起攻击，但试验中期的分析表明，在疫苗注射组和对照组之间，HIV感染率和人体内的病毒数量并没有什么区别。更令人震惊的是，体内已有腺病毒Ad5抗体的受试者在接种疫苗后，甚至比对照组似乎更有可能受到感染。
通过分析默克疫苗，我们发现，接种默克疫苗后的24小时内，人体内就有数千基因开始表达。这种反应与T细胞的活化数量呈指数上升是一致的。进一步分析发现，我们预料中的在先天免疫系统中起主要作用的基因，都包括在这几千个基因之内。但当我们观测临床试验中HIV感染率较高的那些受试者的血液样本时，我们发现先天免疫系统活化倾向受到了明显压制。
我们怀疑，默克疫苗很可能存在一个科学家未曾料到的关键缺陷，使得受试者在与HIV感染者发生性关系，或者共用针头时容易被传染。目前，我们正在做进一步研究，看能否证实上述猜测，并弄清楚为何强烈的T细胞反应却没能让受试者产生哪怕一丁点儿抵抗力。
最成功的疫苗
不管是按传统方法制备的，还是根据系统生物学研究开发的，所有疫苗都含有病毒、细菌或寄生虫的一些碎片（也就是抗原），用以触发相应的免疫反应。制作疫苗时，可能还需要添加佐剂――在人体内激发更广泛的免疫反应的物质。如果一切顺利，免疫系统会对疫苗中的抗原成分作出反应，精确启动一系列分子和细胞事件，让机体以后能够抵抗携带着相同或类似抗原的病毒或细菌。对于疫苗开发者来说，他们要做的就是找到抗原和佐剂的正确组合，以便能诱发最强烈的保护性免疫反应。
尽管黄热病（yellow fever，）疫苗是按传统方式开发的，但却是有史以来世上最有效的疫苗之一。只需一次接种就能在一星期内使人体产生有效免疫力，效力至少可以持续30年。这种疫苗的成功提供了一个机会，可以让科学家测试系统生物学中的一些理念和方法。因为知道黄热病疫苗是有效的，所以我们能够弄清楚这种疫苗在人体内成功触发免疫力后引起的变化及其详细特征。我们确实发现了一个标志性特征，希望能根据这个经验，试着找出HIV疫苗未能使人体产生免疫力的原因。
(小词典：黄热病俗称“黄杰克”、“黑呕”，是由黑热病病毒所致的急性传染病，主要媒介在城市是埃及伊蚊，在农村为趋血蚊和非洲伊蚊，传播途径是经蚊的叮咬。该病在中、南美洲和非洲热带地区呈地方性流行，病死率一般为2%至5%。)
我们找来25名健康自愿者，为他们接种了黄热病疫苗。接着，我们在不同的时间点从他们身上采集血样，每份血样都会送入自动筛选仪中，鉴定哪些基因被激活了。
正如我们所料，黄热病疫苗接种大概10天后，首先会激活先天免疫系统。接着先天免疫系统会刺激适应性免疫系统，使之产生一些抗体，能针对黄热病病毒的多个部分发起攻击。然后，该系统会激活杀伤性T细胞，这些免疫细胞可识别并摧毁体内已被病毒感染的细胞。经过几轮分析，我们找到了65个起关键作用的基因。从这些基因的特征可以明显看出其预示着强大抗体的产生。
来自猴子的暗示
研究表明，猴子也可能被一种与HIV相似的病毒――猴免疫缺陷病毒（simian immunodeficiency virus ，SIV）所感染。迄今为止，我们已经鉴定出了早期先天免疫反应的数个标志性特征，根据这些特征可以预测，接种了疫苗的猴子在接触SIV后，哪些猴子体内的病毒较少。
在猴子身上进行了一系列的试验之后，我们已经能确定某些基因表达产生后，猴子的抗病毒能力就会增强。由于猴与人有太多基因都是相同的，猴子体内最佳免疫反应的那些特征，也许能让我们顺藤摸瓜，对HIV在人体内引发的强烈免疫反应有所了解，而且这些知识还可用来评估不同疫苗在人体内的效能。
就目前而言，一种疫苗的配方确定了以后，要检测它能否让人体产生抵抗力，系统生物学方法似乎是最好的选择。我们的最终目标是，在设计一种疫苗时，在临床实验前就能提前知晓，这种疫苗到底会不会触发理想的免疫反应。
毫无疑问，系统生物学的方法正在将疫苗研发推进快车道，它能让我们更好地了解人体的免疫系统，能让我们在设计疫苗时考虑得更加周全、慎密，也更具预见性。人类曾经征服过许多可怕的瘟疫，也终将能征服那些仍在世界各地肆虐的病毒。
作者简介
艾伦・阿德雷姆（Alan Aderem）是世界著名免疫学家和细胞生物学家。2000年，他在美国西雅图参与创建了系统生物学研究所，目前担任西雅图生物医学研究所所长，致力于疫苗的研发。（艾伦・阿德雷姆）
艾滋病不治会早死，早治才康复 艾滋病不治会早死，早治才康复 艾滋病不治会早死，早治才康复 艾滋病不治会早死，早治才康复
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| 图示∶2011年5月正式出版的《中国特色医疗金鉴》登载的刘君主任及其机构事迹 |
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Vaccine in the spring
2011-05-28 10:42 Source: Guangming Wang - "Guangming Daily"
Global AIDS research several years ago suffered a hit. In clinical trials, the researchers injected 3,000 subjects were high hopes at the time of the HIV vaccine - Merck vaccine, but the results are surprisingly bad: no one got on HIV resistance. Worse, this vaccine would bring some subjects more susceptible to HIV.
In large part, Merck vaccine failed because researchers do not know how to create a perfect vaccine. In fact, many of luck the success of the vaccine components. Then the immune system and pathogens, scientists know very little knowledge, tireless efforts and luck, happened to find the human body resistant to the vaccine. But more often, test results are often disappointing.
There are more fast and efficient way? If you can predict the vaccine before clinical trials on the effectiveness of how the human body? In theory, if you want a vaccine induced a strong protective immune response, we first need to do is a clear understanding in this process must occur each immune response. The scientists then put the information into a systematic pattern in the feature, by contrast, close to the ideal position to choose the vaccine formula. Next, they passed a number of small-scale, short period of clinical trials to improve the candidate formula, until you find the best formula. By comparing the biological characteristics of their ideal characteristics, scientists will be able to know within a very short period of time, a vaccine with greater probability of success.
In today's systems biology, many scientists are building this team, and has taken the first step. To AIDS research, for example, we have already started to study in more detail, if you want a person resistant to HIV, which need to stimulate the immune response.
Tracing cost me
HIV vaccine developed by Merck & Co. took a plunge Why? You know, this vaccine was considered very promising, but this time it failed sentenced to death, shocked the field of AIDS research.
Merck tested the vaccine is not the first of the HIV vaccine. In previous clinical trials, scientists mainly to an effective vaccine induced antibody response to HIV in the body in a firm footing before they get rid of.
Merck vaccine uses a different methodology: the adaptive immune system activated killer T-cells. In theory, the injected vaccine, any person infected with HIV, the virus can be suppressed indefinitely in the resting state. In primates of the initial tests strongly suggest that this vaccine can make the body produce a certain resistance to HIV.
Surprisingly, the Merck vaccine failed to work. Despite the success of the T cell response induced, and this response in 75% of the subjects, but also accurate to attack HIV infected cells, but the mid-test analysis showed that in vaccination group and control group, HIV virus infection and the number of the human body, and no difference. More alarming is that the body has been the subject of adenovirus Ad5 antibodies after vaccination, even more than the control group seemed more likely to be infected.
By analyzing the Merck vaccine, we found that Merck vaccine inoculation within 24 hours, there are thousands of genes in the human body begin to express. This reaction and the number of T cell activation is consistent with the exponential rise. Further analysis revealed that we expected in the innate immune system genes that play a major role, are included in the thousands of genes within. But when we observed a higher prevalence of clinical trials in HIV blood samples of those subjects, we found that activation of the innate immune system was suppressed by the tendency.
We suspect that Merck scientists, the vaccine is not expected that there may be a key defect, making the subjects with HIV infection in sexual relations, or when sharing needles easily be infected. We are currently doing further studies to see whether confirmed that speculation, and find out why the strong T cell response but no subjects have let slightest resistance.
The most successful vaccine
Whether it is prepared according to traditional methods, or research and development based on systems biology, all vaccines contain viruses, bacteria or parasites some of the fragments (ie, antigens), to trigger the appropriate immune response. Production of vaccines, you may also need to add adjuvants - in the body stimulate wider immune response of the material. If all goes well, the immune system antigens in the vaccine composition will respond to start a series of precise molecular and cellular events, so the body can resist after carrying the same or similar antigens of viruses or bacteria. For vaccine developers, they have to do is to find the right combination of antigen and adjuvant in order to induce the strongest protective immune response.
Although yellow fever (yellow fever,) vaccine is the development of the traditional way, but it is the most effective vaccine ever one of the world. Inoculated only once a week so that the body will be able to produce effective immunity, the effect can last for at least 30 years. The success of this vaccine provides an opportunity to allow scientists to test some of the systems biology concepts and methods. Because we know that yellow fever vaccine is effective, so we can figure out the success of the vaccine triggered immunity in the human body induced changes in its detailed characteristics. We did find a landmark feature, hoping the basis of this experience, try to find HIV vaccine failed to cause the body to produce immunity.
(Small Dictionary: yellow fever, commonly known as "Yellow Jack", "black vomit", caused by an acute viral infectious disease kala azar, the main vector Aedes aegypti in cities, rural areas increasingly in the blood and the African Aedes mosquitoes, spread way is through mosquito bites. the disease in Central and South America and Africa, endemic in tropical regions, the general mortality rate of 2% to 5%.)
We recruited 25 healthy volunteers, as they were vaccinated against yellow fever vaccine. Then, we are in different time points blood samples collected from them, each blood sample will be sent automatically screening instrument to identify which genes are activated.
As we expected, about 10 days after yellow fever vaccination, first activate the innate immune system. Then stimulate the innate immune system the adaptive immune system, thus producing a number of antibodies against yellow fever virus can attack many parts. Then, the system will activate the killer T-cells, these immune cells can recognize and destroy the body has been infected cells. After several rounds of analysis, we found 65 genes that play a key role. From the characteristics of these genes is evident that it indicates a strong antibody production.
Implied from the monkey
Studies have shown that monkeys with HIV may also be a similar virus - simian immunodeficiency virus (simian immunodeficiency virus, SIV) of the infection. So far, we have identified the early innate immune response of a number of landmark features, these features can be predicted that the monkeys were vaccinated after exposure to SIV, the monkey which the virus less.
In monkeys, after a series of tests, we have been able to determine the expression of certain genes after the election, the monkeys will enhance the ability of anti-virus. Because there are too many monkeys and human genes are the same, monkeys are the best features of the immune response, may allow us to follow it, cause of HIV in the body have a strong understanding of the immune response, and this knowledge can also be used to assess different vaccine effectiveness in the human body.
For now, a vaccine formulation to determine the future, to test whether it can allow the body to produce immunity, systems biology approach seems to be the best choice. Our ultimate goal is to design a vaccine, in clinical trials before you can know in advance that the vaccine in the end will not trigger the desired immune response.
There is no doubt that systems biology approaches to vaccine development is to promote the fast lane, it allows us to better understand the body's immune system, allows us to consider in the design of the vaccine a more thoughtful, careful, but also more predictable . Humans have conquered many terrible plague, but also those who will eventually be able to conquer the virus is still raging around the world.
About
Alan Adelaide rem (Alan Aderem) is the world's leading immunologists and cell biologists. In 2000, he founded the Seattle Institute for Systems Biology, is currently serving as director of the Seattle Biomedical Research Institute, dedicated to vaccine research and development. (Alan Adelaide rem)
