艾滋病疫苗为何还未诞生
    时间： 2010-11-20 07:52:24　来源： 长春晚报 　

图示∶2010年12月即将出版的《中国特色医疗金鉴》登载的刘君主任及其机构

慢性艾滋病早期中医药治疗保障生命论证

　　艾滋病疫苗为何还未诞生

　　2007年9月，全球瞩目的美国默克公司艾滋病疫苗临床II期试验宣告失败。当美国《科学》杂志披露这一消息时，全世界研究人员的信心受到极大打击，艾滋病疫苗研究也由此跌入低谷。

　　这项被命名为STEP计划的艾滋病新疫苗临床试验一度被寄予厚望，它的失败原因始终是一个谜。2009年7月，《自然-医学》杂志在线版刊发的两篇针对疫苗失败机理的论文，首次揭开了这个谜团的冰山一角。

　　失败之谜

　　2004年，由美国默克公司、美国国立过敏和传染病研究所和艾滋病疫苗试验联盟组成的研究团队，开始对艾滋病新疫苗V520实施一项名为STEP的全球性人体临床试验。

　　被誉为抗艾疫苗中“希望之星”的V520，当时被看成是艾滋病研究史上最先进、最有前途的候选疫苗。研究者为它选择了一种弱化的普通感冒病毒Ad5，作为三种艾滋病病毒基因的载体。最初设想是在STEP试验中，这种携带弱化艾滋病病毒基因的疫苗，会激发接种者体内的细胞免疫反应，使其产生更多的T细胞，从而可对付艾滋病病毒的攻击。

　　不幸的是，II期临床试验的数据与研究者的设想背道而驰。2007年9月18日，美国《科学》杂志披露，对STEP试验的一项中期安全性分析显示，V520疫苗无法保护接种的志愿者免遭艾滋病病毒的侵害，也不能减少艾滋病感染者体内的病毒数量。默克公司随即宣布，这一历经数年的艾滋病疫苗以失败告终。医学界称之为“灾难性的失败”，甚至可以与“挑战者号”航天飞机的失事相提并论。

　　坏消息接踵而至。当年11月，在美国西雅图召开的一次科学会议上，对疫苗失败原因的进一步数据分析显示，在778例对Ad5病毒免疫力较强的男性志愿者中，有21例感染艾滋病，这一数据是对照组的2.3倍。尽管缺乏充分证据，但质疑已经无法避免――Ad5载体疫苗不但不能有效防御艾滋病病毒，反而可能使接种者感染艾滋病病毒的风险增加。

　　该试验的合作伙伴，美国国立过敏症和传染病研究所的福奇博士得知这一结果后沮丧地表示，新的分析结果令人既失望又困惑，因为该疫苗无效的原因至今无人知晓。

　　怀疑目光指向疫苗的载体Ad5病毒。在STEP试验中，注射疫苗之前已经感染Ad5病毒的接种者要比那些之前没有感染Ad5的接种者更容易感染艾滋病病毒，而前者具有高水平的Ad5中和抗体反应水平。

　　因此，在过去的实验中，一个主导性的试验失败解释是，由Ad5载体疫苗激活的Ad5型T细胞是接种者更易感染艾滋病病毒的罪魁祸首。直到2009年7月，《自然-医学》的两篇针对该试验失败机理的研究性文章，对这一解释提出了挑战。

　　研究小组发现，对Ad5病毒有较强免疫力并不预示着接种Ad5载体疫苗后激活的T细胞增多。Ad5中和抗体反应水平与特定Ad5型T细胞反应没有关系，而且与具有低水平的Ad5中和抗体反应的接种者相比，具有高水平的接种者并没有表现出更多的Ad5型免疫反应。

　　STEP试验开展者、艾滋病疫苗试验联盟研究负责人科里提醒，最新的研究没有检测HIV借以进入人体的一些特定组织，如直肠和阴茎包皮，所以就没有排除之前的Ad5病毒免疫性使得这些部位的组织更易受攻击的可能性，先前对失败原因的解释并没有完全被驳倒。

　　专家普遍认为，最新的研究仅仅揭开了艾滋病疫苗设计失败的冰山一角，目前仍无明确答案解释STEP试验中艾滋病感染率增加的问题。

　　不过巴鲁赫表示，新的研究结果还是可以看成是领域内的积极信号，“过去两年来领域内已经相当沮丧了，我们希望能为测试未来艾滋病疫苗候选者提供路径”。

　　障碍何在

　　最新关于STEP试验失败原因的研究进展，并没有扫清艾滋病研究领域内悲观的阴霾。

　　从1981年人类发现艾滋病病毒以来，研制艾滋病疫苗就成为医学界至今难以逾越的障碍。25年前，美国卫生与公众服务部部长“两年内定能研制出艾滋病疫苗”的大胆宣言仍言犹在耳，但直至现在，艾滋病疫苗上市的目标仍遥遥无期。

　　据统计，在过去的二十多年中，全世界已有超过35个艾滋病疫苗进入临床试验，1万多名志愿者参与试验，但是无论是采用哪种策略，最终都遭遇滑铁卢。研发艾滋病疫苗难道真的是人类不可能完成的任务？

　　“艾滋病有效疫苗似乎在未来10至15年内不会被发现。”《自然-医学》杂志的资深编辑克莱尔・托马斯采访25位权威的艾滋病专家后得出的结论，更让致力于该领域的研究者感到沮丧。在托马斯的文章中，包括新英格兰灵长类生物研究中心的德鲁西、美国宾夕法尼亚大学的贝茨以及美国国立健康研究院的马斯科拉等25位接受采访的专家一致认为，屡战屡败的艾滋病疫苗研发工作已经到了重归基础研究的时候了。

　　“如果我们真的能在疫苗研究上有所突破，我们将不再需要复杂的分析来解释它，它会变得显而易见。”新英格兰灵长类生物研究中心专家德鲁西表示，目前艾滋病疫苗研究领域的一个关键性障碍就是，对艾滋病发病机理的基础机制的理解不足。

　　STEP计划的失败让许多研究机构重新将重点放在基础研究上，以期能够找到更好的候选疫苗。

　　2008年7月，美国国立过敏和传染病研究所决定不再进行与STEP试验一样，以Ad5重组疫苗为试验对象的PAVE100计划，取消这项原设计8500人的大规模艾滋病疫苗临床试验。美国斯克里普斯研究所的免疫学家伯顿对此表示，“在没有清晰地认识到我们将发现什么之前，还是不要进行人类试验的好”。

　　据了解，目前国际上进入临床观察的近30种艾滋病候选疫苗几乎均以刺激细胞免疫反应为目标设计，许多候选疫苗之间只有细小的差别，对如何产生艾滋病病毒保护抗体反应缺乏了解，大量重复性的工作在各地的研究小组内展开。专家们的一个共识是，艾滋病疫苗研究在热衷于临床试验的方向上已走得过远了。一部分专家甚至认为，疫苗的临床试验应该停止，直到对病毒传染和调控相关生物学基础知识有了更好的了解。

　　如何决定疫苗设计理论可以转化到临床试验阶段？专家认为，在决定启动候选疫苗大范围的功效试验前，应有筛选程序，能证明这个理论是新颖的，与其他的候选疫苗有显著不同。

　　受访的专家们还一致地认为，研究理论的临床转化应该建立在一个坚固的动物模型的研究基础上。目前，猕猴模型被认为是研究艾滋病发病机理和保护机制的最好的动物模型。但是，默克公司2007年STEP试验的失败给猕猴模型的有效性蒙上了阴影。

　　“要证明灵长类动物模型疫苗的有效性，唯一的途径就是进行人体试验，看看是否是动物模型预示的结果。”美国国立健康研究院的马斯科拉认为，动物们甚至能够给疫苗的设计提供更多的线索，一旦一个清晰的猕猴模型被确定，将非常容易寻找到疫苗候选者第一阶段试验的信号。但是现有的艾滋病研究动物模型都存在不同的局限性，这些猴子的模型应该先做标准化处理，以便于研究者能更可靠地比较它们之间的研究途径。

　　采取措施

　　STEP试验失败后，科学界已经开始着手调整研究的策略。

　　科学家认为，艾滋病研究界有点与世隔绝，而来自其他学科以及发展中国家的艾滋病科学家需要参与进来。这个领域强烈地需要其他学科的专家意见，比如基础免疫学、自身免疫学、肿瘤学、生物化学、生物工程、系统生物学等各种与艾滋病相关的基础性学科，“临床研究和基础研究的科学家们的合作更有可能促进艾滋病疫苗研究的成功”。

　　创立于2009年的美国Ragon组织，正在利用Ragon基金会的10亿美金资助做这样的事情。他们向马萨诸塞州工程学院、马萨诸塞州立医院和哈佛大学的科学家征求意见，这些专家之前都没有在艾滋病研究领域工作过，但在Ragon组织内，他们必须和艾滋病研究者一同合作。

　　发展中国家的科学家在艾滋病研究方面的声音越来越重要。美国西雅图弗雷德・哈钦森癌症研究中心专家欧维巴说：“如果我们想期待着下一代科学家接过火炬时，我们就应该把重点更加放在培训发展中国家的科学领袖上。”

　　对于研究基金问题，托马斯访问的专家们普遍认为，在欧洲和美国艾滋病研究有足够的经费，但是这些资金向大的研究机构倾斜得太严重，那些高风险、有创造性的科研项目要想拿到足够的启动经费很困难，这在一定程度上导致该领域内缺乏革新。

　　一些科学家建议，应该创造一些机会资助一些小的自主集合的研究组织，尤其是年轻的研究者，给他们足够的自由和灵活的空间，在一个长期不变的领域探索革新，去尝试冒险的科学研究。换句话说，资助并且没有目标要求。在美国，2009年健康恢复和再投资计划，提供了一些临时性的资助给那些独立的研究者。

　　2008年，国际艾滋病疫苗行动组织每两年制定一次的《艾滋病疫苗蓝图2008》出炉，明确提出，改变目前大量资源用于传统的经验式的疫苗研发与筛选的方式，重点解决阻碍疫苗发展的关键基础性科学难题。 （本文来源于《南方周末》）

　　相关链接

　　艾滋病就业歧视第一案

　　今年20岁的安徽青年小吴是一名师范毕业生，在今年5月的安徽省安庆市市直学校2010年招聘教师考试中，他连续通过了笔试和面试等环节，不料在最后的体检过程中被查出艾滋病病毒检测呈阳性，复检过后，教育局决定不予录用。

　　8月26日，小吴正式向安庆市迎江区人民法院递交起诉书，将安庆市教育局和人社局告上了法庭。

　　10月13日，这起被称为“艾滋病就业歧视第一案”的案件在安庆市迎江区法院进行了不公开审理。

　　法院根据《公务员录用体检通用标准（试行）》规定，原告体检不合格，不符合《教师法》对从事教师职业身体条件的要求。被告根据原告的体检报告作出不予录用决定，事实依据充分，驳回原告小吴的诉讼请求。

　　对此，小吴表示他不服这一判决，将会提起上诉。他说：“歧视是一堵墙，需要很多人一个一个地撞。”Why has not the birth of AIDS vaccine
    Time: 2010-11-20 07:52:24 Source: Changchun Evening News
    Keywords: AIDS, HIV infection rates of AIDS experts of AIDS vaccine
    Summary: November 12, 2010, of concern, "the first case of AIDS discrimination in employment" in Anqing Yingjiang District Court verdicts. Experts generally believe that the latest research just opened a failure of AIDS vaccine design tip of the iceberg, there is still no clear answer to explain the increase in HIV infection rates in the STEP trial issues.
 
November 12, 2010, of concern, "the first case of AIDS discrimination in employment" in Anqing Yingjiang District Court verdicts. The court held that, Anqing City Board of Education to make the medical report according to Xiao Wu's decision not to hire, the full facts, rejected the plaintiff's claim Xiao Wu. Xiao Wu, after hearing the news, told reporters by telephone, refused to accept the ruling and will appeal. Xiao Wu lawsuit people concerned about the same time, also ask: Can you produce an AIDS vaccine, so that more people away from the problems of AIDS!

Why has not the birth of AIDS vaccine

September 2007, the global attention of the U.S. II Merck's AIDS vaccine clinical trial failed. When the United States "Science" magazine disclose this message, the confidence of researchers around the world hurt by AIDS vaccine research has thus dropped to its lowest.

The STEP program was named the new AIDS vaccine clinical trials once high hopes for its failure is always a mystery. July 2009, "Nature - Medicine" magazine online edition published two papers for the mechanism of vaccine failure, for the first time reveal the mystery of the tip of the iceberg.

Mystery of failure

In 2004, Merck by the United States, the United States National Institute of Allergy and Infectious Diseases and AIDS vaccine trials coalition of the research team began to implement a new HIV vaccine V520 global body called the STEP clinical trial.

Known as the anti-AIDS vaccine in the "Star of Hope," the V520, was seen as the most advanced in the history of AIDS research, the most promising vaccine candidates. The researchers chose for it a weakening of the common cold virus Ad5, as the carrier of three HIV genes. Originally envisaged in the STEP trial, which carry HIV genes weakened vaccine will stimulate the body's cells inoculated with the immune response to produce more T cells, which can deal with the AIDS virus attacks.

Unfortunately, II clinical trial data and the idea runs counter to the researchers. September 18, 2007, the U.S. "Science" magazine revealed that a mid-term of the STEP trial safety analysis, V520 vaccine can not protect volunteers from vaccination against HIV, we can not reduce the virus in AIDS quantity. Merck then announced that after several years of failed AIDS vaccine. Medical profession as "catastrophic failure", even with the "Challenger" space shuttle accident par.

The bad news followed. Year in November, held in Seattle at a scientific meeting, a further reason for the failure of the vaccine data analysis showed that in 778 cases of strong immunity against Ad5 virus male volunteers, 21 were infected with HIV, the data is 2.3 times the control group. Despite the lack of sufficient evidence, but the question has become unavoidable - Ad5 vector vaccine not only failed to effectively prevent HIV, but may inoculation increased risk of HIV infection.

The trial partners, the U.S. National Institute of Allergy and Infectious Diseases, Dr. Fauci frustration after learning of the results, said the new analysis results are disappointed and confused because the vaccine is invalid because it has not known .

Suspected eye point vector Ad5 vaccine virus. In the STEP trial, Ad5 vaccine before the virus infection than those not previously vaccinated were infected with Ad5 inoculation were more susceptible to HIV, while the former has high levels of Ad5 neutralizing antibody response levels.

Thus, in past experiments, a test failure of the dominant explanation is activated by the Ad5 vector Ad5-based vaccine T cells are more susceptible to AIDS virus inoculation of the culprit. Until July 2009, "Nature - Medicine" for the test failure mechanism of two research articles, has challenged this interpretation.

The team found a strong immunity against Ad5 virus inoculation did not indicate Ad5 vector vaccine activated T cells increased. Levels of Ad5 neutralizing antibody response to Ad5-specific T cell response type does not matter, but also has low levels of Ad5 neutralizing antibody response to vaccination than those with high levels of vaccination who did not show more of the Ad5-type immune response .

STEP test carried out, AIDS vaccine trials Union Leader Keli Ti wake of the latest study did not detect HIV to enter the body of some specific organizations, such as the rectum and the penis foreskin, so do not rule out the virus before the Ad5 immunity so that these parts organizations more vulnerable to the possibility of failure previously not been fully explained and refuted.

Experts generally believe that the latest research just opened a failure of AIDS vaccine design tip of the iceberg, there is still no clear answer to explain the increase in HIV infection rates in the STEP trial issues.

But Baruch said the new study area can still be seen as a positive signal, "the area over the past two years has been quite frustrating, and we hope for the future of AIDS vaccine candidates tested to provide the path."

What are the obstacles

Failure on the STEP test the latest research progress in the field of AIDS research is not clear in the shadow of pessimism.

Discovered from the human AIDS virus in 1981, since the development of AIDS vaccine to the medical profession has become an insurmountable obstacle. 25 years ago, the U.S. Department of Health and Human Services Minister, "slated for two years to AIDS vaccine developed" a bold declaration was still ringing in our ears, but until now, the goal of AIDS vaccine is still elusive.

According to statistics, in the past two decades, the world has more than 35 HIV vaccine clinical trials, more than 10,000 volunteers participating in the trial, but no matter which strategy is used, eventually took a plunge. AIDS vaccine research and development really is the impossible task of mankind?

"AIDS vaccine appears effective in the next 10 to 15 years will not be found." "Nature - Medicine" magazine's senior editor Claire Thomas, 25 interviews after the authority of the AIDS experts concluded, leaving dedicated to research in the field are frustrated. In Thomas's article, including the New England Primate Research Center, De Luxi Biology, University of Pennsylvania and the National Institutes of Health Bates Maas Cora and other 25 experts interviewed agreed that the fighting and repeated failure of AIDS vaccine research and development work has been to return to basic research of the time.

"If we can really make a breakthrough in vaccine research, we will not need a complex analysis to explain it, it will become obvious." New England Primate Research Center, De Luxi biological said that the current AIDS vaccine A key obstacle to research is, on the basis of pathogenesis of AIDS insufficient understanding of the mechanism.

STEP planning for many research institutions, the failure to re-focus on basic research, in order to be able to find a better vaccine candidates.

July 2008, the United States National Institute of Allergy and Infectious Diseases decided to no longer be the same with the STEP test to Ad5 recombinant vaccine for the trial subjects PAVE100 plan, the cancellation of the original design of 8,500 large-scale AIDS vaccine clinical trials. Scripps Institute of American immunologist Burton responded by saying that "without a clear understanding that we will find that what was before, or not to carry out human trials of the good."

It is understood that the current international clinical observation into the nearly 30 AIDS vaccine candidates to stimulate cellular immune responses are almost as the target design, the number of candidate vaccines is only a small difference between, on how to generate protective antibody response to HIV lack of understanding, a large number of repeat of work conducted within the research team throughout. A consensus of experts is eager to AIDS vaccine research in the direction of clinical trials have been going too far. Some experts even believe that the vaccine clinical trials should be stopped until the virus infection and related biological control have a better understanding of the basics.

How to determine the vaccine design theory can be transformed into clinical trials? Experts believe that the decision to launch a wide range of candidate vaccine efficacy trial, the proper selection procedures, can prove that this theory is new, with other candidate vaccines are significantly different.

The experts interviewed also consensus that clinical research into the theory should be based on a solid basis of animal model. Currently, the monkey model of AIDS is considered the mechanism of pathogenesis and protection of the best animal model. However, Merck STEP trial failed in 2007 to the monkey cast a shadow over the effectiveness of the model.

"Primate model to prove the effectiveness of the vaccine, the only way is to carry out human trials to see if the results indicate an animal model." U.S. National Institutes of Health Maas Cora that the animals can even give the design of vaccines to provide more clues, once a clear macaque model is determined, will be very easy to find a vaccine candidate for the first phase of testing signals. But the existing animal models of AIDS research have different limitations, the model of these monkeys should first standardized, so that researchers can more reliably compare their research approach.

Take measures to

STEP trial failed, the scientific community have begun to adjust research strategies.

Scientists believe that the AIDS research community a bit isolated, while those from other disciplines as well as developing countries, AIDS scientists to be involved. Strongly in this area needs the expertise of other disciplines, such as basic immunology, autoimmunity, oncology, biochemistry, biotechnology, systems biology, and other AIDS-related basic disciplines, "clinical research and basic research the cooperation of scientists are more likely to promote the success of HIV vaccine research. "

Founded in 2009, the United States Ragon organization, is using Ragon Foundation funded 10 million dollars to do such things. They Massachusetts Engineering, Massachusetts State Hospital, and Harvard University scientists for their comments, these experts have not before worked in the field of AIDS research, but Ragon organization, they must cooperate with and AIDS researchers.

Scientists from developing countries in AIDS research, sound more important. U.S. 西雅图弗雷德 Hutchinson Cancer Research Center, Ouwei Ba said: "If we want to look forward to the next generation of scientists took the torch, we should focus more on training the scientific leaders of the developing countries."

Research Fund for the problem, Thomas visited the experts generally agreed that, in Europe and the U.S. have enough money to AIDS research, but these funds to tilt too much serious research institutions, those high-risk, creative research projects in order to get is difficult enough start-up funds, which to some extent, led to a lack of innovation in the field.

Some scientists have suggested that funding should create some opportunities for some small set of independent organizations, especially the young researchers, giving them enough freedom and flexibility of space, in a long time to explore areas of innovation, scientific adventure to try study. In other words, funding requirements and not goals. In the United States in 2009, restored and re-investment in health plans to provide some temporary assistance to those independent researchers.

In 2008, the International AIDS Vaccine Initiative to develop once every two years, "AIDS Vaccine Blueprint 2008" came out, made it clear that a large number of resources to change the current experience of the traditional type of vaccine development and screening methods, focusing on vaccine development to resolve the key obstacles basic scientific problems. (This article from the "Southern Weekend")

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The first case of AIDS discrimination in employment

20 years old this year, Anhui Normal young Xiao Wu is a graduate of this year, Anqing City in Anhui Province in May 2010, recruitment of teachers directly under the school exam, he passed the written test and interview consecutive such links, but, in the final examination process were found to test positive for HIV, re-examination after the Department of Education decided not to hire.

August 26, Xiao Wu, Anqing City, the official welcome to submit a complaint Wanjiang People's Court will Anqing City Department of Education and Human Resources and Social Council to court.

October 13, this effect is called "the first case of AIDS, employment discrimination" cases in Anqing City, Yingjiang District Court were heard in public.

Court under "General Standard for civil service recruitment examination (Trial)" provides that the plaintiff failed examination, does not meet the "teacher law" on the physical conditions in the teaching profession demands. The medical report the defendant to the plaintiff decided not to hire, the full facts, dismissed the plaintiff's claim Xiao Wu.

In this regard, Xiao Wu said he refuses to accept this verdict will be appealed. He said: "Discrimination is a wall, you need to hit a lot of people one by one."

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