结核病研究:不要重蹈艾滋病覆辙

结核病研究:不要重蹈艾滋病覆辙

 
 
 
 
 

结核病研究:不要重蹈艾滋病覆辙
2009年04月03日08:31  来源:《科学时报》

  我们应该吸取默克公司艾滋病疫苗失败的教训,将阐释基础科学问题作为根本和首要任务。

  结核病研究:

  不要重蹈艾滋病覆辙

  中国医学科学院病原生物学研究所(以下简称病原所)是国家为加强传染病防控体系,对传染病科研布局进行调整后,于2003年12月批准新建的唯一专门从事传染病基础与应用基础研究的国家级科研单位。

  在病原所,每个月有一次结核病沙龙,来自不同研究方向的科研人员聚在一起,共同探讨结核病的最新研究进展。日前,《科学时报》特别就结核病的基础研究现状采访了病原所研究员金奇和4位课题负责人。

  快速早期诊断的技术瓶颈

  《科学时报》:结核病的病理是怎样的?为什么说结核病的发现比较难?在早期诊断上,需要什么样的检查确定患者患有结核病?

  病原所:到目前为止,临床上呼吸系统结核的临床诊断标准仍然是在显微镜下直接观察结核分枝杆菌的痰涂片法,这一技术已经沿用了100年。但是,痰标本细菌学检查的灵敏度非常低,阳性率只有20%至30%,临床上主要还根据临床症状和影像学资料来综合诊断结核病。结核病及耐药结核病的简单、快速、敏感的诊断技术,是全球结核病控制中亟待解决的难题之一。

  《科学时报》:在结核病诊断手段研究中,目前是否有更先进的方法?有哪些突破口?

  病原所:研究人员利用各种新兴的分子生物学以及现代免疫学理论和技术,已经开发出一些有希望的检测方法,比如快速分枝杆菌全自动培养和检测、噬菌体生物扩增法和噬菌体生物发光法、利用DNA或者RNA的扩增技术、利用新型免疫学方法等,以及建立在结核分枝杆菌耐药分子机制基础上的基因突变检测技术,但目前只能检测异烟肼及利福平两种耐药基因型。

  目前,国内外对结核病和耐药结核病早期诊断技术的研究与开发均处于实验室和临床参考阶段。实现结核病快速、早期诊断的技术瓶颈问题是已知的分子标识太少。

  但乐观的一面是,结核分枝杆菌约有4000个基因,目前综合利用免疫学技术和生命组学技术证实,确有免疫原性的抗原组分可能只有30多个。因此,为结核杆菌分子标识(包括高通量发现新的耐药基因突变位点)和保护性抗原的筛选提供了广阔的研究空间。

  疫苗研发应以阐释基础科学问题为本

  《科学时报》:通用的结核病疫苗——卡介苗问世已经超过88年,之后一直没有研制其他新型结核病疫苗。在结核病疫苗方面,儿童与成人的区别是什么?美国的儿童不接种卡介苗,为什么却成为我国新生儿出生后接受的第一针药物?

  病原所:1921年,法国学者Albert Calmette和Camille Guérin研究出了可以用于预防结核病的减毒活疫苗——卡介苗(BCG)。1928年以后,卡介苗在全世界广泛使用,仍然是目前唯一可用于预防结核病的疫苗,是我国新生儿出生后的第一针。自20世纪中期,美国等一些结核病负担弱的国家认为,接种BCG会影响采用皮试方法诊断结核病的正确性,因此,不再推广对新生儿普遍接种卡介苗。

  卡介苗确实对儿童播散性结核有一定的保护效果,但是,其免疫效果在接种10年以后逐步减退。在世界各国进行的数十次临床试验结果显示,BCG对肺结核的免疫保护力是80%~0%。现在普遍认为,BCG对成人结核保护效果不理想。尽管国际上对接种BCG预防肺结核的效果持怀疑态度,但是WHO仍然坚持在新生儿中接种BCG,主要是因为它的安全性和对儿童重症结核病,如粟粒型结核和结核性脑膜炎具有预防保护作用。

  《科学时报》:经过这么多年,为什么没有更为有效的新疫苗推出?存在的顾虑都有哪些?我国在这方面都做了哪些工作?对于下一代新型结核病疫苗的研制,现在世界研究的趋势是什么?

  病原所:结核病疫苗的研究方向,已由早期单一寻找优于卡介苗的替代疫苗,逐渐过渡到针对不同人群研究不同类型的疫苗,研发出一种具有更长久免疫保护效果的新疫苗来取代BCG;或者是研发出一种疫苗来加强正在减弱的免疫反应,以达到对成人的免疫保护。

  现在,国内外学者正纷纷利用分子生物学和组学等技术,寻找更加有效的抗原组分来进行抗原组合,以及改进载体和增强佐剂效果等来提高免疫保护效果,包括保护性疫苗、治疗性疫苗等。

  但是,由于还不清楚结核病的发病机制和细胞免疫保护机制,这在很大程度上限制了疫苗研究的进度,也在一定程度上造成了疫苗研究的盲目性。

  科学家们已经意识到,仅用目前公认的γ干扰素(IFN-γ)作为评估指标无法清晰评估疫苗的效果。所以,在过去的几年中,尽管有几株疫苗已经开展了临床I期实验,并且有1~2株已经初步进入II期临床试验,但是,科学家们仍然无法肯定其保护效果优于卡介苗。

  在结核病疫苗研究这个问题上,我们应该吸取默克公司在艾滋病疫苗上失败的教训,将阐释基础科学问题作为根本和首要任务。

  系统管理和患者坚持是关键

  《科学时报》:结核病的耐药性近年来制约了结核病治疗过程中的药物选择余地。有资料显示,目前全球至少已有37个国家报告发现了广泛耐药结核病病例,产生耐药性的原因是什么?

  病原所:这几十年国际上一直都没有新的抗结核药物出现。而且,有效治疗复发和耐药肺结核病人的治疗方案没有得到深入研究和优化。

  现今威胁最严重的耐药结核病的产生和扩散,主要就是因为结核病人服药不规律、治疗不合理和对病人缺乏有效管理。

  耐药结核的诊断困难、治疗时间长、治疗费用高、治愈率低、不良反应发生率高、死亡率高,尤其是广泛耐多药结核病更是几乎无药可治。更为严重的是,耐药结核病人可作为传染源直接传播耐药结核分枝杆菌,进而使耐药结核病人数成倍增加。

  全社会长期以来对结核病防治工作的忽视,社会关注减少,宣传工作不足,群众对结核病缺乏防治知识,警惕性下降,有病不能及时发现、早期诊断和正确治疗,是导致这种情况发生的重要原因。

  《科学时报》:目前治疗耐药性结核病的主要手段有哪些?是否有新的进展?对于已经产生耐药性的结核病人,现在应该如何继续治疗?

  病原所:虽然我国结核病的治愈率比较理想,但是对于耐药结核病、复发、复治结核病以及与艾滋病病毒合并感染的结核病人的治愈率非常低,比如耐多药结核病的治愈率估计只有25%左右。而且,目前使用的一线药物治疗时间长,一般达到6至8个月以上,并且副作用大,造成病人依从性差而容易产生耐药;同时,对耐多药结核病,特别是广泛耐多药结核病现在仍然没有有效的药物和治疗方案,对于病人来说,得了耐多药结核病,等于是判了“死刑”,病死率很高。因此研制新药迫在眉睫。

  虽然,结核耐药性分子机理的阐述还不全面,但已现曙光。比如:利用生物大分子结晶结构生物学的实验方法,已经将内酰胺水解酶和药物分子复合物的高解析度三维结构解析出来。这一结构精确展示了内酰胺水解酶降解药物分子的瞬间,这无疑为理解耐药性机理和新药设计提供了新的线索。由此例可见,结构生物学能够为病原生物学的研究提供一个独特的原子水平的微观视野。随着结核耐药性和药物靶位研究的推进,更多的药物相关蛋白质分子将会被筛选出来。解析这些蛋白质分子的结构以及药物和蛋白质的共结构,将为发现耐药性新机制或确认新药靶位提供有力支持。

  尽管现在人们对耐药结核病“谈病色变”,但研究数据表明,坚持积极治疗还是能做到减少死亡率,并防止耐药菌株进一步传播的。所以,我们还是说,系统管理和患者坚持是关键。(王莉萍)
 

TB Study: AIDS not to repeat mistakes
At 8:31 on April 3, 2009 Source: "Science Times"

Merck & Co., Inc. we should learn from the lessons of the failure of AIDS vaccine, will explain the basic science questions as the fundamental and primary mission.

TB research:

AIDS not to repeat mistakes

Pathogen Biology Chinese Academy of Medical Sciences Research Institute (hereinafter referred to as pathogens) to strengthen the country are communicable diseases prevention and control system for infectious disease research to adjust the layout after the December 2003 approval of the new Unique specializes in infectious diseases and application of basic basic research units in national research.

At the pathogen, there is a TB per month Sharon, from the direction of different research scientists together to discuss the latest research progress in tuberculosis. A few days ago, "Science Times" in particular in basic research on the status of tuberculosis pathogen researcher interviewed four topics Jin and responsible person.

Express the early diagnosis of the technical bottlenecks

"Science Times": the pathology of TB is like? Why do I say that the discovery of TB more difficult? Up in the early diagnosis, what kind of inspection required to identify patients suffering from tuberculosis?

Pathogen by: So far, clinical respiratory tuberculosis on clinical diagnostic criteria are still under the microscope at direct observation of the Mycobacterium tuberculosis sputum smear method, this technology has been in place for 100 years. However, bacteriological examination of sputum specimens is very low sensitivity, the positive rate was only 20-30%, mainly based on clinical symptoms and imaging data to study the diagnosis of tuberculosis General. TB and XDR-TB in a simple, rapid and sensitive diagnostic techniques, the global TB control are in urgent need of solution of one problem.

"Science Times": At the diagnosis of TB means of study, whether there are more advanced methods? What a breakthrough?

Pathogen by: researchers use a variety of new molecular biology and immunology of modern theory and technology, has developed a number of promising detection methods, such as automatic cultivate Mycobacterium Express and testing, phage amplified biologically assay and phage biology assay, using DNA or RNA amplification techniques, the use of new methods, such as immunology, as well as set up in the drug-resistant Mycobacterium tuberculosis on the basis of the molecular mechanism of mutation detection techniques, but detection of isoniazid and rifampin only two types of drug-resistant genotypes.

At present, both at home and abroad for drug-resistant tuberculosis and tuberculosis research and development of early diagnostic techniques are in clinical reference laboratories and stage. TB achieve rapid and early diagnosis of the technical bottlenecks are too little known molecular identity.

But the positive side, Mycobacterium tuberculosis, about 4000 genes, the current utilization of technology and life Immunology Study Group Technology confirmed that indeed there is the immunogenicity of the antigen may be more than 30 components. Therefore, molecular identification of Mycobacterium tuberculosis (including high-throughput discovery of new resistance gene mutation) and the protective antigen screening study provides a broad space.

Vaccine research and development should be to explain the basic science-oriented questions

"Science Times": a common tuberculosis vaccine - Bacillus Calmette-Guerin has been available more than 88 years after the other has not been a new type of TB vaccine development. Tuberculosis vaccine, the children and adults What is the difference? Children in the United States are not vaccinated, why our country has become after the birth of the first needle drugs?

Pathogen by: 1921, French scholar Albert Calmette and Camille Guérin developed that could be used for the prevention of tuberculosis vaccine - Bacillus Calmette-Guerin (BCG). After 1928, widespread use of BCG in the world still is the only available vaccine for the prevention of tuberculosis, is our country after the birth of the first needle. Since the mid-20th century, the United States and other weak TB burden countries believe that BCG vaccination may affect the use of TB skin test the accuracy of diagnosis, therefore, not the promotion of universal BCG vaccination of the newborn.

BCG is indeed disseminated tuberculosis in children must have a protective effect, but the effect of the immune at vaccination gradually decreased after 10 years. At dozens of countries in the world of clinical trials carried out showed that, BCG immunization against tuberculosis protection force are 80% ~ 0%. Now generally agreed that, BCG tuberculosis protective effect of adults is not ideal. Despite the international recognition of the vaccination effect of BCG against tuberculosis skeptical, but still insists on WHO in vaccination in the neonatal BCG, mainly because of its safety and for children with severe tuberculosis, such as miliary tuberculosis and tuberculous meningitis prevention protection role.

"Science Times": after all these years, why not a more effective introduction of new vaccines? What concerns exist? Our country in this regard, what job to do? For the next generation of new tuberculosis vaccines, study the trend of the world are what?

Pathogen by: TB vaccine research has been looking for an early single alternative is better than BCG vaccine, a gradual transition to study different populations for different types of vaccines, to develop a more long-term effects of immune protection of new vaccines to replace BCG; or to develop a vaccine to enhance the immune response is weakened in order to achieve protective immunity in adults.

Now, scholars are at home and abroad have been using molecular biology and genomics technologies such as looking for a more effective component of the antigen to antigen combinations, as well as to improve and enhance the carrier such as adjuvants to enhance the immune effect of the protective effect, including the protection of the vaccine, treatment of vaccine.

However, because of unclear pathogenesis of tuberculosis and cellular immune mechanisms of protection, to a large extent limited the progress of vaccine research, but also to some extent resulted in blindness in vaccine research.

Scientists have realized that only IFN-γ is currently recognized (IFN-γ) can not be a clear target for evaluating the effectiveness of the vaccine evaluation. Therefore, in the past few years, even though there is Several vaccines have been carried out Phase I clinical experiments, and there is 1 ~ 2 has entered the preliminary phase II clinical trials, but scientists are still not sure of its protective effect is superior to BCG.

In tuberculosis vaccine research on this issue, we should learn at an AIDS vaccine Merck & Co., Inc. on the lessons of failure, will explain the basic science questions as the fundamental and most important task.

System management and patients are key to insist

"Science Times": the drug resistance of tuberculosis in recent years has constrained the process of TB drug treatment choice. Data show that at least the world in 37 countries found cases of extensively drug-resistant tuberculosis, resistance of the reasons for that?

Pathogen by: the international community over the past few decades has not emerged a new anti-TB drugs. Moreover, the effective treatment of recurrent and drug-resistant tuberculosis patients in the treatment program did not receive in-depth study and optimization.

Nowadays the most serious threat to the emergence of drug-resistant tuberculosis and the spread of TB is mainly because people do not take the law of unfair treatment and lack of effective management of the patient.

Difficult diagnosis of drug-resistant tuberculosis, treatment of long hours and high cost of treatment, the cure rate low, the high incidence of adverse reactions, high mortality, especially in a wide range of multi-drug resistant TB is almost no cure. Even more serious, drug-resistant TB can be spread as a direct source of infection of Mycobacterium tuberculosis drug resistance, so that doubled the number of drug-resistant tuberculosis.

Society-wide prevention and treatment of TB has long been neglected by society to reduce the concern, lack of publicity, a lack of people on TB prevention and control knowledge, decreased vigilance, the sick can not be found in time, early diagnosis and proper treatment, cause this to happen are the important reasons.

"Science Times": At present, the treatment of drug-resistant tuberculosis which has the primary means? Whether or not there is new progress? For those who have been resistant TB now should be how to continue treatment?

By pathogen: Although my country a good cure rate of TB, but drug-resistant tuberculosis, relapse, re-treated TB and HIV co-infection of TB cure rate is very low, such as MDR-TB cure rate is estimated Only about 25%. Moreover, the currently used first-line drug therapy a long time to reach the general 6-8 months or more, and side effects, resulting in poor compliance of patients prone to drug resistance; At the same time, multi-drug resistant TB, especially MDR-TB wide now still no effective drugs and treatment programs for patients who had MDR-TB, and then sentenced to "death", the high fatality rate. Therefore urgent to develop new drugs.

Although the molecular mechanism of TB drug resistance is not fully elaborated, it has现曙光. For instance: the use of biological macromolecules crystallization experiments structural biology methods, within already amidohydrolase and drug molecular complex analytic high-resolution three-dimensional structure out. This structure demonstrated with precision amidohydrolase instantaneous degradation of drug molecules, which is no doubt that understanding the mechanism of drug resistance and new drugs designed to provide a new clue. This Example can be seen that structural biology to the study of pathogen biology provide a unique vision of the micro-atomic level. With the TB drug resistance and drug targets to promote the study, more drug-related protein molecules will be screened out. Analysis of the structure of these protein molecules, as well as drugs and the total protein structure, drug resistance will be found or confirm a new mechanism to provide strong support for new drug targets.

Even though people on the drug-resistant tuberculosis is now "terribly sick talk", but research data shows that the active treatment or insist can reduce mortality and prevent further spread of drug-resistant strains. So, we said that the system management and patients insist is the key. (Wang Liping)

个人简介
协和专家门诊部艾滋病治疗中心主任、教授、专家,中医药疑难病专治网站长等。论文《艾滋病中医论治探析》登载《中国性病艾滋病》2003版杂志,发明的艾滋病治疗新药康生丹自2002年临床应用至今疗效显著,现有中国唯一艾滋病新药3代…
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