2 weeks ago
Just recently, the new coronavirus mRNA vaccine launched by Moderna company in the United States is a clinical trial that claims that no animal experiment has been conducted directly. Let's analyze the case first. Moderna's new coronal vaccine mrna-1273 entered phase I clinical trials without animal experimental data, and a total of 45 healthy people are expected to be recruited for the trial. The new crown vaccine of adenovirus vector developed by Tianjin kangxinuo company and the Academy of Military Sciences is a new crown vaccine of recombinant adenovirus vector that entered the animal test in the same period in China. As far as I know, the vaccine was applied for the clinical trial after the efficacy test in mice and non-human primates. Only because of the early start time and the green light of the government, it can be put into the clinical trial very quickly It expects to recruit a total of 108 healthy people for the trial. According to the public information and time line calculation, compared with the traditional vaccine development, the two vaccines have greatly shortened the pre clinical development time due to the green light of government supervision in special period. Based on the public information, we can roughly guess what the preclinical R & D has done and what has been omitted compared with the traditional R & D path: The two companies have developed vaccines in such a short period of time. They should not have carried out comprehensive comparison and screening in the strategy of vaccine sequence construction. It is speculated that only through theoretical research, 1-2 antigen design has been designed. Both companies have their own mature vaccine development platforms and relevant complete evaluation systems or partners. They have conducted safety assessment tests on vaccine products before clinical application, mainly including safety assessment in rodents, rabbits and monkeys. Because this kind of safety assessment test is usually a fixed method, most of the tests can be completed in about one month after the product is quickly obtained. Therefore, I think both of them have done animal safety assessment test, and the results of long-term toxicity test of animal test have not been published when the application is submitted. However, because the similar products have accumulated relevant data for many times, the regulatory department may give a green light to approve first and then supplement the data Kangxinuo has done animal efficacy test, which should be able to prove that its vaccine product can induce neutralization line antibody in mice and monkeys, and neutralization line antibody detection can be completed in the Military Academy of Sciences, because it has obtained the clinical virus strain early, the establishment of neutralization line test should be carried out as soon as it gets the virus strain; and Moderna What we didn't do was just to do this part of the animal experiment. This is because on the one hand, there are special periods, on the other hand, the FDA of the United States has issued such guidance, which can ensure the safety of the premise, without the need to conduct pharmacodynamic tests in animals. This is because on the one hand, some drug development does not have animal models, and animal pharmacodynamics can not be determined; on the other hand, the results of animal experiments often do not really reflect the results in the human body. But there should be no precedent in vaccine field. According to the guidance, the scale of clinical phase I trial of Moderna must be reduced to a certain extent, that is, it can just prove its phase I clinical end point; I think this is one of the reasons why the number of clinical phase I recruitment of Moderna is far less than that of kangxinuo. To sum up, the animal pharmacodynamic test is skipped for the mRNA vaccine of Moderna, and the animal safety assessment test should be done. That is to say, the product can ensure clinical safety within a certain range, but can not guarantee its effectiveness. I think there are two possible dangers in this case: clinical phase I trial failure: this failure may be caused by two reasons: one is that there is no animal experiment, so various conditions of the clinical laboratory are not well designed, such as dose, immune times, etc., which do not first explore a reference value in the animal experiment, resulting in the drug effect is less than expected; the other may be due to I The number of recruits in phase II is small, which leads to a large deviation of results, and cannot form conclusive data enough to promote them to enter phase II clinical practice Because of the particularity of the new coronavirus: theoretically, if time permits, the vaccine should be explored in animal experiments to find out whether it can enhance the virus infection induced by the vaccine. During the development of SARS vaccine, it is found that animals immunized with SARS vaccine will have greater pathological damage when they are infected with the virus; in other words, if it is in clinical application, the severe rate of the population immunized with SARS vaccine may be higher than that of the population not immunized. However, the theory has not been confirmed in human body, but there is partial evidence in animal experiments. Therefore, since the new coronavirus is similar to SARS, it is necessary to evaluate the enhancement effect of the disease in animals to assess its risk in clinical stage. If there is no animal test, it will be a greater disaster if the critical rate increases after vaccination. In addition to the new coronavirus vaccine of Moderna mentioned above, there is also a kind of test in drug development, which also has the situation of skipping the animal pharmacodynamics test and directly entering the human trial. (of course, the premise is that safety assessment is safe, which is very important) when the efficacy of the disease cannot be assessed in animals, or there is no corresponding animal model, we can directly carry out non registered clinical research in a small range under the premise of ensuring safety, and the research fields include auto stem cell and immune cell treatment technology, gene therapy technology, and allogene Stem cell transplantation technology, tumor vaccine treatment technology, etc. With most cell therapy clinical trials in the United States, FDA's ind In China, except stem cell related non registered clinical research filed with the national health and Family Planning Commission and the State Food and drug administration, most of the clinical research of cell therapy is still in the form of the third type of medical technology, and no ind application has been submitted to the drug review department before the clinical research. More is to pass the hospital's ethical review, in clinical research nature of the trial. For example, in recent years, because of the outbreak of new coronavirus and the popularity of mRNA vaccine technology, it is well known as the Shanghai microorganism. The company is the first company engaged in the development of mRNA vaccine in China, and its technical background is also excellent. However, it is speculated that due to the high access threshold in the field of traditional vaccine, the company has not yet obtained the vaccine listing license, so its product development direction initially focused on the field of tumor vaccine. (tumor vaccine belongs to therapeutic vaccine, which is different from traditional preventive vaccine. Therapeutic vaccine should be temporarily classified as drug in China, with different regulatory methods and vaccines). The clinical data it claims to have is the non registered clinical research of its tumor vaccine products in its cooperative hospital. And because they carry out the research direction of tumor personalized vaccine mainly based on neoagent, each patient has customized treatment, of course, the pharmacodynamics of animal experiments is weak even if there are relevant data. It is more suitable for the clinical research of skipping animal experiment. Of course, on the one hand, this situation is also a helpless move. Under the framework of gradually tightening the vaccine development enterprises in China, it is almost possible for new technology and small companies to divide a cake, and they can only report to the thigh or jump out of the traditional vaccine field. If they can do well in the development of this new crown vaccine, they may have the opportunity to enter this huge market in the future and cheer them on first. Secondly, their company has chosen the direction of personalized tumor vaccine since its inception, which can be said to be very bold, because the failure rate is very high, although it is helpless, but it is also very easy to drag itself into the mire. It is hoped that they can actively explore areas other than cancer vaccine in the future, or find some reliable partners to reduce risks, which depends on their CEO's contacts and vision. Having said so much, the main question of the summary answer is: when developing vaccines, the biggest risk of skipping animal experiments and entering human trials directly lies in the failure of clinical trials, and the potential risk may be caused by the unclear mechanism of vaccines themselves, but not necessarily.