17 new crown vaccine projects of 22 institutions are under development. Who will be the antidote to the epidemic?

Author: Hohan people have been fighting against the virus for thousands of years As early as ancient Greek records, we can see that the epidemic swept through cities, but doctors at that time were helpless The emergence of vaccine makes human beings defeat virus for the first time from the perspective of prevention On the day when the who announced the eradication of smallpox, all mankind was excited by the news With the continuous introduction of vaccine products, those infectious diseases that once made people feel frightened, finally stay in the history book From SARS, mers to new coronavirus, this epidemic is the third time in the new century that we are facing the sudden attack of coronavirus In the face of fierce opponents, can vaccines play a significant role in this epidemic? What kind of vaccine will be the first to complete R & D and market? More than ten products have been used to suppress the new coronavirus Since the rapid spread of the epidemic, more than ten enterprises and institutions have begun to develop vaccines related to the new coronavirus Some of the enterprises which have made rapid progress have completed the early research and entered the stage of animal experiment Some enterprises and institutions that are developing new coronavirus vaccine, and some vaccine products that have made rapid progress in arterial network sorting, have entered the stage of animal experiment It can be seen from the statistics that the vaccine products entering the animal test stage mainly include three categories: recombinant protein vaccine, DNA vaccine and mRNA vaccine In terms of recombinant protein vaccine, the team of Institute of Microbiology of Chinese Academy of Sciences undertook the research and development task of recombinant protein vaccine in the process of vaccine research and development At present, they have designed and completed vaccine products, are testing in animals, and are carrying out related work of process research and development Based on the S protein of new coronavirus, clover pharmaceutical company developed the antigen vaccine of "s protein trimer" Although the company has not yet said that the product has entered the stage of in vivo test, the antigen has been detected in the serum of many patients with virus infection after recovery In terms of DNA vaccine, the DNA vaccine jointly developed by inoviopharmaceutical, adnexine, Kangtai biology and other companies has also entered the stage of animal experiment It is said that the technology platform of inovio only needs three hours to complete the sequence research and development of DNA vaccine, and the vaccine research and development of Zika virus, Ebola virus, mers and other epidemic viruses have been carried out before These vaccines have achieved good results in mouse experiments In the aspect of mRNA vaccine, the research work of new coronavirus mRNA vaccine has been announced almost at the same time by domestic microorganisms and American Moderna, and then the candidate vaccine has entered the stage of animal experiment on February 7 and February 10, respectively Most of the other vaccine research and development work that has not yet disclosed more information also focuses on these three vaccine types, especially recombinant protein vaccine and mRNA vaccine, which has become the research focus of this epidemic The experience accumulated in the past research and development of coronavirus vaccine has been applied to this epidemic in the past SARS epidemic, and vaccine research and development has also been the focus of attention However, due to the limitation of technology, the choice of vaccine type was very limited at that time, and the research and development progress was relatively slow The phase I clinical trial of SARS inactivated vaccine in China was not completed until December 2004 and the results were disclosed Although the vaccine has good safety in clinical trials and has initially proved its effectiveness, it is one and a half years since the SARS epidemic ended During the MERS epidemic, people also placed high hopes on the vaccine industry Since its first discovery in 2012, mers virus has been causing sporadic infectious diseases for 7 consecutive years However, it was not until 2015 that researchers in the United States released the research and development results of mers vaccine, which achieved good results in animal experiments The progress of clinical trials is also affected by the dispersion of patients The results of phase I clinical trials of mers virus vaccine were first reported in the Lancet Infectious Diseases in 2019 After two coronavirus attacks, we now know our opponents better Previous research experience on SARS and mers vaccines has been applied to the research and development of new coronavirus vaccines to speed up the research and development of vaccines Yan Jinghua, a researcher at the Institute of Microbiology, Chinese Academy of Sciences, mentioned in the relevant interview that their team has studied mers vaccine in the past two years and has achieved some good results in the design process When the new coronavirus came, they quickly used the relevant strategies and methods in the design of the new coronavirus vaccine "We have been engaged in research on mers virus, influenza virus, tuberculosis virus and other aspects since 17 years ago," said Dr Li Hangwen, CEO of SMIC, in an interview with aonet In particular, mers virus and the new coronavirus belong to the same coronavirus family Our research experience in mers is very helpful for the vaccine development For example, in the design of antigens and dosage forms, we chose s protein as the main antigen and optimized the design of related dosage forms in the vaccine development of mers protein In this outbreak, S protein was immediately labeled as an antigen protein that we need to focus on, and we can also directly apply our dosage form of mers vaccine " S protein is novel coronavirus Spikeprotein The key to infection of human coronavirus is human S binding to ACE2 protein S protein plays the same role in SARS virus and mers virus In the past decade, scientists have done a lot of research on the S protein of SAR virus and mers virus Therefore, in this new coronavirus epidemic situation, scientific research institutions soon responded and began to analyze the S protein in the new coronavirus On February 15, a team from the University of Texas in the United States published a paper on biorxiv, which has used frozen electron microscopy to analyze the structure of the new coronavirus s protein and its affinity with ACE2 In such a short time to complete this research, in addition to the assistance of new technology, the previous research accumulation of S protein is also crucial In addition to the aforementioned s-organisms and Clover organisms, the candidate vaccine mrna-1273 of Moderna also encodes s s s protein All three companies have been engaged in the research and development of mers virus vaccine, and they know s protein as well as their fingers With the help of new technology and previous experience, researchers can complete the early development of vaccine within two to three weeks after acquiring the virus sequence, and quickly enter the animal experiment stage At present, several products that have entered the animal experiment stage will probably enter the clinical trial stage around mid April at the earliest So what are the differences between these different kinds of vaccine products? Who is most likely to be the top? In the past few decades, we have witnessed the development of various new vaccine technologies From live attenuated vaccine with weakened toxicity after specific treatment, to peptide antigen vaccine produced by bioengineering technology, to nucleic acid vaccine based on nucleic acid delivery technology, new biotechnology is increasingly used in the process of vaccine development These different kinds of vaccines have their own advantages and disadvantages, and there is no general optimal solution 1 Inactivated virus vaccine the inactivated virus vaccine is obtained by heating or chemical methods The inactivated virus lost its virulence and retained the main antigenic characteristics of the virus shell, which could stimulate the specific immune response of human body The R & D process of inactivated virus vaccine is very simple and clear Without conceptual design and verification, we only need to find a suitable method of virus inactivation to quickly complete the preparation of vaccine products But from the past experience, inactivated vaccine may produce serious adverse reactions For example, respiratory syncytial virus (RSV), its inactivated vaccine in the mid-1960s has been related to clinical trials, but the vaccine has increased the condition of the subjects More than half of the vaccinated children returned to the hospital for treatment and even died Therefore, although the inactivated virus vaccine has made some achievements in the clinical trials related to SARS virus, it is still necessary to be careful when using the inactivated virus vaccine in the new coronavirus epidemic situation 2 Live attenuated vaccine the live attenuated vaccine processes the pathogen by specific means to make it mutate, and then passes the virus on to the next generation, selects the less toxic strains from the next generation, and continues to repeat the above process until it obtains the strains that will not cause the disease Live attenuated vaccine has stronger immunity and longer action time than inactivated vaccine But its shortcomings are also obvious It is difficult to complete the early product development in a short period of time due to the long process of pathogen generation and screening Based on such characteristics, live attenuated vaccine may not be able to meet the needs of current epidemic control 3 Recombinant protein vaccine recombinant protein vaccine is a kind of gene sequence which can express virus surface antigen It can be transferred into prokaryote by means of gene engineering, so that it can express antigen protein in large quantities Then the expressed antigen protein was extracted and purified for inoculation Recombinant protein vaccine has been widely used in clinical practice For example, HBsAg is used as recombinant protein vaccine in common hepatitis B vaccine Its biggest advantage is that the enriched and even modified recombinant antigen protein has a strong immunogenicity, and the production process has been relatively mature On the other hand, the recombinant protein vaccine can only use one protein antigen at present, and it will lead to some nonspecific immune responses, which are all factors limiting the development of recombinant protein vaccine Based on the mature sequencing analysis technology, at the beginning of the epidemic development, the major scientific research institutions headed by the Chinese Academy of sciences have isolated new coronavirus strains from patients and carried out the relevant sequencing analysis The antigen sequence screened from the sequencing results can be directly used in the production of recombinant antigen protein Therefore, the research and development of recombinant antigen protein vaccine is progressing smoothly, and the relevant achievements of Yan Jinghua's research team have entered the stage of animal experiment 4 Three different vaccines, virus vector vaccine, DNA vaccine and mRNA vaccine, are very similar in biological mechanism They all deliver gene sequence encoding antigen protein to human body, use human cells to produce virus antigen, and cause specific immune response of human body DNA vaccine and mRNA vaccine are mainly delivered in non biological way, such as packaging with nano materials; virus vector vaccine is to package nucleic acid in virus shell which has been removed toxicity, and deliver nucleic acid to cell interior through biological methods, commonly used virus vectors include adenovirus, measles virus, etc The development of virus vector vaccine is the most complex of the three new biological vaccines It is not only necessary to select the right antigen, but also the right vector virus In addition, the virus vector itself can also cause the immune response of the body, so its impact on the human immune system is much more complex DNA vaccine and mRNA vaccine use the general packaging shell to shorten the development time of the dosage form obviously; at the same time, the use of human own cells to produce virus antigen can also ensure that human body has more specific immune response, rather than non-specific immune response under the stimulation of external factors.