Author: John Hao.

Humans have been fighting the virus for thousands of years. As far back as ancient Greek records, we can see that the epidemic has swept across cities, but doctors at the time were helpless.

The emergence of vaccines has enabled humans to defeat the virus for the first time from a prevention perspective. The day when WHO announced that smallpox was eliminated, all humans were excited about the news. With the continuous introduction of vaccine products, those infectious diseases that have made people scared have finally stopped in the history books.

From SARS and MERS to the new coronavirus, this epidemic is already the third time we are facing a sudden attack of coronavirus in the new century. In the face of aggressive opponents, can the vaccine show its power in this outbreak? Which vaccine will be the first to complete the development and marketing?

More than a dozen products have been contaminated by the new crown virus, and the vanguard has carried out animal experiments

Since the epidemic has spread rapidly, more than a dozen companies and institutions have begun research and development of new coronavirus-related vaccines. Some of the companies that have made rapid progress have completed early research and entered the animal experiment stage.

Some enterprises and institutions that are developing new crown virus vaccines are organized by Arterial Network

Some of the vaccine products that have made rapid progress have entered the animal experiment stage. It can be seen from statistics that the vaccine products entering the animal test stage mainly include three major categories of recombinant protein vaccines, DNA vaccines and mRNA vaccines.

In terms of recombinant protein vaccines, the team of the Institute of Microbiology of the Chinese Academy of Sciences undertook the task of research and development of recombinant protein vaccines during this vaccine development process. At present they have designed and completed vaccine products,Tests are performed in animals, and work on process development is ongoing.

Shamrock Pharmaceuticals has developed an “S protein-trimer” antigen vaccine based on the S protein of the new crown virus. Although the company has not said that the product has entered the in vivo test phase, the antigen has detected virus-specific antibodies in the serum of multiple patients with viral infection after recovery.

In terms of DNA vaccines, DNA vaccines co-developed by companies such as Inovio pharmaceutical, Ai Weixin, and Kangtai Biological have also entered the animal experimental stage. It is said that Inovio’s technology platform can complete the sequence development of DNA vaccines in only three hours, and has previously carried out the development of vaccines for epidemic viruses such as Zika virus, Ebola virus and MERS. These vaccines have achieved relatively good results in mouse experiments.

In terms of mRNA vaccines, domestic S. microbes and Moderna in the United States announced the launch of new crown virus mRNA vaccine research at the same time, and subsequently announced on February 7 and February 10, respectively, that candidate vaccines have entered animal experimental stages .

Other vaccine development efforts that have not disclosed more information have mostly focused on these three vaccine types, especially recombinant protein vaccines and mRNA vaccines, which have become the focus of research in this epidemic.

The experience accumulated in the past research and development of coronavirus vaccines has been applied to this epidemic

In the past SARS epidemic, vaccine research and development has also been the focus of attention. However, due to technical constraints, the choice of vaccine types at that time was very limited, and research and development progress was relatively slow. The phase I clinical trial of the SARS inactivated vaccine in China was not announced until December 2004 and the results were disclosed. Although the vaccine has been clinically safe and has initially demonstrated effectiveness, it has been a year and a half since the end of the SARS epidemic.

During the epidemic of the MERS virus, people also placed high hopes on the vaccine industry. Since the first detection of the MERS virus in 2012, it has continued to cause sporadic infectious diseases for 7 consecutive years. However, it was not until 2015 that U.S. researchers announced the results of the MERS vaccine development, which has shown good results in animal experiments. The progress of clinical trials has been affected by the scattered distribution of patients. The results of the first-phase clinical trial of the MERS virus vaccine were not reported for the first time in the 2019 Lancet Infectious Diseases.

One of the two coronavirus attacksLater, today we know our opponents better. Previous research experience on SARS and MERS vaccines has been applied to the development of new crown virus vaccines, accelerating the speed of vaccine development.

Researcher Yan Jinghua of the Institute of Microbiology, Chinese Academy of Sciences mentioned in a related interview that their team has studied the MERS vaccine in the past two years and achieved some good results in the design process. When the new crown virus hit, they soon applied related strategies and methods to the design of the new crown virus vaccine.

Dr. Hangwen Li, CEO of S. Microbiology, also mentioned in an interview with Arterial.com: “We have been engaged in research on MERS virus, influenza virus, tuberculosis virus, etc. since 17 years. In particular, MERS virus and this new crown The viruses belong to the coronavirus family. Our research experience on MERS has greatly helped this vaccine development. For example, in the design of antigens and dosage forms, we chose S protein is used as the main antigen and the design of related dosage forms has been optimized. In this outbreak, S protein was immediately marked by us as the antigen protein that needs to be focused on, and we can also directly apply our dosage form for MERS vaccine. / p>

The S protein is called spike protein. The key to the infection of human cells by the new coronavirus lies in the binding of S protein and ACE2 protein. In SARS and MERS viruses, the S protein also plays the same role.

For the S protein of SAR virus and MERS virus, scientists have carried out a lot of related research in the past ten years. Therefore, in this new crown epidemic, scientific research institutions soon responded and began to analyze the S protein in the new crown virus. In a paper published on February 15th by a team from the University of Texas in BioRxiv, cryo-electron microscopy has been used to analyze the structure of the new crown virus S protein and analyze its affinity with ACE2. Being able to complete this research in such a short time, in addition to the assistance of new technologies, the accumulation of research on S protein in the past is equally important.

In addition to the previously mentioned strains of microorganisms and clover, mRNA-1273, a candidate vaccine for Moderna, also encodes the S protein. All three companies have carried out research and development of the MERS virus vaccine, and are well aware of the S protein.

With the help of new technology and previous experience, researchers can complete the early development of vaccines within two to three weeks after acquiring the virus sequence, and quickly enter the animal experiment stage. Several products that have entered the animal experiment stage at the earliest will probably be introduced around mid-AprilInto clinical trials.


So what are the differences between these different types of vaccine products? Who is most likely to win?

In the past few decades, we have witnessed the development of a variety of new vaccine technologies. From live attenuated vaccines with reduced toxicity after specific treatment, to peptide antigen vaccines produced by bioengineering technology, to nucleic acid vaccines based on nucleic acid delivery technology, new biotechnology is increasingly being used in vaccine development. Each of these different types of vaccines has its own advantages and disadvantages, and there is no universal optimal solution.

1. Inactivated virus vaccine

Inactivated virus vaccine uses heat or chemical methods to inactivate the virus obtained in culture. The inactivated virus loses its pathogenic toxicity while retaining the main antigenic characteristics of the virus shell, which can stimulate the body’s specific immune response.

The research and development process of inactivated virus vaccines is very simple and clear. There is no need for concept design and verification. You only need to find a suitable method for virus inactivation to quickly complete the preparation of vaccine products. However, from past experience, inactivated vaccines may have serious adverse reactions.

For example, respiratory syncytial virus (RSV) , its inactivated vaccine has undergone relevant clinical trials in the mid-1960s, but Instead, the subject’s condition was aggravated. More than half of the vaccinated children returned to the hospital for treatment and even died. Therefore, although inactivated virus vaccines have achieved certain results in clinical trials related to SARS virus, the use of inactivated virus vaccines in the new crown virus epidemic still requires caution.

2. Live attenuated vaccine

Live attenuated vaccines treat pathogens by specific means to mutate them, then pass the virus on, and select less virulent strains from the offspring, and continue to repeat the above process until a virus that does not cause disease occurs Strain.

The live attenuated vaccine is more immune than the inactivated virus vaccine and has a longer duration of action. But its shortcomings are also obvious. Passaging and screening of early pathogensThe process is very long and it is difficult to complete early product development in a short period of time. Based on such characteristics, live attenuated vaccines may not be able to address the current need to control the epidemic.

3. Recombinant protein vaccine

Recombinant protein vaccine is a gene sequence capable of expressing viral surface antigens, which is transferred into prokaryotes by means of genetic engineering, so that it can express antigen proteins in large quantities. The expressed antigenic protein is extracted and purified for inoculation.

Recombinant protein vaccines have been widely used in clinical applications. For example, the commonly used hepatitis B vaccine uses hepatitis B surface antigen HBsAg as a recombinant protein vaccine. Its biggest advantage is that the recombinant antigen protein that has been enriched or even modified has strong immunogenicity, and the production process is now relatively mature. However, on the other hand, recombinant protein vaccines can only use one protein antigen at present, and will trigger some non-specific immune responses in the body. These are the factors that restrict the development of recombinant protein vaccines.

Based on mature sequencing analysis technology, major scientific research institutes headed by the Chinese Academy of Sciences have already isolated New Coronavirus strains from patients and performed related sequencing analysis at the beginning of the epidemic. The antigen sequences selected from the sequencing results can be directly used for the production of recombinant antigen proteins. Therefore, the research and development of recombinant antigen protein vaccine is progressing smoothly, and the relevant results of researcher Yan Jinghua’s team have entered the animal experiment stage.

4. Viral vector vaccine, DNA vaccine, mRNA vaccine

The three different vaccines are very similar in biological mechanism. They all deliver gene sequences encoding antigen proteins to the human body, use human cells to produce viral antigens, and cause the body’s specific immune response.

DNA vaccines and mRNA vaccines are mainly based on non-biological delivery methods, such as packaging with nanomaterials. Viral vector vaccines are packaged with nucleic acids in a virus shell that has been detoxified. Biological methods deliver nucleic acids into cells. Commonly used viral vectors include adenovirus, measles virus, and so on.

The development of viral vector vaccines is the most complex of these three new biological vaccines. Not only need to screen out the appropriate antigen, but also the selection of the appropriate vector virus. And the viral vector itself can cause the body’s immune response, so its impact on the human immune system is much more complicated.

Universal packaging for DNA and mRNA vaccinesThe shell significantly shortens the development time of the dosage form. At the same time, the use of human cells to produce viral antigens can also ensure that the human body develops more specific immune responses, rather than non-specific immune responses generated by external factors. However, neither DNA vaccine nor mRNA vaccine has been approved for marketing. (Veterinary vaccine approved) The potential problems with vaccines are not fully understood.

For two types of nucleic acid vaccines, DNA fragments introduced by DNA vaccines have long-term persistence. Some studies have shown that these DNAs can exist for up to 2 years. The presence of foreign genetic information in the nucleus carries the risk of integration into the host’s genome, which can cause mutations and even cancer.

The mRNA itself is easily degraded, so there is no problem affecting gene recombination. However, in related clinical trials of mRNA vaccines, some patients experienced adverse reactions to varying degrees, which also made the use of mRNA vaccines in large areas possible.

Comparison of advantages and disadvantages of different types of vaccines

In summary, we have summarized a number of different vaccines. In response to this epidemic, the slowest development of live attenuated vaccines and viral vector vaccines can basically be excluded. There is no progress disclosure of inactivated virus vaccines, but in related reports from the Ministry of Science and Technology, inactivated virus vaccines are among the technical routes arranged by them.

The remaining three, Recombinant protein vaccines, mRNA vaccines, and DNA vaccines have been quickly followed up by relevant companies and research institutions, and have achieved staged results.

After the early development, there is no obvious difference between the three vaccines in the subsequent animal experiments and clinical trials. But restructuringProtein vaccines also need to be developed in production processes, which may slow down the progress of their clinical trials. Therefore, we believe that mRNA vaccine and DNA vaccine are more likely to be the first vaccine products to complete clinical verification in this epidemic.

In excitement, we still have to ask a few more questions

The rapid development of new crown virus vaccine development is indeed very encouraging. But in addition to excitement, vaccine development was not an overnight task. Compared with the complete vaccine development process, the vaccine sample developed in the early research has just completed the first step of vaccine development.

After a vaccine has completed the early proof-of-concept in the laboratory, it will need to carry out complex process development, animal experiments, clinical trials, and application approval in order to finally obtain approval from the State Drug Administration For specific prevention or treatment sessions.

For example, on February 7th, Microbe announced that a sample of the candidate vaccine had been sent to the Virus Institute of the Chinese Center for Disease Control and Prevention and Dongfang Hospital of Tongji University for further animal experiments. test. Assume that according to the development of the epidemic, the duration of the phase I clinical trial is controlled to three months, and we will not get the preliminary clinical results of this vaccine until July of this year at the earliest. But according to the past epidemic development, the new crown virus epidemic may end this summer, and this vaccine may eventually not be used for epidemic prevention and control.

With regard to this, Li Hangwen expressed his views: “It is really a big challenge to make a vaccine before the epidemic ends. Of course, we also very much hope that the epidemic will end as soon as possible. But this epidemic is currently The several situations that have been shown so far are different from the past. For example, the existence of intermediate hosts and asymptomatic infections has not yet been determined, which may cause certain hidden dangers to the large-scale spread of the epidemic. Therefore, our vaccine research and development work actually It is preparing for the worst for the development of the epidemic. “

In fact, in addition to the vaccine development of the new crown virus, in addition to controlling the epidemic, it will also be used as a vaccine reserve to prevent a large-scale epidemic of the new crown virus in the future. Therefore, in any case, the development of a new crown virus vaccine has its practical value. The reason why the vaccine research and development should be completed as soon as possible, in addition to putting into use as far as possible before the outbreak of the epidemic, clinical trials of the vaccine must be considered. If the vaccine development time is too long, beyond the duration of the epidemic, it is likely that clinical trials will be halted because there are no patients, and research and development will be suspended.

On the other hand, if the vaccine product can last for the duration of the outbreak,The verification is completed within whether large-scale vaccine production can be completed in a short period of time is another issue worthy of attention . Recombinant protein vaccines have been widely used in clinical practice, and the relevant production technology has also been relatively mature. However, for new technology products such as viral vector vaccines, DNA vaccines, and mRNA vaccines, related production capacity may be difficult to meet clinical needs.

With regard to this issue, Li Hangwen expressed different views: “Although mRNA vaccines are an emerging field, due to the use of new formulation technologies and synthetic technologies, great progress has been made in mass production in recent years; Synthesized, we can also initially meet the needs of large-scale clinical trials, and the production capacity can be expanded rapidly. So we are more confident about the future supply of vaccines. ” ; “> p>