Really 丨 How many vaccines are there in global new coronavirus vaccine development? What“s the latest progress?

2020-08-12 06:07:35 0 Comment 2166 views

The real point: Verifier: No wonder | Doctor of Medicine. By April 25, the number of global infections of the new crown virus exceeded 2.5 million and

The more serious points:

Checker: Don’t blame luck|Doctor of Medicine

Really 丨 How many vaccines are there in global new coronavirus vaccine development? What“s the latest progress?

By April 25, the global infection of the new coronavirus The number exceeded 2.5 million and nearly 200,000 died. It has become a rare global infectious disease.

For such a wide range of infectious diseases, the treatment methods are lackluster, and the treatment is a remedy after the infection. The only hope is to develop an effective vaccine as soon as possible, so that it is possible to suppress the new crown diseaseWith the further spread of the virus, there is hope to curb its future comeback.

So scientists around the world are racing to develop targeted vaccines around the clock. Carry out design tests and clinical trials at an unprecedented speed. Such an extremely difficult race against the virus, no matter which team is the first to develop a vaccine, it will be a great contribution to mankind.

1. Currently, there are approximately 115 vaccine candidates at different stages of development in the world.There are as many as 7 of them. Clinical stage

According to available data, there are currently 115 vaccines against the new crown pneumonia virus in different stages of development in various countries around the world. Some biological giants have joined the competition, and announced vaccine plans before and aftercase. GlaxoSmithKline (GSK) and Sanofi (Sanofi), two major vaccine development companies, announced their cooperation and plan to enter clinical trials by the end of the year. If all goes well, they are expected to enter clinical applications next year. Pfizer also announced that it is expected to start clinical trials this summer, with the goal of applying for clinical use next year.

Readers may be disappointed. So it will be next year at the earliest. But now the virus is killing thousands of people, and it’s too late and too slow to wait until next year.

Yes, it is indeed too late next year. But you must know that if an effective vaccine is really available next year, it will already be a record and an unprecedented speed. The fastest record of vaccine development in recent years is the Ebola virus vaccine, which took 5 years from development to clinical entry. However, the development of a vaccine usually takes 10 or even decades.

Vaccine developmentWhy does it take so long? What types of new coronavirus vaccines are currently under development? What are their advantages and disadvantages?

According to the available information, there are currently 115 vaccine candidates in different stages of development, of which 7 have entered different stages of clinical trials. This number is expected to be in the next few years. It climbed rapidly within a month. The fastest to enter the clinic is Moderna's mRNA vaccine mRNA-1273, CanSino Bio's viral vector vaccine Ad5-nCoV, Inovio's DNA vaccine INO-4800, Shenzhen Institute of Immunogene Therapy's LV-SMENP-DC and pathogen The specific aAPC vaccine, the inactivated vaccine from China Kexing Biotechnology Company, and the ChAdOx1 virus vector vaccine from the University of Oxford, UK. These 7 vaccines have all entered clinical trials, and they all start from different angles, The types are different. There is a feeling that the Eight Immortals cross the sea and show their magical powers.

Second, there are 4 types of vaccines currently under development.Big categories: inactivated virus vaccines, virus-specific protein vaccines, DNAVaccines, RNAVaccines, each type of vaccine has its own advantages and disadvantages

These many vaccines can be summarized into four major categories.

Vaccines are a bit simpler, it is to simulate viruses, let these virus-like microorganisms or certain components of the virus, such as virus protein, DNA or RNA, be artificially imported into the human body before the virus infects humans. Let the body's immune system take precautions and prepare in advance. Because the human body’s immune systemAntibody proteins of the opposite sex, because of the memory ability of human immune cells, these antibodies are expected to exist in the body for a long time. If they come into contact with the virus in the future, they will inhibit or even kill the virus. The so-called knowing oneself and the other can win all battles, and vaccines are the idea. But because of the pathogenicity of viruses, we will not use real viruses to stimulate the human immune system, so we use partial proteins without pathogenic viruses, or inactivated viruses, and in vitro synthesis provided by modern biotechnology. Both the DNA and RNA of the virus can be used as viral components to stimulate the immune response.

Therefore, vaccines for the new coronavirus are roughly divided into inactivated virus vaccines, virus-specific protein vaccines, DNA vaccines, and RNA vaccines.

First understand the basic structure of the virus, which is helpful to understand the design of the vaccine.

The new coronavirus is a coronavirus, which is an RNA virus. This virus isA spherical structure with a double-layer phospholipid shell on the outer periphery. There are various proteins on the shell. Among them, a sharp pointed protruding outward and like a thorn is the spinous protein. It It can help the virus break through the cell membrane and enter the cell. The center of the shell is a single-stranded RNA. After the virus comes into contact with human cells, the spike protein enters the cell through the sharp spines. Once successfully entered, the virus will kidnap various organelles of human cells, "force" or "deceive" the cell to synthesize various proteins required for virus replication according to the genetic code of viral RNA. After the synthesis is complete, the assembled new progeny virus will come out of the cell and then infect neighboring cells. In this way, the virus can replicate endlessly.

Then to develop a new virus vaccine, you have to start with the basic structure of the virus. The virus itself, the surface protein of the virus, the RNA in the virus, and the virus RNA after reverse transcriptionSynthetic DNA is a development object that can be used as a target.

Really 丨 How many vaccines are there in global new coronavirus vaccine development? What“s the latest progress?

3. Inactivated virus vaccine—— The most traditional and classic vaccine, but it takes a long time to develop and is difficult to mass produce.

Inactivated vaccines use real viruses as vaccines, but the viruses lose their pathogenicity in advance. The "empty shelf" is left, retaining the characteristics of stimulating the immune response to produce antibodies. For example, on April 20 this year, China's Kexing Biotechnology Company and the Chinese Academy of Sciences jointly published a preview article, announcing the results of animal experiments on the live vaccine of the new crown pneumonia virus developed by the team. This is the first publicly reported results of animal experiments on the new crown vaccine. ThisThis virus is a typical inactivated vaccine. Inactivated vaccine, as the name suggests, is to use killed viruses to make vaccines. Because it is a virus, once injected into the human body, the immune response is strong and sustained. This is also the most traditional and classic vaccine. Because the activity is eliminated, it will not cause disease, but the vaccine retains many characteristics of the virus, especially the antigenicity, and can simulate the virus to produce specific antibodies in the human body.

According to the published paper data, this vaccine induced the production of new coronavirus-specific neutralizing antibodies in mice, rats and primates. Rhesus monkeys were vaccinated with different doses of inactivated vaccines on days 0, 7, and 14, and the results showed that the new coronavirus-specific immunoglobulin and neutralizing antibodies were induced in the second week and continued to increase. The antibody titer It is similar to the antibody titer in the serum of patients with new coronary disease during the recovery period. Seven days after the inoculation, no virus was detected in the monkey's throat and alveoli. 22ndCompared with the control group, the pathological changes of rhesus monkey lung tissue after vaccine immunization were significantly reduced, and the amount of virus was also significantly reduced. Shows that the vaccine provides the expected protection against the new coronavirus. Encouraged by the results of this animal experiment, the inactivated vaccine began clinical trials on April 13. According to information released by the company, it is expected to enter the second phase of the trial in May.

The shortcomings of inactivated vaccines are long development time, difficult production, and very strict requirements for mass production. Just imagine it to understand that it is necessary to cultivate and isolate the virus, and then make a vaccine after artificial inactivation. It is far inferior to using protein fragments as vaccines, or even directly using viral DNA or RNA as vaccines. In the past, viruses were usually inactivated by high temperature, but now almost all of them are denatured by chemical means. This is a process that requires high precision and is not simple. It not only makes the virus lose its ability to cause disease, but also does not completely lose its ability to activate human immunity.The ability to respond. So multiple attempts are required. Also find a suitable way to mass-produce the virus. In addition, because it is a virus that loses its activity after inactivation, it often does not have the strong immune response capacity of a live virus, and it is still unknown whether it can eventually produce the expected antiviral effect.

So there are some new ways.

Four. Virus-specific protein vaccines-development is faster than inactivated virus vaccines, but it is not easy to find proteins with strong antigen-antibody response

This method does not need to cultivate the virus, but only needs to know the gene sequence of the virus. Through modern biological means, the virus protein (recombinant protein) is directly synthesized in the laboratory according to the virus gene map, and only those special antibodies that the virus can stimulate the immune response are synthesized , Discard the disease-causing part. Such a protein vaccine has no pathogenicity of the virus at all, and only retains the anti-virusOriginal characteristics. And because there is no need to culture the virus, the protein can be synthesized quickly through gene recombination technology. Therefore, rapid development can be achieved, which is more straightforward and simpler than cultivating viruses. But because it is necessary to find viral proteins or protein fragments that can stimulate an immune response and are not pathogenic, the technical content required is very high. There can be many kinds of peripheral proteins of a virus. It is obviously not an easy task to find the best combination, and various attempts are required. It is also possible that the synthesized protein has no desired antigenicity at all, cannot stimulate the production of antibodies, and has no antiviral properties. In addition, the production conditions required for the large-scale synthesis of recombinant proteins are also very harsh and costly, which is also an obstacle to be overcome.

Five. DNAVaccines-more time-saving, direct human body cells to complete protein synthesis, but to find the right DNASTRONG>Sequence is even more difficult

Furthermore, without protein synthesis, the viral DNA sequence used to guide the cell to synthesize viral proteins is directly injected into human cells. Let the human cells themselves complete the work of synthesizing and producing proteins in laboratories and factories according to the DNA information, and move the factories directly into the human cells. This is the DNA vaccine.

Once you know the gene sequence of the virus, find the DNA sequence of the synthetic protein that the virus can most stimulate the human immune response, and add a promoter that promotes DNA transcription and a terminal to terminate the synthesis before and after this piece of DNA. Then put this piece of DNA (usually using a plasmid) into human cells, and the cells will synthesize viral proteins according to the blueprint of DNA. This protein stimulates immune cells and may synthesize the required antibodies. Really next timeWhen the virus is out, the antibody will produce a strong antigen-antibody reaction, thereby killing the virus. In this way, the troublesome process of culturing the virus required for inactivating the virus is eliminated, and even the protein synthesis through biotechnology in vitro is eliminated, and the somatic cells are directly allowed to complete the protein synthesis. The benefits are obvious, saving precious time, and avoiding the harsh conditions and cumbersome process of synthesizing a large number of recombinant proteins. Moreover, the protein synthesized by the cell itself will perform secondary processing of the protein according to the mechanism within the cell to synthesize the protein that is most suitable for the internal environment. DNA is easy to synthesize and can also be produced in large quantities, and the required conditions are not high. A small laboratory can synthesize DNA fragments by itself. But the disadvantages are also obvious. It is not easy to find a suitable protein with strong antigen-antibody reaction. To find the DNA sequence that directly encodes this protein, it is also necessary to ensure that the desired protein can be synthesized as expected after entering the cell. This segment is before entering the human cell.DNA must also ensure that it is not destroyed by human immune cells first, and the difficulty can be imagined.

To solve this problem, there is a vector DNA vaccine.

VI. Vector DNAVaccines—Using adenovirus as a vector to deliver DNA, the technical difficulties are increasing step by step, but the precision is stepped up Steps are improved and time is greatly shortened

For example, the ChAdOx1 vaccine of Oxford University. This vaccine loads the DNA sequence of the spike protein on the surface of the virus that can trigger an antigen response by the new coronavirus into another adenovirus. Adenovirus can easily be modified in the laboratory and lose its pathogenicity, but it retains the characteristics of easily entering human cells. Put the section of DNA that synthesizes the surface spike protein of the new coronavirus into a harmless adenovirusThen, by letting the adenovirus infect human cells, it can take the opportunity to bring the new coronavirus DNA into human cells, and take advantage of the easy replication characteristics of adenovirus to synthesize the new coronavirus protein in human cells, thereby obtaining the expected Viral antigens stimulate the human immune system to produce corresponding antibodies. The function of the vaccine is achieved.

Simply put, it is to use adenovirus as a means of transportation to deliver the new coronavirus DNA code to human cells. Human cells function as a factory, synthesizing virus proteins according to DNA blueprints. This is a relatively perfect solution. From inactivated virus vaccines, to virus proteins synthesized in vitro without viruses, to direct use of virus DNA as vaccines, and then using adenovirus as a vector to deliver DNA, the technical difficulties have increased step by step, but the accuracy has been improved step by step. Significantly shortened. If this can achieve the expected effect in clinical trials, it is obviouslyOne of the best solutions. But the disadvantages of DNA vector vaccines are also obvious. Because there are so many steps, if one step is wrong, you will lose everything. The DNA is finally delivered into the cell through the carrier, but the cell does not produce protein according to the predetermined plan, or the protein produced does not meet the standard, does not have the desired ability to stimulate the immune response, and even the vaccine DNA is uncontrolled into the body itself It is possible that unexpected side effects will occur in the DNA sequence of the DNA sequence. After all, the more steps, the higher the technical requirements, and the more uncontrollable factors.

Seven. RNAVaccines-the development time is shortened, and the steps to generate immunity are the most simplified, but it is possible that the immune response generated by the final synthetic protein is too weak

You can go a step further, do not use reverse transcription to synthesize DNA,Instead, they directly use part of the virus's RNA as a vaccine.

Moderna's mRNA vaccine mRNA-1273, the first to do clinical trials, did just that. RNA vaccines are similar to DNA vaccines, but more direct. We know that the genetic code of an organism is stored in the DNA in the nucleus. The genetic code of DNA controls all biological activities and guides the cells in the organism to synthesize what kind of protein to ensure and maintain the normal operation of physiological activities. But DNA has only four basic codes, CGAT, and DNA exists in the nucleus, which cannot synthesize protein. To translate the code of DNA into protein, RNA is needed. RNA writes down the code of the DNA (transcription), and then comes out of the nucleus and into the cytoplasm. According to the coding instructions of RNA, the organelles in the cytoplasm translate and synthesize these 4 basic codesAmino acids. Different combinations of amino acids form different proteins. Therefore, after the DNA vaccine is delivered to the cell, it must enter the nucleus to be transcribed into RNA. RNA comes out of the cell nucleus, directs the organelles in the cytoplasm to synthesize virus-like proteins, and after release, stimulates the body to produce antibodies. Then directly use RNA as a vaccine, and directly send the part of the RNA that stimulates the antibody production by the virus into the human cytoplasm. There is no need to enter the nucleus. Proteins can be synthesized directly in the cytoplasm, which is another step less than DNA vaccines. More direct.

The advantages of RNA vaccines are many. The steps are the most simplified, the less side effects are possible. There will be no other obstacles caused by proteins or vectors or DNA, and there will be no serious unexpected immune stress response like proteins, and there is no need to worry about being integrated into human chromosomes like viral DNA. And long-term existence,Even produce variant proteins. Moreover, the shortening of the process not only shortens the time, but also saves the process of testing, regulating and modifying proteins in vitro. Because only the genetic code of the virus is needed to design an mRNA vaccine in a short time. This is why Moderna can conduct clinical trials so quickly. The mRNA carries the genetic code that the virus stimulates the immune response. After entering the cell, the human cell regards it as its own genetic information, and directly synthesizes the "weapon" according to the drawings. The synthesized "weapon" is compared with the one synthesized in the in vitro "processing factory". More "factory-oriented", it may be more precise and "lethal". In addition, mRNA vaccines can edit multiple protein information at the same time, such as the genetic codes of multiple disease-causing proteins in different parts of the same virus. , Which is synthesized in the cell body at one time to form a more complex and comprehensive vaccine.

But there are many shortcomings. For example, it is possible that the immune response of the final synthesized protein is too weak. A recent paper reported that no antibodies were found in young infected persons after recovery, indicating that the RNA virus may not leave any long-term antibodies after being cleared by the human immune system. This also puts a big question mark on how strong and durable the antibodies produced by the RNA vaccine can be. In addition, because RNA is not as stable as DNA or protein, it is easily degraded and destroyed by various environments in vitro and in vivo. How can it be ensured that the RNA vaccine enters human cells, synthesizes protein, and ultimately produces the expected antibody? problem.

The research and development of the new coronavirus vaccine is a competition between scientists from all over the world, and it is also an unprecedented collaboration. I hope to see the good news of clinical trials as soon as possible. No matter which kind of vaccine or which team succeeds, it is a huge impact on humans.Great contribution.

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Really 丨 How many vaccines are there in global new coronavirus vaccine development? What“s the latest progress?