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Does Chinese COVID-19 Vaccine have Low Antibody Value?

 

What do you think of the low antibody value of China's COVID-19 vaccine? A hidden worry about vaccines in China

Putting aside the value part of this table that attracts attention, what is really important is the choice of vaccine antigen. At this point, there is a hidden worry about vaccines in China, which is worthy of detailed analysis and pointing out.

On August 13, the results of phase I/II human clinical trials of the inactivated COVID-19 vaccine of Zhongsheng Group Wuhan Biotechnology were published in the international medical journal Journal of the American Medical Association, becoming the world's first officially published clinical trial data of an inactivated vaccine , The data on immunogenicity has attracted the attention of the industry.

 

Weibo netizen is a netizen who is engaged in biomedical research in the United States. He compiled the seven vaccines that have released immunogenicity data into a table for reference and comparison.

 

In the table, the neutralizing antibody titers representing immunogenicity data are in red font. However, the cellular immunity on the right side of the antibody titer is also an important part of immunogenicity, but because there is only [with or without] qualitative data, it is not as conspicuous as the precise quantitative antibody titer.

 

 

Note 1: Among the adverse reactions of adenovirus vaccines in China, 9% are grade 3 adverse reactions, not serious adverse reactions

 

Note 2: The adenovirus vaccine in the UK is 2 doses, not 1 dose

 

Infographics on  Chinese COVID-19 Vaccine have Low Antibody Value

 

Two antibody titer numbers are obviously low, particularly conspicuous. The lowest is the adenovirus vector vaccine co-operated by Academician Chen Wei and Kangsino (no more than 20), the second lowest is the inactivated vaccine of Kexing Zhongwei (no more than 70), and the highest inactivated vaccine of Wuhan Biology reaches 316.

The titers of the latter several foreign vaccines reached hundreds, the highest being Novavax's trimeric recombinant protein vaccine, the highest reaching 3906.

 

Looking at the antibody titers alone, Chinese vaccines seem to be at a disadvantage. However, due to the inconsistent detection methods and reagents, it is actually difficult to directly compare the antibody titers of different vaccines horizontally.

 

However, using the same testing methods and reagents to simultaneously test the blood of local vaccinators and those who have recovered from infection, the immunogenicity of different vaccines can be evaluated based on the relative value of antibody multiples.

 

Assuming that the vaccines of country A and country B are to be compared, the antibody level of vaccine recipients in country A is 10 times the antibody level of local survivors, and the antibody multiple of country B vaccine is 3 times, then there is reason to think that the immunogen of country A vaccine Sex is better than country B.

 

Three of the last four foreign vaccines in the table provide the level of antibodies of the survivors. Most of the antibodies of the vaccinators are 1 to several times higher than those of the survivors. Dr. Tao hopes that my country's vaccines will also provide antibody multiples for international comparison.

 

 

We use immunogenicity to infer the true protective effect, but immunogenicity cannot be equated with the true protective effect. The two are not the same thing.

If the antibody multiples required for real protection are only 2 times, then the vaccines of both countries can win. If the prices of the two vaccines are the same, the country B vaccine can be considered more cost-effective; if the country B vaccine is much more expensive, it is likely that the country A vaccine has more advantages.

 

The above discussion on antibody comparison, immunogenicity, and protective effect is logically okay, but all must be tested in practice. This is the key significance of the vaccine phase III human clinical trial. We still don't know the level of antibodies to prevent COVID-19 infection and how long it lasts, what percentage of the protective effect of cellular immunity accounts for, and how to unify the evaluation of cellular immunity.

 

Putting aside the value part of this table that attracts attention, what is really important is the choice of vaccine antigen. At this point, there is a hidden worry about vaccines in China, which is worthy of detailed analysis and pointing out.

 

The so-called antigen is the effective ingredient of the vaccine, and the ingredient that best represents the pathogenicity of the pathogen should be selected.

 

By choosing the right vaccine ingredients, the human body can produce antibodies or/and cellular immunity that make pathogens lose their pathogenicity. That is a successful vaccine. If you choose the wrong one, there is a high probability that antibodies and/or cellular immunity will be produced, but this immunity is likely to fail to make the pathogen lose its pathogenicity, and that is a failed vaccine.

 

Of the seven vaccines in the table, two are full-length virus inactivated vaccines, and the other five are virus components, including two major categories: S protein (including S-2p protein) or the key part of S protein (ie RBD protein) ).

 

The full-length virus inactivated vaccine means that the vaccine component is the entire virion, including all components except the S protein and the S protein. If the S protein-based vaccine fails, then the inactivated vaccine may still be successful.

Dr. Tao believes that in the field of inactivated vaccines, my country is the only one in the world. It should be based on the consideration of the success rate, not the most advanced, but the most secure.

 

However, it should not be accidental that there are more vaccines based on S protein in the world, and the probability of success of S protein vaccines should also be high.

However, the situation of S protein is far more complicated than I thought, and it may also affect the validity period of the vaccine. The devil lies in the conformation of S protein (protein conformation is the three-dimensional structure of the protein).

 

The S protein of COVID-19 virus has two conformations: pre-fusion protein and post-fusion protein. We all know Chinese characters, but how do we understand them?

 

Dr. Tao didn't know how to handle it. He consulted a specialist, a Weibo netizen who is engaged in the research and development of coronavirus vaccines in the United States, and finally understood this key issue.

 

Everyone knows that the COVID-19 virus must rely on the S protein to fuse with human cells. If this process is blocked, the virus cannot infect us. The problem is that the S protein is deformed, and there are obvious differences in morphology before and after fusion with human cells.

 

The S protein is like Megatron in Transformers. It has two appearances: robot state and weapon state, which is very different at a glance. For the human immune system, S protein before fusion and S protein after fusion also look different, and antibodies against the latter may not be able to recognize the former.

 

The figure below shows the results of the structural biology study of S protein recently published by the University of Cambridge in Nature.

The study applied cryo-electron microscopy and tomography technology to depict for the first time the dynamic structure of the S protein trimer on the intact virus particles, visually showing the appearance of the S protein before and after the fusion with human cells, which is impressive.

 

Although they are all S proteins in essence, the conformations are quite different, which is very critical for vaccines.

 

If the pre-fusion S protein is used as a vaccine, the produced antibody specifically binds to the pre-fusion S protein (specificity is like a key to open a lock), you can understand that the antibody binds the pre-fusion S protein, and the virus is the protein cannot be used to fuse and infect cells.

 

If the S protein after the fusion is used as a vaccine, the antibodies produced only recognize the S protein after the fusion, and it may be difficult to recognize the S protein before the fusion. Also, it will not be able to block the fusion of the virus and the cell. This vaccine antibody is an ineffective or low-efficiency antibody, no matter how high the antibody titer is, it is meaningless.

 

 

In addition, scientists have also found that the S protein of the COVID-19 virus is the most unstable of all coronaviruses (SARS and MERS are also coronaviruses).

Even if it is not combined with human cells, it will spontaneously undergo degeneration [before fusion → after fusion] This inevitably makes Dr. Tao worry about the validity period of the inactivated vaccine and the recombinant S protein vaccine.

 

For inactivated vaccines and recombinant S protein vaccines, the pre-fusion S protein may be the mainstay when they are first produced, but over time after being loaded into the vaccine bottle, they may slowly degenerate into the post-fusion S protein.

Will the effect be greatly reduced?

It is hoped that companies that produce these two vaccines must pay attention to this issue and not stumbling.

 

Unlike inactivated vaccines and recombinant protein vaccines produced in vitro, virus vector vaccines or nucleic acid vaccines using in vivo production technology do not need to worry about the S protein conformation.

Because these two vaccines are packed in the vaccine bottle, it is not the degenerated S protein, but the stable S protein coding gene.

 

These two vaccines introduce the S protein encoding gene into human cells to produce pre-fusion S protein in the cell, which transfers from the cell to the outside of the cell, simulating the natural infection process, and can fully stimulate the body's antibody immunity and cellular immunity.

These pre-fusion S proteins are now produced and used, and they are recognized by the human immune system before they regress into the post-fusion S protein. The immune mechanism produced by the latter is also directed against the pre-fusion S protein.

 

Both inactivated vaccines and recombinant protein vaccines are vaccines made by producing pre-fusion S protein in vitro. Before the vaccine is inoculated into the human body, both have the possibility of degenerating into the fusion S protein, which will affect the effect of the vaccine.

 

Is there a way to stabilize the S protein in the vaccine in its pre-fusion conformation?

Yes, S protein needs to be modified.

 

The aforementioned expert is the key person who invented this modification technique. He inserted 2 prolines (Proline) into a certain position of the amino acid sequence of the S protein, and successfully stabilized the S before fusion. protein. This modified S protein is also called S-2p antigen.

 

 

This S protein modification technique has been patented in the United States, and the National Institutes of Health (NIH) is responsible for authorizing the patent. At present, BioNTech/Pfizer, Johnson & Johnson, Novavax, and CureVac all use this patent to improve their COVID-19 vaccine antigen design.

Because Morderna has been cooperating with NIH and has a better understanding of the characteristics of the coronavirus S protein, it has been used from the beginning. S-2p protein.

 

In theory, virus vector vaccines or nucleic acid vaccines produced in vivo do not need to worry about S protein degeneration. However, actual studies have found that these vaccines use S-2p protein instead of S protein, and the immunogenicity is indeed better.

Dr. Tao speculates that this is because The S-2p protein is more stable than the S protein before natural fusion, and can stimulate the human immune system for a longer time.

 

The hidden worries of China's COVID-19 vaccine are here. I don't know whether Chinese companies understand the S protein conformation problem and this patent, and whether they have the opportunity to use this patent under the current Sino-US situation.

 

If it is not technically possible to obtain a stable pre-fusion S protein, then another way of thinking is feasible-using the key part of the S protein that is not affected by conformation but at the same time allows the body to produce effective antibodies, that is, the RBD protein.

Think of the S protein as Megatron, then the RBD protein is equivalent to the key component of Megatron-the conspicuous cannon. No matter how Megatron deforms, the change in this part of the cannon is very small, so it is not difficult to identify it.

Recombinant RBD protein vaccines are less affected by changes in protein conformation and should be more secure than recombinant S protein vaccines. However, because RBD protein is not a complete S protein, its immunogenicity may not be as good as S protein.

 

Zhihu also has a master who is following up on global vaccine progress. His ID is called a second-hand scientist, and his identity is a PhD in microbiology from the University of Chinese Academy of Sciences.

 

He recently wrote an article "Clinical Progress in New Coronary Vaccines" (http://t.cn/A6U9GrJ4), and compiled a global latest vaccine research and development schedule (as of August 6), a total of 28 vaccines entered human clinical trials, respectively:

4 inactivated vaccines

8 recombinant protein vaccines

6 viral vector vaccines

10 nucleic acid vaccines

 

Most of these 28 vaccines have identified the type of vaccine antigen, which is a better understanding of global vaccine technology trends than the 7 vaccines by the expert.

From this, we may confirm the hidden worries of China's COVID-19 vaccine.

 

It can be seen that in addition to the inactivated vaccine, the vaccines of the other three technical routes all use stabilized S protein and S-2p protein. The latter appears many times in the table.

 

In addition, my country’s inactivated vaccines use traditional aluminum hydroxide adjuvants, but various new adjuvant technologies are being tried internationally, including: adjuvant AS/CpG1018, adjuvant Advax, adjuvant CpG1018, and adjuvant Matrix-M.

Inactivated vaccines and recombinant protein vaccines produced in vitro require adjuvants, while viral vector vaccines and nucleic acid vaccines produced in vivo do not seem to require adjuvants.

 

Novavax's vaccine (code-named NVX-CoV2373) is currently the only vaccine with the highest neutralizing antibody value exceeding 1,000 (up to 3906). It is likely to be related to two advanced technologies used in the vaccine:

 

The first is nanoparticle antigen technology. The use of genetic engineering to efficiently produce highly immunogenic antigens against various viruses and form them into multimeric particles through nanotechnology may be more effective than the immunity obtained from natural infection or traditional vaccines.

 

The second is Matrix-M adjuvant technology. The adjuvant is composed of 40 nanometer particles, which are saponins extracted from the bark of a South American saponaria tree (Quillaja saponaria Molina), as well as cholesterol and phospholipids.

Matrix-M can induce antigen-presenting cells, activate immune cells, produce an effective, strong and long-lasting immune response, and reduce the amount of vaccine antigens used.

 

Two of the six viral vector vaccines and four of the ten nucleic acid vaccines use the S-2p protein. For these two in vivo production technologies, the direct use of S protein as an antigen is not a problem, but there are still many models that use stable S-2p protein, which is in pursuit of excellence.

According to the animal test data of several antigen comparisons released by Johnson & Johnson, the level of neutralizing antibodies produced by S-2p protein is significantly higher than that of natural S protein, and significantly higher than that of recovered patients.

 

China's three whole virus inactivated vaccines all use natural virus strains as vaccine strains, and all have the problem of S protein degeneration after the vaccine is produced.

 

Is it possible to modify the S protein of the vaccine virus first to regenerate a stable S-2p protein inactivated vaccine?

Unfortunately, it doesn't work. Because the modified virus will lose the ability to infect cells, it will not be able to be cultured in large numbers in cells to achieve mass production.

 

There are two recombinant protein vaccines in China, one uses the dimer of two RBD proteins as vaccines, which avoids the S protein conformation problem; the other uses stabilized S protein (only trimer technology) , There should be a big gap between the stability of S-2p protein), and the use of advanced adjuvants, its immunogenicity is likely to be better than the former.

 

China has participated in 3 nucleic acid vaccines, using S protein, RBD protein and S-2p protein respectively.

 

Conclusion: When selecting the antigenic components of the COVID-19 vaccine, the conformational stability of the S protein needs to be considered.

 

During the development of the COVID-19 vaccine in China, public reports did not see any discussion about the effect of the S protein conformation on the vaccine effect (Dr. Tao realized the potential seriousness of this problem only after a few days of supplementation). This may be due to this The technical point is too esoteric.

 

However, many vaccines of foreign companies use the S-2p protein as the antigen. According to the analysis of and @Used Scientists, this is because they conducted long-term basic research on SARS virus and MERS virus in the early stage.

Deeply understood and reached a consensus on [using S protein as a vaccine must solve its stability], and finally made the original technological innovation of S protein modification patent.

 

The small details of the stability of the S protein of the COVID-19 vaccine reflect the necessity for China to change the mode of technological development.

In the past 20 years, China has made great strides in science and technology. However, China’s past technology development strategies were mainly imitative and follow-up development, keeping a close eye on the frontiers of global technology, looking for the direction and operating fiercely. In many cases, we can indeed use our advantages to catch up and surpass.

 

Nowadays, in many fields of science and technology, we have worked hard to enter the first echelon, there is no way to go ahead, and we are at a loss. But we can't stop, and we can't wait for others to find a way out. We are chasers. The only way we can achieve excellence is to do it ourselves and encourage original technological innovation.

 

In the "Several Opinions of the State Council on Comprehensively Strengthening Basic Scientific Research" issued by the State Council in 2018, it is mentioned that: highlight original innovation and promote the development of financing. Put the enhancement of the original innovation ability in a more prominent position, strengthen the confidence in innovation, have the courage to challenge the most cutting-edge scientific problems, put forward more original theories, and make more original discoveries.

 

In the field of vaccines, my country has long been a major vaccine country and is also becoming a vaccine power. I have no doubt that my country’s COVID-19 vaccine can be successful, but global research and development progress shows that details determine success or failure, and original innovations such as vaccine antigen design and modification and new adjuvants still need to be strengthened. Asian vaccine industry is at the international advanced level. The gap may be around 10 years.

 

 

 

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