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
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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