In the past few days, a new crown vaccine developed by Stanford University has become popular because it was reposted by Facebook CEO Mark Zuckerberg .
Is this new vaccine really that strong? Will the COVID-19 pandemic end with this vaccine?
Too long not to read the version
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“Ferritin vaccine” is still in the pre-clinical stage, and it is too early to use it
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Antibody titers are high, but the research stage is still in the early animal stage
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“A hundred times better than mRNA vaccines” lacks data support
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Humoral immunity (antibodies) faces the challenge of escape from mutant strains
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‘End of Covid’ is far away, but we can expect better vaccines to make disease less risky
nanoparticle vaccine
When it comes to the development route of the new crown vaccine, many people will definitely think of domestic inactivated vaccines, virus recombinant vaccines (adenovirus/influenza virus), recombinant subunit vaccines, and mRNA vaccines developed overseas. But in fact, the new crown vaccine does not stop there. The development platform also includes DNA vaccines, virus-like particle vaccines, and antigen-presenting cell-based vaccines [1] , etc.
COVID-19 Vaccine Technology Platform
The “ferritin vaccine” mentioned by Zuckerberg is actually not in the above classification, but a ” nanoparticle vaccine “. Nanoparticles (NPs) are made of biodegradable materials (polylactic acid, metals, lipids, etc.), and vaccines prepared therefrom are facilitated by their stability and delivery mechanism (easier uptake by antigen-presenting cells). B cell activation), is also considered to be a feasible idea for vaccine development [2] .
To put it more simply, “nanoparticle vaccines” are like our common Lego toys (not advertisements), which can assemble the antigenic structure of pathogens and other particles together to become ” customized antigens “, and even fuse multiple antigens in Together [3] , that is, a vaccine against multiple pathogens at once.
Customized Antigen｜Flip
Due to the feasibility of the theory, many scientific research teams, including those in China, are working on the development of “nanoparticle vaccines” [3]-[6] , including of course our protagonist “ferritin vaccine” today.
Worrying Antibodies
Why continue to study a new crown vaccine?
The reason is that the existing new crown vaccine “is still not good enough.”
Over time, whether it is the basic dose or the booster dose, the antibody in the vaccine recipients decreases [7]-[11] , and the emergence of mutant strains increases the risk of breakthrough infection [12] [13] , which has also kept scientists working hard to find a new crown vaccine that can produce a better immune response and protect longer .
You must know that the half-life of measles antibodies is estimated to be as long as 3014 years, and the half-life of chickenpox antibodies is estimated to be as long as 92 years [14] (so we often say “lifelong immunity”), while the half-life of neutralizing antibodies for the new crown is only about 2 months , and The half-life after half a year is only 27 days [15] .
Durability of COVID-19 Neutralizing Antibody Response
The antibody decreases rapidly, and the mutant strain further reduces the neutralizing activity of the antibody, so what should we do?
As the saying goes (and not) : the half-life is not enough to make up the amount of antibodies ! The ultra-high antibody level induced by the “ferritin vaccine” this time has brought new hope to people.
“Ferritin vaccine” is not actually an official name. The full version of the nanoparticle vaccine prepared by researchers at Stanford University with ferritin as the core is called… Delta-C70-Ferritin-HexaPro (DCFHP). Due to the addition of aluminum hydroxide adjuvant, the official full name is DCFHP-alum .
How strong is the antibody induced by DCFHP-alum? To borrow Zuckerberg ‘s words: 100 times stronger than mRNA vaccines !
Compared with the most widely used inactivated vaccines in China, mRNA vaccines can produce more specific T cell 16 responses against S protein and higher antibody levels [17] , so there are certain advantages in the protective effect [18] , And DCFHP-alum is 100 times higher than mRNA vaccine antibody level.
But does this mean that the new crown epidemic can be ended?
Let’s take a closer look at the development details and related data of this vaccine.
super new crown vaccine
The related research of DCFHP-alum [6] is actually just a preprint published on bioRxiv, which has not been peer-reviewed. However, since it can be considered as a continuation of a previous ferritin vaccine study [19] , the content is also worthy of reference.
In previous studies, researchers at Stanford University used Helicobacter pylori ferritin, the full-length ectodomain (S-Fer) or the C-terminal 70 amino acid residues of the main antigen spike protein (S protein) of the new coronavirus Base-deleted (SΔC-Fer) combined to form nanoparticles shaped like sea urchins .
Previous research on ferritin-based nanoparticle vaccines
Among them, S∆C-Fer contains a mutated furin cleavage site and a prefusion stable substitution of 2-proline (2P); the deleted 70 residues in the S protein structure contain immunoremarkably The deletion of these epitopes, which are often targeted by antibodies, renders the S protein structure multivalent. This modification allows the vaccine antigen to induce a broader spectrum of antibody classes .
Compared with S-Fer, S∆C-Fer has better immunogenicity, so it can be developed as a candidate COVID-19 vaccine.
And this time the preprinted research can be said to be an upgrade of the previous S-Fer, adding four proline substitutes to 2-proline, creating a six proline substitute (HexaPro), the upgraded antigen is today’s protagonist DCFHP, and the latter has better stability (meaning it is more conducive to storage, transportation and application).
The red part is the change of DCFHP compared with S∆C-Fer
The DCFHP-alum prepared by this method brought positive results after inoculation to mice and rhesus monkeys, which can be simply summarized as follows:
1. Good stability : no cryopreservation is required, and DCFHP-alum can still maintain good immunogenicity after being stored at 4-37°C for two weeks;
2. Extensive coverage of mutant strains : After 2 doses of 0-21 days (group A) or 0-92 days (group B) immunization schedule, antibodies that can effectively neutralize the mutant strains can be produced;
3. Effective against new mutant strains : the activity of group B is about 4 times higher than that of group A, and the induced antibodies have neutralizing activity against new coronaviruses and SARS viruses including Omicron BQ.1 and BQ.1.1;
4. Good immunity persistence : All non-human primates have a neutralizing antibody response to the original strain of the new coronavirus, which lasted for at least 250 days;
5. T cell immunity : After vaccination, a balanced Th1 and Th2 immune response is produced in the animal (but no CD8+ T cell response);
6. It can be used as a booster injection : on day 381 (one year after the second dose), rhesus monkeys can be inoculated with a booster dose to induce an antibody level equivalent to the peak value 14 days after the second dose of vaccination.
*The above immunogenicity data are all derived from in vitro pseudovirus neutralization test
Cross-immune responses induced by DCFHP-alum in nonhuman primates
In summary, the researchers believe that the new DCFHP-alum vaccine has low cost, high yield, good stability , can provide high- level and long-lasting humoral immunity , and can also induce immune memory , so it can be used as a new crown candidate vaccine. The aluminum hydroxide adjuvant used in the vaccine has also proven its safety for decades, so it is considered safe to vaccinate even infants .
As for the statement that the antibody is “100 times stronger than the mRNA vaccine”, the researchers did not mention it in the article, but Zuckerberg himself said it – after all, the full name of another scientific research institution “Biohub” in cooperation with Stanford University Called “Chan Zuckerberg Biohub”, it is a non-profit organization funded by Zuckerberg and his wife, including Stanford University, as a research center [20] .
In other words, Xiao Zha gave a thumbs-up to the research he sponsored, and just praised it.
Corona Terminator
Now that there is such a good vaccine, does that mean that the new crown epidemic can officially end? Or can we see the dawn of the eradication of the new crown virus?
Actually not yet .
Although the antibody response of DCFHP-alum vaccine may be better than that of mRNA vaccine, and it brings together the advantages of new crown vaccines from multiple technical platforms including inactivated vaccines and mRNA vaccines, we still need to clearly understand the following points:
1. DCFHP-alum has not yet carried out clinical trials, and the safety and effectiveness in humans cannot be confirmed;
2. Relevant data also come from animal experiments, whether the human immune response can reach the same level is unknown;
3. There are many uncertain factors in the vaccine research and production process, and it is impossible to predict what will happen in the middle before the vaccine is approved.
The process from drug discovery to development, and the failure rate of each step of clinical research｜Reference [21]
The last and most critical point is that we have to look at the “face” of the new coronavirus, such as asking whether the new coronavirus can stop escaping mutations.
But the new coronavirus may answer this way:
I disagree !
Previous research on the mutation trend of the new coronavirus [2] found that the stress screening of humoral immunity (which can be understood as the survival of the fittest in the natural selection of the new coronavirus) promoted the evolution of the RBD on the S protein of the new coronavirus, so whether it is natural infection Neither the vaccine against the variant strain of BA.5 alone is the solution to the new crown epidemic.
Broad-spectrum vaccines and broad-spectrum monoclonal antibodies are the priority research and development priorities in the future.
The broad-spectrum vaccine that truly kills the new coronavirus should induce neutralizing antibodies that can more widely cover virus variants with escape mutations.
A truly effective broad-spectrum monoclonal antibody should not only efficiently respond to various mutant strains, but also avoid virus escape and pressure screening of the virus.
With the emergence of DCFHP-alum, broad-spectrum, high-level and active humoral immune responses may be considered to have solved certain problems, but another preprint study [23] really poured a lot of humoral immunity Cold water close to freezing point.
The researchers analyzed subjects who were still infected with Omicron BA.1, BA.2 or BA.4/BA.5 breakthrough after receiving 3 doses of mRNA vaccine, and found after analyzing 506 NTD and RBD epitopes of S protein : Compared with the original strain, the neutralizing B-cell epitope of the mutant strain is missing, and in Omicron BA.2.75.2 and XBB mutant strains, less than 12% of the wild-type strain epitopes are conserved.
In other words, after the new coronavirus mutates, it is easy to escape humoral immunity .
T cell epitopes against the S protein are largely conserved
And this also explains why the antibodies induced after vaccination have less and less neutralizing activity against new coronavirus variants, especially Omicron variants.
Fortunately, T cell immunity can still provide some support, which also explains why even if the antibody is reduced after vaccination, it can provide effective protection against severe illness and death .
And this is only the result of the Omicron XBB mutant strain. What kind of escape mutations the new coronavirus will produce in the future is still unpredictable . Therefore, a broad-spectrum vaccine may solve this problem to a certain extent, but it cannot completely reverse the situation.
In addition to vaccines, a variety of monoclonal antibodies studied in the past have been widely escaped by Omicron mutants [23][24] , so broad-spectrum monoclonal antibodies targeting the conserved epitopes of the new coronavirus S protein will become a future research and development One of the key points.
Fortunately, high-throughput sequencing technology has been able to predict the escape mutation trend of the new coronavirus to a certain extent in the future, and since then, the new coronavirus monoclonal antibody drug has been freed from the embarrassing situation of ” chasing the virus “, and there are many domestic and foreign Institutions are also developing broad-spectrum neutralizing antibodies for the preparation of monoclonal antibodies [24]-[28] .
Acquisition and research of broad-spectrum monoclonal antibody
Therefore, if we want to completely end the new crown epidemic, either the new crown virus will remain unchanged to give us enough time to study effective vaccines and monoclonal antibodies, or the new crown virus will mutate to destruction , but at present, both seem unlikely .
In short, it is still impossible to “end the new crown epidemic” with a new crown vaccine alone.
The ferritin vaccine praised by Zuckerberg is a new vaccine worth looking forward to, but more clinical research is needed. The “100 times stronger than mRNA vaccine” data comes from animal experiments , and it is still unknown whether it can greatly increase the amount of antibodies in the human body .
In any case, technological development brings better vaccines and better drugs, which can benefit more people’s lives and health, which is also worth looking forward to!
references
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Author: boiled vaccine
Editors: You Shiyou, Xiaotowel
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