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Scientists have developed a universal vaccine strategy that can target both coVID-19 and SARS

The paper was published in advance in the journal Cell.
Vaccines based on this strategy have been shown to be far more effective in animals than similar vaccines and have now been approved for clinical trials.

On 29 June, according to the World Health Organization (WHO), the worldwide novel Coronavirus infection mark had passed the ten million mark and the cumulative number of deaths had reached 500,000.
However, a SPOKESMAN for the WHO said this did not mean the outbreak had peaked and confirmed cases would continue to rise in the future.
Based on current prevention and treatment measures and the number of underlying cases, the time frame for increasing from 10 million to 20 million will only be shorter.

Because traditional measures, such as isolation, only block transmission without establishing immune barriers, effective vaccines are still needed to increase immunity against the virus.
One might argue that the human body does not develop lasting immunity to coronavirus, and that vaccines may not help.
Because in the past experience, for example, after SARS and MERS virus infect human body, human cannot produce long-term immune protection ability, usually only 6 months to 1 year, and human body may have similar reaction to novel Coronavirus.

But with so many people infected, vaccines remain the only hope of protecting healthy people.
Even if protection is given for only one year after vaccination, it can be made up for by regular injections, or by modifying vaccine efficiency to extend protection.
Without a vaccine, human beings will have to novel Coronavirus resistance by hand.

Vaccine Design idea

Currently, there are basically two ways of thinking in the production of vaccines. One is gene-based vaccines, such as novel Coronavirus DNA vaccine or mRNA vaccine and recombinant vector vaccine. After entering the human body, these vaccines can utilize the relevant genes of the host cells to replicate the virus and generate antigens to generate immunity.

The other is a classic vaccine, made from viral proteins or protein subunits that are mass-produced in vitro and injected into the body to provide immunity.
This traditional method of activating immunity by protein is relatively more effective and safe.

Among coronaviruses, the S protein, commonly known as spike protein, is best targeted for vaccines.
Conventional vaccine production methods can directly treat The S protein as the antigenic component of the vaccine. The intact S protein, because of its large size (about 600 kDA), usually has high immunogenicity, which enables the body to produce a strong immune response.

A few years ago, researchers at the Scripps Research Institute in the United States designed a vaccine against MERS using the S protein of the MERS virus. In their experiments, the vaccine stimulated the production of a large number of neutralizing antibodies.
This indicates that traditional vaccine preparation methods are adequate to cope with the invasion of coronavirus.

However, there is a disadvantage to vaccines made with S protein. S protein includes RBD (receptor binding domain) and non-RBD, such as n-terminal domain, which enables the body to produce neutralizing antibodies, while other protein regions may produce non-neutralizing antibodies, leading to ADE effect.
ADE is a so-called antibody-dependent enhancer, in which the antibodies produced, mostly non-neutralizing antibodies, not only fail to kill the virus, but also increase its ability to invade cells.
This has been observed in patients with SARS and MERS.

Improving vaccine efficiency

As a result, subsequent vaccine production has focused more on immunological focusing, which focuses on areas producing neutralizing antibodies to develop vaccines.
The RBD of coronavirus S protein is the region suitable for immune focusing.
At present, there are some VACCINES based on RBD for MERS and SARS virus, and the novel Coronavirus vaccine is also quite a part of the development of RBD for SARS-COV-2.

Although the immune focus of such vaccines is indeed better, the efficiency of relying on a single RBD antigen as a vaccine component is not high, and many vaccinated animals produce low neutralizing antibody titers, indicating that THE immunogenicity of RBD monomer is not strong.
Some current immunogenicity enhancement strategies, such as polypolymerization or antigen-presenting particles, introduce additional exogenous sequences, adding to clinical application approval.
The new work by the Institute of Microbiology and Academician Gao Fu is to improve the immunogenicity of RBD vaccine more simply and universally, while ensuring the immune focus.

The main idea of this design is not complicated. The S protein trimer is split to obtain RBD monomer and then the two RBD monomers are connected by disulfide bond.
When RBD dimer is used as the component of vaccine, it can not only significantly improve the immunogenicity and the titer of neutralizing antibody, but also ensure the efficient production of neutralizing antibody.

Design idea: Split S protein trimer, obtain RBD, and connect RBD dimer with disulfide bond.
As a component of the vaccine, the immune system of inoculated mice against coronavirus can effectively prevent the virus from invading and protect the individual.

The MERS coronavirus was first used as the test target, and THE RBD of MERs-COV was expressed in insect cells in large quantities.
These collected RBD monomers were treated by disulfide bonds to form RBD dimers.
After purification and concentration adjustment, THE RBD dimer becomes the final component of the vaccine.

Schematic diagram of RBD dimer
According to the description of the paper (the paper is published in advance, and the picture data is not complete), mice injected with RBD dimer vaccine will have stronger immunity and higher titer of neutralizing antibodies than mice injected with RBD monomer vaccine.
Mice that were themselves susceptible to MERS were able to resist the virus for a long time after receiving the new vaccine.

A common design strategy

This result gave great inspiration to researchers such as Gao Fu, who thought that this method could also deal with SARS and Novel Coronavirus.
In subsequent studies, they designed an upgraded version of the RBD dimer, using multiple dimers to form a series form of the RBD dimer (SC-Dimer). Sc-dimer has the same immune effect as a single dimer, but the immune efficiency is again improved.

In addition to MERS coronavirus, this modified SC-Dimer is also suitable for SARS coronavirus and novel Coronavirus.
The neutralizing antibody titers produced by sc-Dimer vaccine in mice were 10 to 100 times higher than those produced by traditional RBD vaccine.
This means that this RBD dimer tandem approach, suitable for the various -coronaviruses, can be said to be a common design approach for the production of SARS-COV, MERS-CoV and SARS-COV-2 vaccines.

Based on this common design strategy, the Institute of Microbiology of the Chinese Academy of Sciences has designed and developed a recombinant protein vaccine for COVID-19.
The results of the rhesus monkey challenge protection test showed that the vaccine could induce high level of neutralizing antibody, significantly reduce the viral load of lung tissue, reduce the lung injury caused by virus infection, and have an obvious protective effect.

On June 19, the National Medical Products Administration approved a coVID-19 recombinant protein vaccine jointly developed by the Institute of Microbiology and Anhui Zhiffilongcoma for clinical trials, which is also the first recombinant protein vaccine to receive clinical approval among the five technical routes of CoVID-19 vaccine in China. The vaccine is composed of RBD dimer antigen.
The phase I clinical trial of the new vaccine will focus on testing its tolerability and safety in humans, while the emergence of more types of vaccine will provide additional protection and hope for the healthy population in the future.

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