COVID-19: Development Update on Coronavirus Vaccines

COVID-19: Development Update on Coronavirus Vaccines.  The COVID-19 virus COVID-19 has been sweeping the world since the beginning of last year. As of today, more than 2.66 million people have died of the virus. Therefore, the most important thing is to develop a vaccine against the virus as soon as possible, because the vaccine is to control and prevent The most effective means of the COVID-19 pandemic.

At present, in addition to the production and use of two human adenovirus vector vaccines, three inactivated vaccines and one peptide vaccine in China and Russia, there are also a new generation of mRNA technology and non-replicating viral vector vaccines from the United States. The main technologies have been invested in the development and production of vaccines.

So, what is the development of these vaccines? From the School of Public Health of China Southern Medical University, the Institute of Medical Microbiology of Jinan University and Harvard Medical School in the United States in December last year, they published the title “COVID-19: Coronavirus Vaccine Development Updates” in the internationally renowned journal “Frontier in Immunology”. The article summarizes and analyzes the progress of vaccines against SARS-CoV, Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and SARS-CoV-2, including:

• Inactivated vaccines,
• Live attenuated vaccines,
• Sub-combined vaccine,
• Granular virus,
• Nucleic Acid Vaccine
• Viral vector vaccine.

So far, there are 6 types of coronaviruses that can infect humans. The new coronavirus that ravaged the world last year is the seventh coronavirus that is known to infect humans. The remaining six are HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV (causing severe acute respiratory syndrome) Sign) and MERS-CoV (causing Middle East Respiratory Syndrome).

It is understood that about 30% of upper respiratory tract infections worldwide are caused by the four coronaviruses HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1. These four coronaviruses are second only to rhinoviruses that cause the common cold. Two causes. The other three are highly pathogenic coronaviruses, all of which cause serious human respiratory diseases.

The seventh is the SARS-CoV-2 outbreak in Wuhan in December 2019. This is what we know as the new coronavirus COVID-19.

As of October 19, 2020, of the 212 SARS-CoV-2 vaccine candidates being developed worldwide, 50 are undergoing clinical evaluation and 162 are undergoing preclinical development (Figure 1). Among them, 14 types of inactivated vaccines, 4 types of live attenuated vaccines, 72 types of protein sub-vaccines, 17 types of DNA vaccines, 27 types of RNA vaccines, 16 types of virus-like particle vaccines, 26 types of non-replicating virus vector vaccines, and 18 types of replicating virus vector vaccines Species (Figure 1A).

In clinical trials, 8 are inactivated vaccines, 15 are protein subunit vaccines, 6 are DNA vaccines, 6 are RNA vaccines, 2 are VLPs vaccines, 9 are non-replicating viral vector vaccines, and 4 are replication Viral vector vaccine (Figure 1B).

About inactivated vaccines

In the development of inactivated vaccines, China is at the forefront. Various studies have shown that the overall, inactivated SARS-CoV vaccine induces a considerable degree of neutralizing antibodies in animal models.

Regarding the SARS-CoV inactivated vaccine, the researchers pointed out: The evaluation of the SARS-CoV whole virus vaccine inactivated by formalin and ultraviolet radiation in ferrets and non-human primates shows that it can Prevent SARS-CoV specific T cell infection and neutralize antibody response. The immunogenicity profile caused by the double inactivated SARS-CoV vaccine may not be comparable to the immunogenicity produced by the vaccine inactivated by only one method.

For the inactivated vaccine of Middle East Respiratory Syndrome Coronavirus (MERS-CoV), researchers believe that the formalin-inactivated MERS-CoV combined with alum and CpG induces high titers of anti-S IgG and neutralizes the response. Sex> 60%, and has a stronger Th1/Th2 response in mice. Therefore, the researchers pointed out that in the vaccinated animals, whether it is inactivated SARS-CoV and MERS-CoV vaccines caused by gamma rays or formalin, when developing an inactivated SARS-CoV-2 vaccine Both should attract attention.

As for the SARS-CoV-2 inactivated vaccine, the β-propiolactone inactivated SARS-CoV-2 vaccine is mainly developed in China. Unlike SARS-CoV and MERS-CoV, the SARS-CoV-2 inactivated vaccine showed no evidence of immunopathological changes in the lungs of vaccinated and SARS-CoV-2 infected animals. Currently, three domestic vaccines in China are inactivated vaccines.

(▲The SARS-CoV-2 vaccine is being used in Phase III clinical trials and early use or limited use)

Live attenuated vaccine

Live attenuated vaccines are the most successful vaccines available. They have made countless achievements in the battle against infectious diseases, such as preventing measles and polio. Live attenuated vaccines are pathogens with reduced virulence or non-toxic that are screened from nature or cultivated in the laboratory. These pathogens can survive but do not cause disease. After vaccination, the virus in the vaccine can grow and replicate, thereby causing the vaccinated Immune response.

In the SARS-CoV live attenuated vaccine, Nsp10 is the main replication regulator in SARS-CoV. Its deletion generates replication-deficient virus by interfering with and preventing the activation of nsp14 ExoN (85), which indicates a potential epitope for vaccine development .

CoV accessory protein is involved in interferon signal transduction and the regulation of pre-inflammatory cytokines. ORF3, 4a, 4b and 5 are important for pathogenesis, and the MERS-CoV strain combined with deletion of accessory genes 3, 4a, 4b and 5 (rMERS-CoV-DORF3-5) significantly attenuates virulence and reduces its inhibition The role of resistance to IFN, a possible vaccine candidate.

As for the SARS-CoV-2 live attenuated vaccine, the researchers wrote that the Bacillus Calmette-Guerin (BCG) vaccine is designed to prevent tuberculosis (TB). It “trains” the immune system to deal with other subsequent infections with greater intensity, thereby enhancing immunity. In order to determine whether it can reduce the risk of COVID-19 infection among health care workers and home care workers who are particularly vulnerable to coronavirus infection, the candidate vaccine is entering the Phase III “BRACE” trial, in which as many as 10,078 health care workers are in Australia Of hospitals to participate. In the Netherlands, it is in the fourth phase of the trial and is recruiting 5,200 elderly people.

Subunit vaccine

Although the researchers also used some data to tell us some relevant subunit vaccines, this information was taken out by the editor and shared with you again: the recombinant new coronavirus vaccine (CHO cell) jointly developed by the Chinese Academy of Sciences Microbiology Research and Cooperative Enterprise Recently (this month), it was approved for emergency use in China, becoming the fourth domestic new coronavirus vaccine approved for emergency use and the first international new coronavirus recombinant subunit protein vaccine approved for clinical use.

The vaccine has completed Phase I and Phase II clinical trials in October 2020. The results showed that after the whole course of vaccination of the vaccine, no serious adverse reactions occurred, which conformed to the characteristics of small adverse reactions of subunit vaccines, and the level of neutralizing antibodies produced was equivalent to the current international recombinant protein vaccines and mRNA COVID-19 vaccines, reaching the international advanced level.

Researchers also introduced bacteria-like particles (Bacterium-like particles, BLPs), virus-like particles (VLPs), genetic vaccines (nucleic acid vaccines), DNA vaccines, etc., but there are two vaccines that need to be introduced.

Viral vector vaccine

Viral vector vaccine: is the use of a certain virus as a carrier to deliver antigens. The viral vector can be seen as a truck carrying the spike protein of the new coronavirus into the human body. The virus itself does not cause disease, but it can cause a strong cellular immune response to the inserted gene.

Historically, attenuated live replication vaccines, rather than inactivated vaccines, have provided humans with more effective protection. Attenuated vaccines such as measles, mumps, rubella, polio, etc., basically cause life-long protective immunity. In contrast, immunity induced by inactivated or subunit vaccines usually lasts for a limited time.

Viral vectors are divided into two categories:

• One is a replication-deficient vector virus, which has no hidden dangers of detoxification, and can express the target antigen at the same time to produce an effective immune response;
• The other is a virus with replication ability, which can be used as a carrier of foreign genes to maintain their own infectivity.

**The first adenovirus vector COVID-19 vaccine jointly developed by Academician Chen Wei’s team and Cansino Bio is also the only COVID-19 vaccine that uses a single-dose vaccination procedure. **The type 5 adenovirus vector it uses is a non-replicating adenovirus vector.

mRNA vaccine

At present, in the field of mRNA vaccine development, the three most powerful companies are Moderna from the United States, BioNTech and CureVac from Germany. As of a few days ago, Moderna and BioNTech have successively released the data of mRNA vaccine clinical trials, and CureVac has also begun to enter the clinical trial stage.

To put it simply, mRNA vaccine is to inoculate the human body with the antigen after attenuated, inactivated, etc., to induce the human body to produce corresponding antibodies. When the human body is exposed to the pathogen again, the human body’s immune system will be based on the original memory. , To produce more antibodies to resist the invasion of pathogens and achieve a preventive effect.

There are two main forms of mRNA vaccines currently in use: ① traditional mRNA vaccines based on mRNA (non-replicating mRNA vaccines), and ② self-amplifying (SAM) mRNA vaccines (also known as replicons).

Traditional mRNA vaccine is a complete mRNA encoding antigen protein transcribed in vitro. The upstream and downstream contain 5’cap structure and 3’poly(A) tail respectively, which only encode the target antigen. The advantages are simple structure, short RNA sequence, and no The disadvantages of encoding other proteins are the short half-life in the body and the low antigen expression level, requiring a higher amount to induce an effective immune response.

The SAM mRNA vaccine is a genetically engineered mRNA viral genome, in which the gene encoding the RNA replication mechanism is complete. The mRNA encoding the antigen protein is used to replace the structural protein encoding gene of the original virus, which can achieve self-amplification in the body. The amount can induce an effective immune response.

Antibody-dependent enhancement (ADE)

ADE can be mediated by viral internalization associated with antibody Fc receptors, leading to greater viral replication and cytokine release in the presence of virus-specific antibodies. Especially when antibody levels are relatively low, ADE may occur. According to reports, SARS-CoV uses ADE to enhance the infectivity of human prokaryotic cells. TNF-a, IL-4 and IL-6 levels were detected in human primary cells isolated from leukemia patients (HL-CZ cells) infected with SARS-CoV, and highly diluted antiserum treatment against SARS-CoV With higher levels of virus infection in cells and increased cytopathic effect (CPE).

The researchers mentioned: So far, ADE has not been observed in MERS-CoV and SARS-CoV-2. However, due to the similarity in classification and structure of SARS-CoV, MERS-CoV and SARS-COV-2, when designing MERS-CoV and SARS-CoV-2 vaccines, especially those with full-length S protein, Neutralizing epitopes can trigger stronger protective immunity, but ADE has few or no side effects. Recent studies have found that MERS-CoV vaccine candidates based on shorter S1 domains or shorter RBD have a stronger immune response than candidates based on the full-length S protein. Whether ADE is common during all coronavirus infections requires further research and verification.

Finally, researchers believe that the SARS virus in 2003 disappeared after only six months of existence, so there are not many things that can be provided; the MERS virus in 2012 has only completed phase I trials so far; therefore, when the new coronavirus in 2019 At the time of the outbreak, all available for research were also based on the 2003 SARS and MERS.

Up to now, we have developed inactivated vaccines, mRNA vaccines, adenovirus vaccines, etc. Although clinical treatment strategies have been optimized to save lives and improve prognosis, safe and effective vaccines will have far-reaching effects on controlling and stopping the COVID-19 pandemic. Public health significance.

Clinical trials are indispensable to determine the safety and effectiveness of the COVID-19 vaccine. In the future, it is necessary to commit to medical strategies for children, the elderly, and pregnant women and provide complete medical equipment and basic medical conditions.

(source:internet, reference only)

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