COVID-19: Inactivated accine VS mRNA vaccine

COVID-19: Inactivated accine VS mRNA vaccine. The COVID-19 virus epidemic has not ended yet. The mutation of the virus and the Spring Festival travel of the population is about to come. Now the best way to fight the epidemic is vaccines.

There are currently seven types of new coronavirus vaccines developed by various countries:

• Inactivated vaccines,
• Attenuated vaccine,
• Viral vector vaccine,
• Protein subunit vaccine,
• DNA vaccine,
• Nucleic acid vaccine
• Nanoparticle vaccine.

And China has five technical routes:

• Inactivated vaccine
• Attenuated vaccine with influenza virus as carrier,
• Adenovirus vaccine,
• Nucleic acid vaccine,
• Protein subunit vaccine.

Among them, there are mainly two types of vaccines: China’s inactivated virus vaccines and Pfizer’s mRNA vaccines in the United States. What are the differences between these two types, and their advantages and disadvantages, this article will introduce systematically.

Inactivated virus vaccine

At present, China’s COVID-19 vaccine is leading the world and close to perfect. The reason is that China’s inactivated virus vaccine has the following advantages:

1) Inactivated virus vaccine technology has been quite mature, safe and stable in the development of more than 100 years.

Among the 50 or 60 vaccines that have been marketed in China, the inactivation technology route accounts for 2/3 of them. In addition, even the technical route of inactivated vaccines is qualitatively different from that of inactivated vaccines decades ago. From cell culture methods, culture media, carriers, culture vessels, purification media and processes, quality inspection methods and quality Control indicators have systematically improved the technological content of inactivated vaccines.

2) The effective rate can reach about 80% of the peak in inactivated virus vaccines.

On December 30, the Phase III clinical trial data of China’s new biological COVID-19 vaccine approved by the National Food and Drug Administration was announced. The data showed that the protection rate of the interim analysis of the Phase III clinical trial was 79.34%. The positive conversion rate of neutralizing antibody was 99.52%.

3) The storage and transportation conditions are not very demanding.

It can be stored at room temperature for 1 week or at 2~4℃ for a long time (it is expected to reach 36 months), and the cold chain cost is low. Can achieve mass vaccination among the population.

In particular, the last one is definitely the only one in the world that can quickly cover a large area, and it can be vaccinated almost anywhere, so as to effectively prevent and help economic recovery. According to the forecast of the IMF, in 2020 and 2021, the GDP losses of various countries will reach a staggering 12 trillion US dollars.

At present, Pfizer’s mRNA vaccine needs to be stored at -70 degrees. This is because the single-stranded mRNA is unstable and easily degraded. This problem has caused false negative results in the nucleic acid test of the new coronavirus. When testing, it is necessary to reverse transcribed RNA into DNA before testing.

Therefore, the stability of the mRNA vaccine has yet to be resolved, and it should be difficult to solve in a short time. Therefore, the vaccine needs to be stored and transported under minus -70 degrees, which can be stable for 6 months, and only under 2-8°C. Can be stable for 5 days. This condition has very low adaptability to the vaccinated communities or various situations around the world. Therefore, China’s new coronavirus inactivated virus vaccine is very good.

Why don’t other countries make inactivated vaccines?

The production of inactivated vaccines requires manufacturers to have Level 3 biosafety protection standards. At that time, China temporarily transformed the P3 laboratory used for experiments into an environment where vaccines can be produced.  As there are many biosafety issues,  Biotech companies in Europe or U.S. didn’t do same.

mRNA vaccine

However, mRNA vaccines also have huge irreparable advantages over traditional inactivated virus vaccines:

1) The development cycle is short and the production process is relatively simple.

As long as you know the gene sequence of the virus, you can design a new candidate mRNA vaccine within a few days. The current in vitro transcription technology can produce RNA vaccines on a large scale very quickly and cheaply. Compared with the traditional vaccine production cycle of 5-6 months, mRNA vaccines The vaccine is expected to complete the production and preparation of vaccine samples within 40 days, so it is expected to better respond to sudden infectious diseases.

For example, on January 11, China shared the entire sequence of the new coronavirus RNA with the world, which means that from this moment, “wishful people” with mRNA vaccine technology can begin vaccine development.
On January 13th, Moderna Corporation of the United States announced that it had cooperated with the National Institute of Allergy and Infectious Diseases under the National Institutes of Health (NIH) (NIAID, the chief epidemiologist Fauci of the United States is the director of this institute). The Vaccine Research Center (VRC) cooperated to start the development of the COVID-19 vaccine.

2) There are no viral components and many allergens are avoided.

The mRNA vaccine is to use machine-synthesized mRNA fragments and then wrap them in a lipid envelope to produce tiny plasmids. There are no components directly derived from viruses, there are no safety risks brought by viruses, and it can also reduce the appearance of allergic reactions. Inactivated virus vaccines are difficult to completely avoid medium residues, stabilizers, antibiotics, preservatives, latex, and adjuvants, which may become allergens.
Allergies are very common in daily life. In developed countries, about a quarter of people suffer from one or more allergic diseases. (We have not found statistics on allergies in China for the time being) Therefore, the safety of the COVID-19 vaccine should be treated scientifically. After the vaccine is injected, there may still be some systemic or local adverse (or allergic) reactions, such as fever, muscle aches, nausea, headache and other systemic adverse reactions, as well as local adverse reactions such as pain, redness and swelling at the injection site, according to the process technology There will be differences in different routes.

Severe allergic reactions caused by common vaccination

Of course, adverse reactions (or allergic reactions) are divided into mild, moderate, and severe. There has not been a single case of severe adverse reactions among all the volunteers currently vaccinated with the COVID-19 inactivated vaccine developed in China, and most of the adverse reactions produced are mild. The most common adverse reaction is also local pain at the injection site. These can also be treated well based on the current medical level.

3) Dual action mechanism, so the effective rate can reach more than 95%.

The mRNA vaccine can stimulate the body’s humoral immunity and T cell immunity, and is highly immunogenic. In contrast, traditional vaccines mainly only activate humoral immunity and weakly activate cellular immunity. Because the mRNA vaccine is expressed in human muscle cells, etc., antigen markers appear on the surface of the cell membrane, which are then recognized by cytotoxic T cells and generate memory T cells to produce cellular immunity.

In the section of “Immune Regulation” in the high school biology textbook, the types and activation methods of specific immunity are mentioned: In cellular immunity, cytotoxic T cells need the stimulation and differentiation of target cells, and then act on target cells.

Inactivated virus is to cultivate the new coronavirus to a state of low toxicity and then inactivate it, that is, it loses the ability to infect cells, but maintains antigenicity, which can cause the recognition of helper T cells and B cells, and then generate humoral immunity And memory B cells; but because they lose the ability to infect, that is, they cannot enter normal human cells. There is no host cell or target cell. As a result, cytotoxic T cells have no recognizable antigen molecules on the cell membrane surface and cannot stimulate If cellular immunity is produced, there will be no memory T cells. Therefore, the protection rate of the inactivated virus vaccine cannot reach 95% or more.

After introducing the mRNA vaccine, it can be found that there are many advances compared to the inactivated virus vaccine, but the biggest challenge and risk facing the mRNA vaccine at this stage is-a lot of uncertainties:

• a. The mRNA vaccine does not inactivate many of the allergens in the virus vaccine, but there are still cases of severe allergies. At present, the mechanism of allergies is still in a state of unclear, which requires special attention.
• b. For the first time when it is applied to healthy people, the subsequent long-term effects on the human body are temporarily unknown, perhaps still full of uncertainty. After all, it enters normal cells. What else can it cause besides causing cellular immunity? Just like the impact of genetically modified animals and plants on humans, I don’t know a clear answer.

The discovery of the central law confirms that RNA plays an important role as a bridge between DNA and protein. As early as the 1990s, scientists injected in vitro transcribed mRNA into mice, and found that it can be expressed in mice to produce related proteins that are dose-dependent and can induce immune responses. This is the embryonic form of mRNA vaccines. Therefore, when the mRNA encoding the antigen protein is injected into the human body, the antigen protein can be synthesized in the body to cause the human immune response to fight pathogen infection, which is an mRNA vaccine.

Although the role of mRNA as a vaccine was discovered in the 1990s, the subsequent development was not smooth. The stability of mRNA and drug delivery are the main issues that need to be faced. Naked mRNA is easily attacked by RNA cleaving enzymes in the body, and mRNA also needs to be efficiently delivered into cells for translation and function.

The key technology of mRNA vaccine: RNA modification and delivery

Although it seems a simple step to “enter the cell”, how to modify the sequence, how to design a suitable delivery system, how to be safe and non-toxic and other technical problems, each step of the technology must be precise, just like the success of Chang’e 5’s flight to the moon. Not open to the accumulation and deposition of each technology. From the failure of the first immune test of the mRNA vaccine to its successful development, it took about 25 years for scientific research around the world to usher in today’s first official mRNA vaccine approval.

Main application areas of mRNA vaccines

Although there are many uncertainties, it is difficult to conceal the impact of mRNA vaccines on humans in the future:
Different from common preventive vaccines, the main development direction of mRNA technology currently lies in therapeutic vaccines. Due to the characteristics of rapid, individual design and synthesis of mRNA, it has also become a good solution for personalized vaccines in the context of precision medicine, especially for cancer diseases with extremely high heterogeneity. In addition to immunotherapy, mRNA can also directly express functional proteins used to treat diseases, monoclonal antibodies that target specific antigens, and serve as gene editing methods in the process of cell therapy. Its main application areas are as follows:

• Anti-tumor mRNA vaccine
• Infectious disease mRNA vaccine
• Rare disease mRNA vaccine

At present, many foreign companies have already engaged in research and therapeutic applications in these directions, such as:

United States: Moderna Corporation,

Founded in 2010, the company’s mRNA drug R&D covers infectious diseases, tumors, cardiovascular diseases and rare genetic diseases. From the perspective of the company’s R&D pipeline, 15 of the company’s 23 projects under development have entered clinical research, and the fastest vaccines are the therapeutic tumor vaccine mRNA-4157 for solid tumors and the preventive vaccine mRNA for cytomegalovirus- 1647, in clinical phase II.

Germany: BioNTech

Founded in 2008, it is one of the largest and fastest-growing biotech companies in Europe. The company has built four major technology platforms, including mRNA therapy platform, cell and gene therapy platform, protein therapy platform, and small molecule therapy platform, covering therapeutic fields such as tumors, infectious diseases and rare diseases, while its clinical pipeline is mainly focused on mRNA In terms of tumor treatment, the combination of the personalized mRNA tumor vaccine iNeST (BNT122) and immune checkpoint inhibitor jointly developed with Genentech for the treatment of metastatic melanoma is progressing fastest and is in clinical phase II.

Germany: CureVac

Established in 2000, it started the first vaccine development work based on mRNA technology in 2011. It is the only unlisted company among the mRNA “Big Three”. The company has 4 RNA technology platforms: RNActive, RNArt, RNAntibody and RNAdjuvant, focusing on the development of therapeutic mRNA therapies for tumors, rare diseases and infectious diseases. At present, the company’s tumor vaccine CV8102 for melanoma, etc., tumor vaccine CV9202 for non-small cell lung cancer, and CV7202, a preventive vaccine against rabies virus, have all entered clinical phase I, and the new coronavirus vaccine is in the preclinical development stage, originally planned for 2020 From June to July 2007, it was declared to enter clinical trials. In June, there was news that the German government would buy a stake in Curevac to prevent it from leaving Germany; in July, Tesla CEO Elon Musk tweeted that Tesla would build an RNA micro factory for CureVac.

In addition to the above three most representative mRNA companies, there are still foreign companies:

• TranslateBio and Inc.,
• eTheRNA Immunotherapies,
• ethris GmbH,
• Argos Therapeutics, Inc,
• In-Cell-Art,
• Tiba Biotech,
• Arcturus Therapeutics Holdings Inc.,
• ArbutusBiopharma Corporation,
• Acuitas therapeutics

The above are world-renowned mRNA companies, each with their expertise in synthesis, delivery and other fields.

(source:internet, reference only)

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