2 Covid-19 Vaccines have been Approved for Marketing, What is the Future Prospect of mRNA Vaccines?

According to FiercePharma statistics, the list of TOP20 companies with total revenue in 2021 has been released. Pharmaceutical giants such as Johnson & Johnson, Pfizer, and Roche still occupy the list firmly. It is worth noting that thanks to the good performance of mRNA vaccines, Moderna and BioNTech entered the list for the first time. In the top 20, the sales increased by dozens of times. The COVID-19 pandemic has brought the mRNA technology to the market for the first time from the experimental field, and has demonstrated its great value and potential. The attention to mRNA-related technology products has reached an unprecedented level.

01 Introduction to mRNA Vaccines

mRNA (ribonuclease) is a type of single-stranded nucleotide that is transcribed from one strand of DNA and carries genetic information that directs protein synthesis. The principle of mRNA vaccine treatment is that mRNA encoding one or more target antigens is delivered to the host, and the target antigen is translated and expressed, so that the body recognizes the antigen and produces an immune response. mRNA research began in the 1960s. Due to the instability in vitro and the lack of a good delivery system, the research progress was slow. Before the mRNA covid-19 vaccine was launched, the research on mRNA was in the laboratory. At present, mRNA vaccines are mainly divided into two types, non-replicating mRNA and self-amplifying mRNA. The structure of non-replicating mRNA is relatively simple, including 5' cap end, ORF open reading frame, 5' and 3' structure and poly A tail structure (As shown in Figure A), most of the mRNA vaccines currently under development and on the market are of this type. On this basis, self-amplifying mRNA adds a sequence that encodes an RNA-dependent RNA polymerase complex (as shown in Figure B), which can encode viral proteins to complete replication and amplification in vivo. Therefore, self-amplifying mRNA vaccines can pass small The dose can obtain a higher level of antigen expression, but the disadvantages are also obvious, the preparation is complex, and the replicating protein may bring unexpected immune responses. The self-amplifying RNA vaccine ARCT-154 developed by Arcturus Therapeutics has entered Phase III clinical trials test.

Vaccines generally include inactivated virus vaccines, virus vector vaccines, recombinant protein vaccines, DNA vaccines, etc. Compared with vaccine technical routes and vaccination effects, mRNA vaccines have the following advantages:

1. High R&D and production efficiency: mRNA can encode and express all antigenic epitopes. Faced with the variation of viral antigens, mRNA encoding different antigens follows the same design and process flow, and mRNA production does not depend on cell culture, and the in vitro transcription process is mature. It has high synthetic production efficiency.

2. High safety: Compared with the risk of integrating DNA vaccines into genetic material, after mRNA vaccines enter cells, protein translation is performed in the cytoplasm without causing the risk of insertional mutations, and mRNAs are easily metabolized, which is less harmful to the body. The production of mRNA vaccines does not involve viral components, and the safety is high.

3. High immune efficiency: mRNA vaccine enters the body, and the expression of virus-specific protein can not only induce humoral immunity, but also induce T cell immunity through antigen presentation.

mRNA alone is easily degraded by enzymes in body fluids or phagocytosed by the phagocytic system, and needs to penetrate the cell membrane and enter the cytoplasm to function. Therefore, the delivery system has high requirements and usually needs to have the following capabilities:

(1) Capable of encapsulating mRNA and successfully passing through the in vivo circulatory system without being phagocytosed by RNA-degrading enzymes or mononuclear-phagocytic cells;

(2) The delivery system is biocompatible with the cell membrane, and mRNA is delivered into the cell through endocytosis;

(3) Entering the cytoplasmic delivery system can release the carrying mRNA in time.

The currently developed delivery systems include lipid nanoparticles, cationic liposomes, cationic nanoemulsions, polymers, cell-penetrating peptides, and novel drug carriers. Lipid nanoparticles (LNP) are the most mainstream delivery systems at present. BioNTech and The mRNA vaccines listed by Moderna all use the LNP delivery system.

02mRNA vaccine marketing and clinical progress

In 2018, the global mRNA drug market size was 3.43 billion US dollars, and it will rise to 3.92 billion US dollars in 2020, with a compound annual growth rate of 7%. In the future, the global mRNA drugs will maintain a steady upward trend, according to a report published by the Boston Consulting Group in the nature subsidiary. The article predicts that the overall market size of mRNA vaccines will reach about US$12 billion by 2035, and the successful listing of mRNA vaccines will also bring market opportunities for therapeutic mRNA vaccines and mRNA therapeutic drugs. In 2020, two mRNA vaccines, BioNTech and Moderna, were approved for marketing. The protective efficacy of the vaccines in phase III clinical trials was 95% and 94.1%, respectively. Although the incidence of adverse reactions such as local pain and headache after injection exceeded 50%, the academic community believes that it is known And the potential benefits far outweigh the adverse risks. As the two vaccines that the FDA has urgently approved for marketing, the production companies BioNTech and Moderna became famous in battle, with sales reaching US$18.8 billion and US$18.5 billion respectively in 2021, becoming a hot mRNA industry leader. , The research and development of mRNA drugs covers the fields of infectious disease prevention, tumor treatment and genetic disease treatment. By sorting out the mRNA vaccine pipeline layout of the two companies (as shown in Table 1), the pipeline in the field of mRNA vaccine is rich, mainly for infectious disease preventive vaccines, Focus on the prevention and treatment of COVID-19 and influenza.

The four giants in the vaccine industry, Pfizer, Merck, Sanofi, and GSK have long occupied major global market shares. In terms of mRNA, they have deepened their industry layout through cooperative acquisitions. For example, BNT162b2, a partnership between Pfizer and Biontech, will bring $36.781 billion in 2021. Sanofi cooperated with Biontech, Merck and Moderna to promote the research of mRNA in the field of tumor immunotherapy, and GSK and Curevac cooperated in the field of infectious disease prevention and treatment.

Domestically, the fastest progress is Watson Bio’s introduction of the mRNA vaccine ARCoV developed by Aibo Bio and the Military Medical Research Institute of the Academy of Military Sciences. The phase III clinical field work has been completed, and follow-up data collation and serum testing are underway. This vaccine Advantages: 2℃-8℃ storage and transportation conditions, single pre-filled dosage form, very convenient for cold chain transportation and vaccination use. Previously, in September 2021, the mRNA modular vaccine production plant of the new crown vaccine industrialization base was completed and delivered for use. The annual production capacity has reached 200 million doses, making sufficient preparations for the launch of the first domestically produced mRNA vaccine.

Sri Lanka Microorganism is an early enterprise that has carried out mRNA drug research in China. Its unique delivery system LPP is a double-layer structure with polymer-encapsulated mRNA as the core and phospholipid structure as the outer shell, which is better than LNP for encapsulating mRNA. The mRNA vaccine SW0123 developed according to this system has entered Phase II clinical trials. Since the biological activity of mRNA is easily affected by temperature, the listed mRNA vaccines have strict requirements on storage and transportation. Cold chain transportation may become one of the main factors affecting the volume of mRNA vaccines. Adjusting the formulation of mRNA-LNP preparations and adding suitable freeze-drying protective agents can realize the preparation stability of the vaccine under the conditions of 2 degrees and 25 degrees, and improve the accessibility of mRNA vaccines.

In addition, many companies such as Genting Xinyao and Zhuhai Livanda have applied for mRNA vaccines in clinical trials. With the good drive of the new crown vaccine, leading vaccine companies such as Watson Bio, Zhifei Bio, and Kangtai Bio have passed the mRNA vaccine. Drug innovation companies (Aibo Bio, Lanque Bio, Jiachen Xihai) have reached a strategic cooperation agreement to carry out research on mRNA vaccines in the field of infectious disease prevention and treatment, and the overall market is developing rapidly.

03 Development status of domestic mRNA vaccine industry chain

The "14th Five-Year Plan" for the development of the pharmaceutical industry points out that it will closely follow the development trend of vaccine technology, support the construction of mRNA vaccines, improve the guarantee level of the vaccine supply chain, and support the cooperation between vaccine enterprises and enterprises of important raw materials, consumables, production equipment and packaging materials, and improve various Class product quality and technical level. With the imminent commercial production of mRNA vaccines, the demand for raw materials and equipment in the upstream industries of mRNA vaccines will increase significantly. The production of mRNA vaccine mainly includes three steps: DNA stock solution generation, mRNA stock solution generation and delivery system packaging. The raw materials involved mainly include enzymes (RNA polymerase, linearase, modification enzyme, capping enzyme), DNA plasmids, lipids and Separation and purification of materials, etc. GenScript can provide the plasmids required for the whole process from preclinical to commercial production, and has reached a strategic cooperation with Watson Bio. Nearshore Protein, Kaika Bio, etc. can provide the enzyme raw materials required for translation and modification.

mRNA vaccine production equipment mainly includes fermenters, disposable bioreactors, chromatography columns, liquid chromatography, microfluidic equipment, etc. Domestic companies such as Tofflon, Jinyi Shengshi, and Concentration Technology have broken through the complete monopoly of foreign countries. To achieve domestic substitution, relevant equipment or solutions can be provided.

04 Summary

mRNA vaccines are in a blue ocean in the domestic market. Although no products have been approved for marketing yet, the listing of two new coronavirus vaccines abroad has greatly stimulated market enthusiasm. The research and development of mRNA vaccines at home and abroad is booming, and the upstream supply chain is domestically produced. The replacement process is accelerating, and it is foreseeable that there will be products on the market in the short term.