The COVID-19 pandemic has been raging around the world for more than two years, and the virus has been iteratively mutating and its spread has increased significantly. In the face of the Global Sweep of the Aomi Kerong strain, Zhang Wenhong, director of the National Infectious Disease Medical Center and director of the Department of Infectious Diseases of Huashan Hospital affiliated to Fudan University, said that a country and region need a strong immune barrier and medical resources to resist the threat of the Aomi Kerong mutation.
In China, mRNA vaccine research started late. Since the outbreak of the new crown epidemic, the government has laid out five technical routes, mRNA vaccine is one of them, and the national policy support and investment have promoted the rapid development of domestic mRNA vaccines. Related vaccines and new therapies developed based on mRNA technology are one of the important frontiers in the development of biomedicine. Since the beginning of the epidemic, the research and development of the new crown mRNA vaccine has not decreased. A number of strong enterprises such as Si Microbial and Aibo Bio have emerged, attracting attention from many parties. At present, domestic enterprises represented by Si Microbial and Aibo Bio are actively carrying out clinical research on the new coronavirus mRNA vaccine.
Messenger ribonucleic acid (mRNA) is a type of single-stranded ribonucleic acid that is transcribed from a chain of DNA as a template, carries genetic information and can guide protein synthesis, and plays a key role in the transmission of genetic information and the regulation of physiological activities in life. mRNA vaccine is the main biological function of physiological mRNA, the synthesized mRNA molecules are delivered to cells through technologies such as lipid nanoparticles, which promote cells to produce specific proteins usually produced by pathogens or cancer cells, stimulate the body to produce an acquired immune response, thereby recognizing and destroying the corresponding pathogens or cancer cells.
As a platform technology, mRNA is widely used and is currently mainly used to develop preventive vaccines, therapeutic vaccines or drugs. The mRNA is used to encode different proteins and can be used in tumor therapy, rare disease treatment, gene editing, protein supplementation therapy, infectious disease prevention, and immunotherapy. At present, there are more than 150 mRNA vaccine and drug research pipelines in the world, mainly for infectious diseases, tumor diseases, protein replacement and gene therapy, most of which are currently in the early stage or clinical trial stage.
Globally, BioNTech and Moderna launched the development of mRNA vaccines at the first time. Both companies use a liposome-encapsulated vaccine design encoding the new coronavirus spike protein mRNA, when the vaccine enters human cells, it can synthesize a large number of viral proteins through imported foreign mRNA, inducing the body's immune system to recognize this protein and generate immunity to the new crown virus to resist viral infection.
On December 2, 2020, the novel coronavirus mRNA vaccine BNT162b2, developed by Pfizer and BioNTech, was granted an emergency use authorization in the United Kingdom, becoming the world's first covid-19 vaccine to be licensed for use, which is of landmark significance. On December 11, BNT162b2 was granted emergency access rights approved by the U.S. FDA. On December 18, 2020, Moderna also obtained emergency use rights approved by the U.S. FDA. Not long ago, Pfizer CEO Albert Bourla publicly stated that the company's specific vaccine against the Aumiqueron variant will be ready in March this year.
Founded in May 2016, Siwei (Shanghai) Biotechnology Co., Ltd. (hereinafter referred to as "Siwei") is one of the first platform enterprises in China to carry out mRNA drug research and development. In June 2021, Smicrobial completed a new round of financing to accelerate clinical research on COVID-19 vaccines, the construction of GMP production workshops, and the expansion of R&D pipelines. Suzhou Aibo Biotechnology Co., Ltd. (hereinafter referred to as "Aibo Biotechnology") was established in January 2019. At the same time, China is involved in the research and development of mRNA vaccines, such as Livanda, Xinxin Biology, Blue Magpie Biology, St. Regis Biology, Houcun Nano, Anderson Anderson.
At the end of 2020, two novel coronavirus mRNA vaccines (mRNA-1273 and BNT162b2) were approved for emergency use worldwide. The results of Phase III clinical trials show that the effectiveness of preventing symptomatic COVID-19 diseases is as high as more than 94%. The immunization dose, storage conditions and applicable populations are different. Immunizing the 30 μg BNT162b2 mRNA vaccine has fewer side effects than immunizing the 100 μg mRNA-1273 vaccine. The Pfizer-BioNTech vaccine is 90% and 75% effective against B.1.1.7 and B.1.351 infections after 14 days of full immunization; the vaccine is 100% effective against serious, critical or fatal diseases.
The currently approved mRNA vaccine is effective in protecting infections of classic strains, but the coronavirus's multiple variants raise concerns about increased transmission and the possibility that these mutant strains could bypass natural infection or vaccination. Compared with the original COVID-19 strain, the infectivity of the Delta strain increased by 60% and the immune escape capacity increased by 45%. Some research data show that the mRNA vaccine remains relatively efficient against the Delta strain, and the public health England (PHE) survey report shows that the complete vaccination of two doses of the BNT162b2 vaccine is 88% effective in preventing symptomatic infection of the Delta strain and 95% effective in preventing hospitalization. The current preliminary research results show that for the Omicron strain that has attracted global attention, the neutralizing antibody titer of 2 doses of BNT162b2 after inoculation has decreased by 25 times, but after the third injection of the booster needle, the neutralizing antibody titer of the Omicron strain has returned to the original level, which can effectively defend against the Omicron strain. Thus, mRNA vaccines have clear advantages over mutant strains.
In fact, from July to August 2020, Si Microorganism soberly realized: First, the most advanced antigen design commonly used by Moderna and Pfizer in the world: prefusion P2, is the key to the production of efficient antibodies by mRNA vaccine technology, so it took the lead in designing and developing an iterative seedling, not only using P2 technology, but also adding Novax's fusin mutation, thus becoming one of the most advanced designs in the world.
At the same time, Sys microbials realized that the virus must mutate, so according to the British strain at that time (D614G), a vaccine against the mutant strain was designed. Although the new coronavirus has since produced a variety of variants, including delta, omicron, the composition of D614G is inside. This is why the iterative seedlings of Siwei can resist the delta, omicron mutant strain.
In the view of Li Hangwen, co-founder and chairman of Si microbiology, it is important to seize the opportunity, but comprehensively assessing its own strengths and weaknesses for targeted improvement and improvement is the core concept of maintaining a leading position on the mRNA track, achieving sustainable development, and ultimately achieving the expected goals.
In the new crown mRNA vaccine research and development track, to accelerate the research and development of new crown vaccine products, Chinese companies still have opportunities. Because in these areas, Europe and the United States do not have mature products on the market; accelerate the construction of production capacity and form a real industrialization capacity to truly solve the problem of localization supply chain; at the same time, patent work should be strengthened to truly solve the patent problem. Li Hangwen believes that after the new crown, the requirements for patents in Europe and the United States will be strict, and Chinese enterprises need to strengthen the research and development of truly independent innovation patents.
As an innovative drug, mRNA has some advantages that traditional drug types do not have, and the maturity of personalized vaccine technology has also made mRNA drugs hot. As the chairman of the mRNA technology platform innovation enterprise, Li Hangwen believes that mRNA is currently closely integrated with vaccine technology, nano-delivery, immunotherapy and gene therapy, providing new methods and ideas for human beings to solve infectious diseases, cancer and genetic diseases.
Li Hangwen explained in detail: First of all, mRNA vaccine has high safety, it has non-infectious, non-integrative and other characteristics, mRNA does not need to enter the nucleus of the target cell can be translated into proteins in the cytoplasm, so there is no potential risk of host infection or the risk of mutagenesis integrated into the genome of host cells; secondly, mRNA vaccines have a good effect, not only can induce humoral immunity of the body but also induce cellular immunity, while avoiding T cell failure that may be caused by continuous antigen expression Third, mRNA vaccines are easy to produce, with the potential to be produced quickly, cheaply, and rapidly expand capacity.
In view of the unique advantages of mRNA vaccines in the prevention and control of the new crown pneumonia epidemic, in the future, the research and development and industrialization of mRNA technology will surely enter a sudden stage, and the development speed will become faster and faster. Sigbiology is a mRNA platform and technology enterprise, and the new crown mRNA vaccine is just one of the many research and development pipelines of Scorpio. On the future development prospects of mRNA therapy, the microbial decision-making level has a clear and calm view: mRNA technology is a new technology, which has great prospects for drug research and development, and can use mRNA technology to carry out all drug treatments, such as: alternative treatment, modified car-T treatment, etc. It is foreseeable that a large proportion of drugs will be mRNA drugs in the future.
Li Hangwen said that the governments and enterprises of Europe and the United States and other countries have invested heavily in the field of mRNA technology research and continue to increase investment, and more Chinese research and development companies may pour into the field of mRNA vaccines in the future. The research and development of mRNA technology will not only be limited to the field of infectious diseases, but also rapidly develop in tumor vaccines, protein replacement therapies, rare disease treatments and other aspects.
"Delivery technology is the core barrier of the mRNA industry, and how to accurately deliver in vitro transcriptional mRNA to specific types of cells, that is, targeted administration, inhalation administration, etc., still requires continuous efforts." Li Hangwen pointed out that European and American enterprises generally have relatively complete delivery system patents, and they are also investing a lot of manpower and material resources to develop new patents. It is understood that in addition to mRNA-based candidate factor expression technology, mRNA-based gene editing has also received more and more attention from scientific research.
In fact, at present, infectious disease vaccines have become the main direction and pillar products of various biomedical enterprises. At the same time, companies are vigorously developing tumor products, antibody products, gene therapy products and so on. Internationally, mRNA production capacity has developed to 100 grams to kilograms, continuous automated production has become a trend, nano preparation technology tends to adopt new processes, and upstream and downstream industrial chains tend to aggregate and integrate. Li Hangwen believes that for Chinese enterprises, the large-scale production process is still a bottleneck, the cost of raw materials and consumables is still very high, and the supply of raw materials is also a challenge for scale.
In the design and preparation of mRNA vaccines, techniques such as modified nucleosides can significantly inhibit the body's immune recognition of exogenous mRNA, thereby reducing toxic side effects and improving the expression efficiency of mRNA. In addition, the purity of synthetic mRNA in vitro is critical, especially when the double-stranded RNA impurities that may be generated during mRNA synthesis are recognized by pattern recognition receptors (PRR), resulting in unnecessary non-specific immune responses and inhibiting the production of candidate immunogens. Li Hangwen said bluntly that in terms of modifying nucleosides to reduce side effects, Chinese companies are still at the international level of tracking, and lack of independent intellectual property rights of nucleoside modification methods and patent protection. At the same time, the relationship between the clinical effects, side effects and prognostic responses of mRNA therapy has not been studied on a large-scale systematic and comprehensive basis.
In Li Hangwen's view, although the above may be difficult for the development of mRNA therapy in China in the future, it will also become a new direction for the efforts and research and development of Chinese biomedical enterprises.
*Cover image source: 123rf