The Newcastle pneumonia epidemic has been ravaging the world for more than two years, and the virus continues to iterate and mutate, increasing its transmission power significantly. In the face of the global sweep of the Omicron strain, Zhang Wenhong, director of the National Center for Infectious Diseases and chief of the Infection Division at Huashan Hospital, Fudan University, said that a country and region need a strong immune barrier and medical resources to protect against threats such as the Omicron variant.

In China, mRNA vaccine research started late. Since the outbreak of the new crown epidemic, the government has laid out five technical routes, of which mRNA vaccines are one. The state's policy support and investment have facilitated the rapid development of mRNA vaccines in China. The development of vaccines and novel therapies based on mRNA technology is one of the important frontiers of biopharmaceutical development nowadays. Since the beginning of the epidemic, the research and development of new mRNA vaccines has continued to be enthusiastic. A number of strong companies, such as SMC and Able Bio, have emerged and attracted much attention. Currently, domestic companies, represented by SMC and AIB, are actively conducting clinical research on new coronavirus mRNA vaccines.

Messenger RNA (mRNA) is a single-stranded RNA transcribed from a strand of DNA as a template, carrying genetic information and capable of directing protein synthesis, which plays a key role in the transmission of genetic information and regulation of physiological activities. mRNA vaccines are based on the main biological functions of physiological mRNA, and the synthesized mRNA molecules are delivered to cells through lipid nanoparticles and other technologies to promote the development of mRNA vaccines. mRNA vaccines are based on the main biological functions of physiological mRNAs and deliver synthetic mRNA molecules to cells through technologies such as lipid nanoparticles to induce the production of specific proteins normally produced by pathogens or cancer cells, stimulating the body to generate an acquired immune response to recognize and destroy the corresponding pathogens or cancer cells.

As a platform technology, mRNA is used in a wide range of scenarios and is currently used to develop preventive vaccines, therapeutic vaccines or drugs. The use of mRNA to encode different proteins can be used for tumor therapy, rare disease treatment, gene editing, protein supplementation therapy, infectious disease prevention, and immunotherapy, among others. Today, there are over 150 cumulative mRNA vaccine and drug pipelines for infectious diseases, oncology, protein replacement and gene therapy, most of which are currently in early stage or clinical trials.

Globally, BioNTech and Moderna are the first companies to initiate the development of mRNA vaccines. Both companies have designed their vaccines with liposome-encoded neocoronavirus stinger protein mRNAs that, when introduced into human cells, synthesize a large amount of viral protein from the introduced exogenous mRNAs, inducing the body's immune system to recognize the protein and generate immunity to neocoronavirus to fight the virus.

On December 2, 2020, Pfizer and BioNTech collaborated on the development of a new coronavirus mRNA vaccine, BNT162b2, which became the world's first neocoronavirus vaccine to be marketed with an emergency use authorization in the U.K. On December 11, BNT162b2 was granted emergency use authorization by the FDA in the U.S. On December 18, 2020, Moderna was also granted emergency use authorization by the FDA in the U.S. On December 18, 2020, Moderna also received emergency access approval from the FDA. Not long ago, Pfizer CEO Albert Bourla publicly stated that the company's specific vaccine against the Omicron variant would be ready in March of this year.

In June 2021, SMC completed a new round of financing to accelerate clinical studies of new vaccines, build a GMP production plant, and expand its R&D pipeline. In June 2021, SMC completed a new round of financing to accelerate clinical research, build a GMP production plant and expand its R&D pipeline. Ltd. was established in January 2019. At the same time, other companies involved in mRNA vaccine development in China include Levantar, Conviction Bio, Blue Magpie Bio, Ruiji Bio, Houcun Nano, and Meno Heng Kang.

By the end of 2020, two new coronavirus mRNA vaccines (mRNA-1273 and BNT162b2) were approved for emergency use authorization worldwide. Phase III clinical trial results have demonstrated effectiveness of over 94% in preventing symptomatic neo-coronavirus disease. The immunization doses, storage conditions and population groups differ between the two vaccines. Immunization with 30 μg of BNT162b2 mRNA vaccine had fewer side effects than immunization with 100 μg of mRNA-1273 vaccine, and Pfizer-BioNTech vaccine had 90% and 75% protection against B.1.1.7 and B.1.351 infections, respectively, after 14 days of full immunization; the vaccine was 100% effective against severe, critical or fatal disease.

Currently approved mRNA vaccines are effective in protecting against infection with classical strains, but multiple mutations of the new coronavirus have raised concerns about increased transmission and the potential for these mutants to bypass natural infection or vaccination. The Delta strain has a 60% increase in infectivity and a 45% increase in immune escape capacity relative to the original New Coronavirus strain. Data from several studies suggest that mRNA vaccines remain relatively effective against the Delta strain, with Public Health England (PHE) surveys reporting that two complete doses of BNT162b2 vaccine were 88% effective in preventing symptomatic infection with the Delta strain and 95% effective in preventing hospitalization. Preliminary results from the current study show that the neutralizing effectiveness of the two doses of BNT162b2 against the Omicron strain, which is of global concern, decreased 25-fold, although after the third booster dose, the neutralizing antibody titers against the Omicron strain returned to their initial levels and were effective against the Omicron strain. This shows that the mRNA vaccine has a clear advantage against mutated strains.

In fact, since July-August 2020, SMC has been conscious of the fact that the most advanced antigen design, prefusion P2, which is commonly used by Modrrna and Pfizer internationally, is the key to efficient antibody production in mRNA vaccine technology, and has taken the lead in designing and developing an iterative vaccine, not only using P2 but also Novovax. This was one of the most advanced designs in the world, not only by applying P2 technology but also by adding Novovax's fusin mutation.

At the same time, recognizing that the virus was bound to mutate, SMC designed a vaccine against the mutated strain, based on the then British strain (D614G). Although multiple variants of the new coronavirus have been produced since then, including delta , omicron, the components of D614G are all present. This is the reason why the iterative vaccine of SIV can resist the delta and omicron variants.

As the epidemic is raging, there is no time to wait for the research of new crown mRNA vaccine in China. In the opinion of Li Hangwen, co-founder and chairman of SMC, it is important to seize the first opportunity, but the core concept to stay ahead in the mRNA race, achieve sustainable development and finally reach the expected goal is to evaluate our strengths and weaknesses comprehensively and make targeted improvements and refinements.

In the new crown mRNA vaccine R&D track, there are still opportunities for Chinese companies to accelerate the development of new crown vaccine products. Because there are no mature products listed in Europe and the United States in these fields; accelerate the construction of production capacity to form a real industrialization capability to really solve the problem of localization supply chain; at the same time, the patent work should be strengthened, and then really solve the patent problem. According to Li Hangwen, after the new crown, the requirements for patents in Europe and America will be strict, and Chinese companies need to strengthen the research and development of truly independent innovation patents.

As an innovative drug, mRNA has some advantages that traditional drugs do not have; at the same time, the increasing maturity of personalized vaccine technology also makes mRNA drugs hot. As the chairman of mRNA technology platform innovator, Hangwen Li believes that mRNA is now closely integrated with vaccine technology, nano-delivery, immunotherapy and gene therapy, providing new methods and ideas to solve infectious diseases, cancer and genetic diseases.

Firstly, mRNA vaccines are safe because they are non-infectious and non-integrating. mRNAs can be translated into proteins in the cytoplasm without entering the nucleus of target cells, so there is no potential risk of host infection or mutagenic integration into the host cell genome. Secondly, mRNA vaccines are effective in inducing not only humoral but also cellular immunity, while avoiding T-cell failure that may result from continuous antigen expression; thirdly, mRNA vaccines are easy to produce and have the potential for rapid, low-cost production and rapid capacity expansion.

In view of the unique advantages of mRNA vaccines in the prevention and control of NCCP, the R&D and industrialization of mRNA technology will definitely enter a stage of emergence and development at an increasingly rapid pace in the future. SMC is an mRNA platform and technology-based company, and the New Crown mRNA vaccine is only one of the many R&D pipelines of SMC. The mRNA technology is a new technology and has great promise for drug development. mRNA technology can be used to develop all kinds of drug therapies, such as replacement therapy and modified car-T therapy. It is foreseeable that a large proportion of drugs will be mRNA drugs in the future.

The government and companies in Europe and the US have already invested heavily in mRNA technology research and continue to invest more in it, and more Chinese R&D companies are likely to enter the field of mRNA vaccines in the future, said Hangwen Li. mRNA technology research and development will not only be limited to infectious diseases, but will also develop rapidly in tumor vaccines, protein replacement therapies, rare disease treatment and other aspects.

"Delivery technology is the core barrier of mRNA industry, how to precisely deliver in vitro transcribed mRNA to specific types of cells, i.e. targeted drug delivery, inhalation drug delivery, etc., still needs continuous efforts." Li Hangwen pointed out that European and American companies generally have more complete delivery system patents, and are also investing a lot of manpower and resources to develop new patents again. It is understood that, in addition to mRNA-based candidate factor expression technology, mRNA-based gene editing is also receiving increasing attention in scientific research.

In fact, currently, vaccines for infectious diseases are the main direction and pillar products of biopharmaceutical companies. At the same time, companies are vigorously developing oncology products, antibody products, gene therapy products, etc. Internationally, mRNA production capacity has been developed to hundred grams to kilograms, continuous automated production has become a trend, nano-formulation technology tends to adopt new processes, and upstream and downstream industry chains tend to gather and integrate. According to Hangwen Li, for Chinese companies, the scale up 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 to scale up.

In the process of mRNA vaccine design and preparation, techniques such as modifying nucleosides can significantly inhibit the immune recognition of exogenous mRNA in the organism, thus reducing the toxic side effects and improving the efficiency of mRNA expression. In addition, the purity of in vitro synthesized mRNA is critical, especially the double-stranded RNA impurities that may be generated during mRNA synthesis can be recognized by Pattern Recognition Receptors (PRRs), thus generating unwanted non-specific immune responses and inhibiting the production of candidate immunogens. According to Hangwen Li, Chinese companies are still tracking the international level in modifying nucleosides to reduce side effects, and lack independent intellectual property rights for nucleoside modification methods and patent protection. Meanwhile, there is a lack of large-scale systematic and comprehensive comparative studies on the relationship between clinical effects, side effects and prognostic responses of mRNA therapies.

In the opinion of Hangwen Li, all of the above may be difficulties for the development of mRNA therapies in China in the future, but they will also become new directions for Chinese biopharmaceutical companies to strive and develop.

Translated with www.DeepL.com/Translator (free version)