Large transactions reappear in the mRNA technology field, and domestic innovative pharmaceutical companies enter the new crown vaccine research and development

The COVID-19 pandemic has made mRNA technology a hot topic, and the investment of 3.2 billion yuan by domestic innovative pharmaceutical company Everest Pharmaceuticals in the development of mRNA vaccines has attracted attention. Can this represent the future direction of vaccine development?

Written by reporter Liu Daheng Edited by Liu Zhao

New Media Editor/Fang Yongzhen

The COVID-19 pandemic has put mRNA technology on the map, and major deals are now happening again in this field. On September 13, Everest Medicines, a Chinese innovative pharmaceutical company, announced that it had reached two definitive agreements with Providence Therapeutics (hereinafter referred to as "Providence"), a Canadian biotechnology company.

According to information disclosed by Everest Medicines, the first agreement is about obtaining authorization for Providence's mRNA COVID-19 candidate vaccine in emerging Asian markets such as Greater China, Southeast Asia, and Pakistan; the second agreement is about establishing a broad strategic partnership to use Providence's leading mRNA technology platform to develop mRNA products globally. In terms of the COVID-19 vaccine, Everest Medicines will pay Providence a $50 million advance payment and other royalties in cash. In terms of cooperative products, other products and mRNA technology platforms, Everest Medicines will pay Providence a $50 million advance payment in cash, and will pay up to $300 million in milestone payments in the form of stock in the future. The transaction totals $500 million (approximately RMB 3.2 billion).

(Photo source: Everest Medicines)

The COVID-19 pandemic has brought mRNA vaccines into the public eye

Vaccination is an effective way to prevent infectious diseases. With the widespread use of vaccines, countless lives can be saved every year around the world. Conventional vaccines such as inactivated, attenuated and subunit vaccines can provide protection against a variety of dangerous diseases.

The outbreak of the COVID-19 epidemic has brought a new type of vaccine, mRNA vaccine, into the public eye. mRNA (Messenger RNA) is a type of single-stranded RNA that carries genetic information and can guide protein synthesis and is transcribed from a strand of DNA as a template. mRNA vaccines introduce mRNA encoding disease-specific antigens into the body, and use the protein synthesis mechanism of host cells to produce antigens, thereby triggering the body's immune response. Usually, mRNA sequences of specific antigens can be constructed according to different diseases, which are packaged and transported into cells by new lipid nanocarrier particles, and then the human ribosomes are used to translate the mRNA sequences to produce disease antigen proteins, which are secreted and recognized by the body's immune system to produce immune responses, thereby achieving the effect of preventing diseases.

▲The working mechanism of mRNA vaccine (Image source/CDC)

With the development of medicine, especially in the past decade or so, significant technological innovation and research investment have made mRNA the most promising therapeutic tool in vaccine development and protein replacement therapy.

mRNA vaccines have advantages over traditional vaccines

According to the official website of the National Health Commission, as of September 14, 2021, a total of 215,693,800 doses of COVID-19 vaccines have been administered nationwide. Currently, four COVID-19 vaccines have been approved for conditional marketing in my country, and one vaccine has been approved for emergency use. The vaccines we commonly use are inactivated vaccines, which have mature technology and good stability and have been widely recognized. However, it is undeniable that inactivated vaccines also have problems such as insufficient activity, long production cycle, and low vector conversion rate.

Although mRNA vaccines are uncommon in most cases, they are by no means new and unknown technology, and they can be developed in the lab using readily available materials. This means the process can be standardized and scaled, making vaccine development faster than traditional vaccine manufacturing methods.

Since mRNA vaccines do not rely on cell amplification, their detection and quality control are relatively simple; secondly, since the time for cell culture and amplification is saved, the vaccine production capacity is greatly improved, and the speed of vaccine production is also increased. At the same time, mRNA vaccines can accurately express antigens and activate the dual immune mechanism of "humoral + T cells", with strong immunogenicity and no need for adjuvants.

Traditional vaccines such as attenuated vaccines and inactivated vaccines are generally transformed through vectors, and their immune efficiency is low. Studies have found that attenuated vaccines may also have toxic residues, leading to the risk of secondary infection. As a new type of vaccine, mRNA vaccines can activate the body's immune mechanism through specific pathways, thereby achieving rapid immunity, which is safer and more efficient than traditional vaccines.

In addition, mRNA vaccines can be administered in a variety of ways, and choosing the right mRNA vaccination route will help improve the conversion rate of vaccines. In the future, mRNA vaccines will surely become an indispensable biological product in the fields of human disease prevention and treatment, and have broad application prospects.

(Photo source/Visual China)

In addition to being used in the prevention and control of viruses, mRNA vaccines can also play a vital role in the prevention and control of a variety of diseases such as bacteria, parasites, and tumors.

Domestic and foreign pharmaceutical companies are competing to develop mRNA vaccines

Although mRNA vaccines had not yet entered the public's sight before 2020, many scientists still gave mRNA technology a very high evaluation. At the beginning of the outbreak, many scientists predicted that mRNA technology would subvert the vaccine industry and even bring about huge changes to the entire biotechnology field.

Today, the dream is becoming a reality. Currently, domestic and foreign pharmaceutical companies are launching an attack on the research and development of mRNA vaccines and have achieved historic breakthroughs. The application of mRNA technology in other fields has also become the focus of Chinese innovative pharmaceutical companies. This time, Everest Medicines has entered the mRNA vaccine market and plans to build an mRNA vaccine factory in China, which marks that the mRNA COVID-19 vaccine track has ushered in a strong new player.

At the same time, according to Caixin.com, the National Medical Products Administration has basically completed the approval of the mRNA COVID-19 vaccine "Fubitai" jointly developed by Fosun Group and Germany's BioNTech. It has passed the expert review and is currently accelerating the administrative approval stage. An informed source said that in the future, Fubitai will most likely be used as a follow-up booster shot for people who have received the inactivated vaccine in China.

According to China Biologic's introduction at the Services Trade Fair, the company is also accelerating the development of two new-generation vaccines, including a recombinant protein vaccine and an mRNA vaccine. The recombinant protein vaccine has completed phase I and II clinical trials and is expected to be launched at the end of this year; the mRNA variant COVID-19 vaccine with independent intellectual property rights is also under development, and the mRNA platform construction and large-scale production workshop layout are currently being improved, and it is expected to be launched next year.

▲On September 5, 2021, the mRNA variant COVID-19 vaccine exhibited by Sinopharm Group China Biologic at the booth of the China International Fair for Trade in Services (Photo source/Visual China)

As early as the beginning of 2020, my country had deployed five technical routes for the development of new crown vaccines, including inactivated vaccines, adenovirus vector vaccines, recombinant protein vaccines, attenuated virus vector vaccines and nucleic acid vaccines, including mRNA vaccines. At the 2021 National Vaccine and Health Conference, Academician Gao Fu called on "everyone to pay attention to mRNA vaccines, which provide humans with unlimited thinking."

Nowadays, nucleic acid vaccines (including DNA vaccines and mRNA vaccines) can be used in infectious diseases, tumors, asthma, etc. As the new crown epidemic rages around the world, mRNA vaccines may play a role as a vanguard.

Consider establishing a vaccine production base in China

The COVID-19 pandemic has accelerated the development of mRNA technology, changed the landscape of the world's vaccine industry, and led to the rise of cutting-edge biopharmaceutical companies such as BioNTech and Moderna.

Providence is a Canadian biotechnology company focused on the development of mRNA drugs and vaccines. Its main mRNA COVID-19 vaccine candidate, PTX-COVID19-B, is currently in Phase 2 clinical trials, and the results show the overall safety and good tolerability of the vaccine.

The S protein pseudovirus neutralizing antibody experiment showed that the serum of subjects vaccinated with PTX-COVID9-B had high levels of neutralizing antibody titers against the SARS-CoV-2 (G614) strain. All subjects produced neutralizing antibodies after the first vaccination, and the antibody level increased by more than 10 times after the second vaccination. PTX-COVID19-B vaccine recipients had high levels of serum neutralizing antibody titers against the original strain and variants of concern such as Alpha, Beta and Delta, which performed better than the currently approved mRNA vaccines.

Everest Medicines is a biopharmaceutical company focused on the development and commercialization of innovative drugs, dedicated to meeting unmet medical needs in emerging markets in Asia. Currently, Everest Medicines has created a portfolio of eight drugs that have the potential to become first-in-class or best-in-class drugs in the world, most of which are already in the late stages of clinical trials. The company's therapeutic areas include tumors, autoimmune diseases, cardiorenal diseases and infectious diseases.

According to the agreement reached between Everest and Providence, Providence will transfer all technologies of current and future manufacturing processes to Everest. According to China Business News, Everest CEO Dr. Kerry Blanchard said that the company is considering building a vaccine production base in China and plans to build a production plant with an annual production capacity of hundreds of millions of doses in eastern Zhejiang Province by the end of the year. He also said that the timetable for establishing a production line depends on when the company and Providence complete the technology transfer.

mRNA vaccines still have problems to be solved

Although mRNA vaccines have brought us quite a surprise, the development and application of mRNA vaccines have not been smooth sailing, and there are still many difficulties. Moreover, as a human vaccine, the new crown mRNA vaccine still has significant side effects based on current feedback, and there is controversy in the industry about the safety of its technical line.

From the production stage of mRNA vaccines, DNA first needs to be translated into protein via mRNA. In fact, only some fragments of mRNA will become the sequence that makes up the protein, and the rest controls and regulates the translation efficiency and structure of the protein. Therefore, the mRNA sequence is the focus of vaccine research and development and the core of competition in the industry. In addition to containing the antigen protein code, other parts of the sequence also directly affect the quality of the mRNA vaccine.

Secondly, after mRNA enters the cytoplasm in the form of an inclusion body, the inclusion body envelope needs to be broken to release the mRNA. Therefore, the mRNA needs to be "safely escorted". Katalin Kariko, a scientist from Hungary, has previously discovered that synthetic mRNA is easily affected by the body's natural defenses. In other words, synthetic mRNA may be destroyed before reaching the target cell.

Even more unfortunately, the resulting biological damage may trigger an immune response, which makes mRNA therapy a health risk for some patients. Therefore, for the development of mRNA vaccines, sequence structure and vaccine delivery system are crucial, which may still hinder the application of mRNA today.

▲Storage conditions of COVID-19 vaccines of some companies (Source/Official websites of various companies, New York Times, Emirates News Agency, etc., CITIC Securities Research Department)

Note: Data is as of September 5, 2021

In addition, many industry insiders also mentioned that strict storage conditions make it inconvenient to store and distribute, and difficult to apply. Most mRNA vaccine nanoliposomes (LNPs) in the laboratory can remain stable for several days at 4°C, but then they will increase in size and gradually lose their biological activity, making it difficult for them to be effective. The transportation and storage conditions of the mRNA vaccines currently available are usually extremely harsh.

Simply put, the original intention of developing the COVID-19 mRNA vaccine is to avoid the shortcomings of traditional vaccines, increase the production capacity of vaccine supply, and accelerate the development of the global vaccine industry with the help of mRNA technology. It represents the future development direction of the vaccine industry. However, before the complex problems of mRNA vaccine development and application are solved, it will take some time for mRNA vaccines to truly become the leader in the vaccine industry.

References:

1. mRNA COVID-19 vaccine "Fubitai" passed professional review Caixin.com
https://www.caixin.com/2021-07-14/101740353.html

2. Everest Pharmaceuticals enters the mRNA vaccine market and plans to build a Chinese factory with a planned production capacity of hundreds of millions of doses. First Financial
https://www.yicai.com/news/101173249.html

3. COVID-19 vaccination status National Health Commission official website
http://www.nhc.gov.cn/jkj/s7915/202109/db13ecdcd1e74b66972d86c270491039.shtml

4. Metz Morning Reading | Domestic mRNA COVID-19 vaccines are still on the way, moving forward with difficulty Metz Medicine
MedScihttps://view.inews.qq.com/media/5579092?tbkt=H&uid=

5.5 technical routes are being developed together, 4 vaccines have been launched, what progress has been made in the research and development of new crown vaccines in my country? Guangming.com
https://m.gmw.cn/2021-09/14/content_1302577067.htm

6. Guo Feifei, Wei Runan, Shen Sijia, et al. Hot and difficult issues in the prevention and control of novel coronavirus pneumonia[J]. Chinese Journal of Clinical Infectious Diseases, 2021, 14(01):1-6.

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