Someone once compared the benefits of vaccination with safe drinking water. More than two years ago, in the face of the new crown pandemic, the vaccine once again appeared as a synonym for hope. People's expectations and awareness of vaccines have risen unprecedentedly, and many local vaccine companies have begun to come to the forefront.
When the epidemic suddenly broke out, many domestic scientific research teams and vaccine companies hit the development of new crown vaccine , and several self-developed vaccines were approved one after another. The scientific research results and the policy green light have greatly compressed this dangerous path, which was originally going to take 8 to 10 years. Behind the over 3.4 billion doses of COVID-19 vaccination nationwide so far is the accumulation of China's vaccine industry.
On August 2, 2021, citizens were vaccinated at the new coronavirus vaccine centralized vaccination site of Wutaishan Sports Center, Gulou District, Nanjing. Xinhua News Agency Picture
Over the past decade, the marketization of my country's vaccine industry has been increasing. In 2020, there were 334 domestic vaccine approval documents in my country, which belonged to 53 vaccine companies. The hot research and development and the prosperity of the market are catalyzing each other. In recent years, HPV vaccine , influenza vaccine, pneumonia vaccine, rabies vaccine - more innovative vaccines with independent intellectual property rights are accelerating their launch.
At the same time, the national immunization program has always been strongly guaranteed - the national "payment" immunization program has 15 infectious diseases that can be prevented by vaccines, and the central government's investment has exceeded 4 billion every year. Now, the preventable infectious diseases of a variety of vaccines in my country have dropped to the lowest level in history.
New Coronavirus Vaccine Race: Short-term Catalysis, Accumulating Thickness
On August 5, the leading private vaccine enterprise Chongqing Zhifei Bioproducts Co., Ltd. (hereinafter referred to as "Zhifei Bio"), issued an announcement stating that its wholly-owned subsidiary Anhui Zhifei Longkema Biopharmaceutical Co., Ltd. (hereinafter referred to as "Zhifei Longkema") recently obtained an invention patent certificate issued by National Intellectual Property Office . The patent name is "A method of preparation of a recombinant novel coronavirus NCP-RBD protein expressed by CHO cells and its application."
Zhifei Bio introduced to Pengpai News that the patent has been used to prepare its independently developed recombinant novel coronavirus protein vaccine (CHO cells) (hereinafter referred to as " recombinant protein vaccine ").
Zhifei recombinant novel coronavirus protein vaccine (CHO cells). Visual China Picture
In March 2021, when the epidemic was in full swing, this recombinant protein vaccine was included in the emergency use, becoming the fourth new coronavirus vaccine approved for emergency use in China at that time, and it is also the world's first new coronavirus vaccine approved for emergency use. On March 1, 2022, the vaccine was approved for conditional marketing. During the same period, the vaccine was included in the "enhanced shot" for sequential vaccination.
Zhifei Bio's 2021 annual report disclosed that during the reporting period, this recombinant protein vaccine has provided protection to more than 100 million people.
This vaccine was developed by Zhifei Biology and High-Fu, Institute of Microbiology, Chinese Academy of Sciences, High-Fu and Yan JinghuaHigh-Fu. Recently, in an interview with The Paper, Zhifei Biological Party Committee Secretary, Chairman and President Jiang Rensheng introduced that " microbial is the most upstream, and the RBD (receptor binding domain) dimer uses their patents, and we are responsible for the subsequent process."
On May 4 this year, the top international medical academic journal "New England Journal of Medicine" published the results of the phase III clinical trial of the vaccine online. The clinical results showed that after the subjects (≥18 years old) completed the full vaccination, the protective effect of the vaccine to prevent any severity of new coronary pneumonia reached 81.4% (95% CI, 73.3~87.3); In the long-term effectiveness analysis 6 months after the full vaccination, the amplitude of effectiveness decreased slightly, but the protective effect of preventing COVID-19 of any severity can still reach 75.7% (95% CI, 71.0~79.8).
"This data is encouraging. Domestic new crown vaccines can also compete with the globally developed new crown vaccines in terms of safety and effectiveness." Jiang Rensheng said.
In order to cope with the rapid mutation of the virus, the "update" research of this recombinant protein vaccine is underway. Jiang Rensheng introduced that the "new generation" of recombinant protein vaccines are expected to become a "bivalent vaccine" that can prevent both the Omickron and the Delta variant.
On April 26 this year (local time), the top international academic journal "Cell" reported on the research progress of this "new generation" vaccine. The author is the team of Academician Gao Fu, a partner of Zhifei Bio, and other cooperative teams. Researchers have developed a method for designing a chimeric RBD dimer protein vaccine against the COVID-19 epidemic variant, which is formed in tandem with two heterologous RBDs.
researchers designed the Delta-Omicron chimeric protein vaccine. Compared with the prototype (prototype strain) homologous RBD dimer vaccine, its immune mice stimulated a broader spectrum of antibody responses, and showed better protective effects on the challenge of Delta and Omicron variants. The researchers said that these research data support the development of multivalent vaccines adapted to mutant strains to prevent epidemic mutant strains.
In May this year, Gao Fu said in a public interview that the team is not only designing dimer vaccines for two variants, but also designing trimer vaccines for three variants. Gao Fu introduced that the advantage of this design is that "the launch tower remains unchanged", and new mutant strains will appear in the future, "the warhead can be replaced at any time." The emergence and rapid epidemic of the Omickron mutant strain
made the originally fierce vaccine research and development race start another game.
Since late April this year, the inactivated Omickron vaccine developed by China Biologics and Sinovac have entered the clinical trial stage. Zhang Yuntao, chief scientist and vice president of China Biotechnology, introduced in May this year that in response to the Omickron mutant strain, Zhongsheng not only deployed the inactivated vaccine , but also the technical routes for recombinant and mRNA are also being carried out simultaneously.
August 29, 2022, China International Service Trade Trade Fair, Sinopharm Group's new coronavirus mRNA vaccine. Visual China Picture
The new racing is like a repeat of the epidemic, but everything seems to be more rapid and orderly.
At the beginning of the 2020 epidemic, my country's vaccine research and development has been simultaneously promoted on the five technical routes of inactivated vaccines, adenovirus vector vaccines, recombinant protein vaccines, nucleic acid vaccines (mRNA vaccines and DNA vaccines), and attenuated influenza virus vector vaccines. According to Xinhua News Agency on October 12, 2022, at present, 46 new coronavirus vaccines in my country have entered clinical trials, 21 have been approved for phase III clinical trials overseas, 9 vaccines including inactivated vaccines, adenovirus vector vaccines, and recombinant protein vaccines have been approved for conditional marketing or emergency use, and 3 vaccines have been included in the World Health Organization emergency use list.
At the same time, my country has made new progress in the research and development of new coronavirus vaccines. There are three inactivated vaccines for the unit price of Omickron variants in my country that are conducting sequential clinical trials in mainland China, Hong Kong and the UAE, and the trials are currently progressing smoothly. Nine multivalent vaccines involving mutant strains have entered the clinical trial stage, some of which are undergoing phase III clinical trials. At the same time, my country is actively deploying and promoting the research and development of broad-spectrum vaccines.
The new crown epidemic is like a "catalyst" for the development of the domestic vaccine industry, and it burst out in a flash.
HPV vaccine boom: imported fragrance, domestically produced
Before the new crown vaccine, another vaccine that is hotly discussed by the whole nation was the HPV (Human Papilloma virus) vaccine. On the one hand, demand is overwhelming, and on the other hand, supply is tight, and the topic of "it is difficult to get a shot of HPV vaccine" is constantly flooding the screen.
At present, 5 HPV vaccines have been approved for registration in my country, of which 2 are domestic vaccines and 3 are imported vaccines. The two domestic vaccines are the bivalent HPV vaccine under , Watson Bio's , which was approved in March this year and the bivalent HPV vaccine under Wantai Bio's , which was approved in December 2019. The three imported vaccines are GSK's bivalent vaccine, Merck tetravalent vaccine and ninvalent vaccine.
Medical staff demonstrated GSK's bivalent HPV vaccine Visual China Picture
HPV vaccine higher the price of HPV vaccine, the more HPV types are prevented. However, even if the divalent vaccine is vaccinated, there are good benefits. The two HPV types that can be prevented by divalent vaccine are type 16 and type 18. epidemiological research shows that HPV16 and HPV18 are the most common high-risk HPV types in cervical cancer. In China, about 84.5% of cervical squamous cell carcinoma cases are related to these two high-risk HPV infections.
Cervical cancer is a common malignant tumor that seriously threatens the health of women around the world.IARC (World Health Organization International Cancer Research Institute) data shows that in 2020, 600,000 new cervical cancer cases and 340,000 deaths worldwide; among them, 110,000 new cervical cancer cases and 60,000 deaths in China, accounting for about 20% of the world's new deaths each year.
Cervical cancer is also the only cancer in the medical community with a clear cause. Persistent high-risk HPV virus infection is considered an important cause of cervical cancer. The HPV vaccine is the first vaccine in the world to include cancer as an indication in the instructions.
At the National Health Commission press conference held on May 30 this year, Wang Linhong, chairman of the Women's Health Branch of the Chinese Preventive Medicine Association and chief expert of Chronic Diseases in the Chinese Center for Disease Control and Prevention, introduced that the national conventional vaccine report data shows that from 2018 to 2020, the number of HPV vaccinations in my country has been increasing year by year, from 3.417 million in 2018 to 12.279 million doses in 2020. But overall, HPV vaccines are still in short supply, and the HPV vaccination rate for women of appropriate age is still at a low level.
Citizens are vaccinated with HPV vaccine Visual China Picture
Faced with a huge demand gap, many domestic vaccine companies have been racing to develop in recent years. Judging from the research and development and marketing process of the two bivalent HPV vaccines that have been on the market, both have gone through nearly 10 years or even longer.
Wantai Bio stated on the investor interactive platform in November 2021 that the bivalent HPV vaccine project was launched in 2003, completed the third phase clinical application and listing in November 2017, was approved for listing on December 30, 2019, and officially launched on the market in May 2020. According to this calculation, it took about 17 years from launch to listing.
In addition, the bivalent HPV vaccine of Zerun Biotechnology Co., Ltd., a subsidiary of Watson Biotechnology, obtained a drug clinical trial approval document as early as June 2011, and applied for a new drug marketing authorization to obtain the "Acceptance Notice" for application for a new drug marketing authorization, which lasted about 9 years.
In addition to the HPV vaccines that have been launched, many domestic vaccines under development are intensively advancing clinical trials.
For bivalent HPV vaccine, in addition to the already-marketed GSK, Wantai Bio and Watson Bio products, Rico Bio is also making arrangements here. Chengdu Institute of Biological Products, Weibo Biologics, Shanghai Institute of Biological Products, etc. are conducting clinical trials of quadrivalent vaccines in a intensive manner. For the nine-valent vaccine, except for the Merck nine-valent vaccine approved for marketing, the nine-valent vaccines of Wantai Biologics, Rico Biologics and Conlegus all entered the Phase III clinical stage.
The research and development of more innovative vaccines is also making efforts simultaneously.
At present, the 11-valent HPV vaccine jointly developed by the China Institute of Biological Research and the Chengdu Institute of Biological Products has started phase III clinical trials, and the 14-valent HPV vaccine jointly developed by Shenzhou Cell and Beijing Nonning Biotechnology has entered phase II clinical trials. In March this year, the fifteen-valent HPV vaccine developed by chengdabio and Conleguard were approved for clinical trials, which was the highest-priced HPV vaccine approved for clinical trials worldwide at that time.
In the view of industry insiders, with the acceleration of domestic substitution of HPV vaccines, market supply is expected to increase rapidly.
At the same time, at the policy level, the areas for free vaccination of HPV vaccine in my country are constantly expanding, and the accessibility of vaccines has been further improved.
In July this year, the National Health Commission introduced that at present, my country's HPV vaccination has not been included in the national immunization plan, and it is vaccinated according to the principle of self-payment and voluntary self-payment. Guangdong, Hainan and Fujian provinces have successively launched and implemented the work of free vaccination of domestic bivalent HPV vaccine for girls of appropriate age across the province, and included it in the 2022 practical projects of the provincial party committee and government for the people.
The National Health Commission stated that it will vigorously promote the experience of provinces such as Guangdong, Hainan, Fujian, etc., summarize the experience and practices of local governments using government livelihood projects and medical insurance funds to raise funds through multiple channels, encourage local governments to take the lead in trying out, and focus on promoting regions with mature conditions to take the lead in introducing free HPV vaccination policies to continuously improve the HPV vaccination rate for girls of appropriate age.
Class II vaccine "battlefield": independent research and development, insist on innovation
In my country, vaccines are divided into two categories: Class I vaccine and Class II vaccine. Among them, Class I vaccine is a national immunization program vaccine, which is purchased by the government and provided to citizens for free, while Class II vaccine is voluntarily vaccinated by citizens at their own expense.
Our country is one of the few countries in the world that can rely on its own strength to solve all immunization program vaccines.At present, there are 15 infectious diseases that can be prevented by the National Immunization Program vaccine in my country, mainly covering children aged 0-6.
From the supply side, the profit of Class I vaccine is low, mainly provided by China Biotechnology Co., Ltd. (referred to as " China Biotechnology "), a subsidiary of China Pharmaceutical Group Co., Ltd. (referred to as " China Biotechnology "), in comparison, the second-class vaccine that follows the market orientation is the main competition for the majority of private vaccine enterprises. The HPV vaccine mentioned above is a distinctive case.
Visual China Picture
In recent years, many local companies are focusing on the independent research and development of large-scale second-class vaccines such as influenza vaccine, pneumonia vaccine, rabies vaccine, meningitis (epidemic encephalospinal medulitis) vaccine.
In 2019, China's vaccine industry ushered in a historic major change - on December 1 of that year, the " Vaccine Management Law of the People's Republic of China " was officially implemented. This is the world's first comprehensive vaccine management law, which fully reflects the Party Central Committee's high attention to vaccines and is of great significance to promoting innovation in the vaccine industry and healthy development of the industry.
The "Vaccine Management Law" clearly states that the state encourages vaccine marketing authorization holders to increase investment in research and development and innovation, optimize production processes, improve quality control levels, and promote the progress of vaccine technology; support the development of new vaccines such as multi-linked and multi-valent.
At that time, there were 45 vaccine manufacturers in my country, which could produce more than 60 vaccines and prevent 34 infectious diseases. The annual production capacity exceeded 1 billion doses, and domestic vaccines accounted for more than 95% of the actual vaccination volume. However, the lack of R&D and innovation capabilities still restricts my country's vaccine industry to further strengthen, improve and expand.
R&D power and innovation capabilities are increasingly becoming the ultimate question for a vaccine company in the market. This is also a question that needs urgent answer for Zhifei Bio. In 2019, its agent products accounted for 87.37% of total revenue; by 2020, this number further rose to 92.09%. In comparison, its independent research and development products accounted for less than 10% of total revenue, which has triggered a lot of discussion in the market.
And by 2021, this situation has changed significantly. The revenue share of Zhifei's independently developed products has increased significantly to 31.64%. The company's performance also achieved a breakthrough, with revenue of 30.652 billion yuan that year, an increase of 101.79% over the same period last year.
For performance drivers, the first point of the company's 2021 annual report analysis is "independent research and development, insist on innovation." In 2021, not only did it develop its own recombinant novel coronavirus protein vaccine (CHO cells) for emergency use, but the company's independent product Mycobacterium cow (microcard) was also approved to increase indications in June 2021, and it has added new prevention of tuberculosis disease in people with latent infection of Mycobacterium tuberculosis .
microcard is an independent product of Anhui Zhifei Longcoma, a wholly-owned subsidiary of Zhifei Bio. In the past two years, Zhifei Longcoma has become famous as a research and development company for recombinant protein vaccines. In fact, when it was acquired by Jiang Rensheng in 2008, Longcomma's mission was not to develop viral vaccines, but to make tuberculosis and prevention and control products.
Zhifei Bio's independent products: Mycobacterium cow for injection (microcard) Zhifei Bio's official website picture
Tuberculosis commonly known as tuberculosis. In the past, there was a saying among the people of our country that "nine out of ten tuberculosis died". Before the founding of the People's Republic of China, tuberculosis was once widely popular and even became a cultural phenomenon. In Lu Xun's novel "Medicine", Hua Laoshun and his wife bought human blood buns for their son in order to cure tuberculosis. Lu Xun himself also died of tuberculosis .
As an wasting disease, tuberculosis will gradually lose the ability to work and require long-term medication. Therefore, the common people still have the saying that "I have achieved wealth for ten years and I have nothing to do with tuberculosis."
Before resigning in 2002, Jiang Rensheng worked in the grassroots disease control system for 25 years. In the first ten years, he was at the Guanyang County Epidemic Prevention Station in Guilin City, Guangxi Zhuang Autonomous Region. "At that time, I went all over the villages and villages. I was familiar with 138 production brigades and more than 300 village doctors." At that time, he was responsible for tuberculosis prevention and control work. He clearly remembered that many families' main laborers were infected with tuberculosis , unable to engage in heavy physical labor, and had to spend money to treat the disease, which caused the whole family to live in distress.
At present, the situation of tuberculosis prevention and control in my country is still not optimistic. The "2021 Global Tuberculosis Report" released by WHO shows that in 2020, the estimated number of new tuberculosis patients in my country was 842,000, with an incidence rate of about 59/100,000. The total number of new cases of tuberculosis ranks second in the world, only lower than India (2.59 million).
According to the People's Daily Health Client in March this year, Gao Lei, a researcher at the Institute of Pathogen Biology, Chinese Academy of Medical Sciences, introduced that "the number of latent infections in my country (tuberculosis) is very large. epidemiological survey found that about 18.1% of the national population over 5 years old is latently infected, and the latent infection rate for adults over 15 years old is about 20.3%. Zhao Yanlin, director of the China Center for Disease Control and Prevention Center, said that preventive intervention in this part of the latent infected population is crucial.
, deputy director of the Chronic Infectious Disease Control Institute of Jiangsu Provincial Center for Disease Control and Prevention, Zhu Limei, introduced that "common drugs for preventing and treating chemical drugs include first-line anti-tuberculosis drugs isoniazid , rifampin, and rifampin. Immune prevention and treatment is the "microcard" of Mycobacterium cows independently developed by my country. It has now obtained the national drug registration certificate. WHO is recommended in the "Tuberburn Research and Development Strategy Plan". "The approval of this product provides a new method for preventive treatment of latent tuberculosis infections, which is conducive to controlling the tuberculosis epidemic."
, from the acquisition of Longcoma in 2008, to the approval of "microcard" in 2021, the research and development of this tuberculosis prevention and control product has been 14 years.
Chinese vaccine set sail: Forge ahead and surpass
For the research and development risks of the biological products industry, there is a jargon in the industry: "Ten years, billion US dollars, 10% success rate." So vaccine development is more like a bet.
is so risky, who will do it at the beginning? Of course it is the "national team".
The pattern of the six major biological products research institutes in my country was formed in the 1950s, including six biological products research institutes including Beijing, Changchun, Lanzhou, Chengdu, Shanghai, Wuhan, etc. The early measles vaccines, group A meridian and cystosaccharide vaccines, etc. all came from these major institutes. In addition, the same important one is Institute of Medical Biology, Chinese Academy of Medical Sciences. The institute was founded in 1958 and the sugar pills for preventing polio (polio) are from the institute.
Once upon a time, the "national team" made great contributions to curbing the epidemic of malignant infectious diseases such as polio, smallpox, meningitis (epidemic cerebrospinal medulla) after the founding of the People's Republic of China.
Jiang Rensheng's "first pot of gold" after resigning from his job, that is, the self-developed vaccine that represented the "national team" - A+C group meningococcal polysaccharide vaccine developed by the Lanzhou Institute of Biological Products .
In 2002, this vaccine was first launched in the country and won the first prize of Gansu Science and Technology Progress that year. Zhifei Bio was the first to proxy the vaccine before the outbreak of C group meningitis in China, and introduced it to the market from the end of 2003 to the beginning of 2004 when the outbreak of C group meningitis in many places in China. Zhifei Bio's vaccine agency business also started from now on.
Initially, Lanzhou Institute and other research institutes were not only a scientific research and production unit, but also an public institution that performs some government functions. It was not until 1989 that the separation of government and enterprises was implemented, and the former six major biotechnology institutes were integrated into China Biotechnology Corporation. After being renamed and reorganized, it was reorganized into China Biotechnology Co., Ltd. in October 2011, referred to as "China Biotechnology".
As the "national team" of biomedical , China's bioproduction and supply more than 80% of the vaccines used in the national immunization program.
also started from the 1980s, a large number of private biological products enterprises have joined the market competition and gradually developed and grew in the wave of reform and opening up .
In the past decade, the marketization of my country's vaccine industry has been increasing. In 2020, my country had a total of 334 domestic vaccine approval documents, which belonged to 53 vaccine companies, of which the six major subsidiaries of China Biologics accounted for 55.7%.
In 2020, facing the new crown epidemic, a group of local vaccine companies ushered in a "big training".
Associate Professor Xu Juan, School of Public Administration, Northwestern University, wrote in the "Industry Blue Book: China's Industrial Competitiveness Report (2021)" that China's new crown vaccine is a milestone product, and the accumulated R&D, clinical and commercialization experience will help a group of outstanding Chinese local enterprises grow rapidly. In the development of the new crown vaccine, a number of Chinese vaccine companies represented by Sinopharm Middle School, Sinovac Zhongwei , CanSino , Zhifei Bio, Kangtai Bio , and Watson Bio/Aibo Bio have grown rapidly.
June 1, 2021, Beijing Sinovac Biotechnology Co., Ltd. 's vaccine packaging production line. Visual China Picture
Xu Juan also compared the differences between the vaccine industries in China and developed countries in Europe and the United States: the characteristics of the vaccine industry driven by large varieties are very obvious. The top ten blockbuster vaccines in the world in 2020 were all produced by four multinational vaccine companies. The first one was the 13-valent pneumonia vaccine of Pfizer . The sales of this vaccine alone reached US$5.85 billion, which is approximately the total size of China's vaccine market that year (36.4 billion yuan).
"Whether China can produce world-class vaccine companies in the future, the new crown vaccine provides an unprecedented development opportunity for China's vaccine industry," Xu Juan wrote.
According to Xinhua News Agency on October 12, recently, another inhaled adenovirus vector vaccine and a recombinant protein vaccine in my country have been approved, which can carry out sequentially strengthened immunity emergency use in the prescribed population six months after completing two doses of inactivated vaccination. Among them, the key data analysis results of the recombinant novel coronavirus fusion protein vaccine phase III clinical trial showed that the recombinant protein vaccine was used to sequentially strengthen immunity on the basis of two inactivated vaccines, which can produce good protective power and have good safety for the new coronary pneumonia (light and above) caused by infection with the Omickron mutant strain.
On November 12, 2021, the 5th Hainan International Health Industry Expo opened in Haikou City, Hainan Province. CanSino has unveiled its first inhaled adenovirus vector COVID-19 vaccine, g Wisa . A reporter used pure water to experience the process of imitation atomized inhalation vaccination. China News Service reporter Luo Yunfei/Visual China Picture
This recombinant novel coronavirus fusion protein vaccine is "made in Zhuhai" and has independent intellectual property rights. According to the official WeChat account of Zhuhai Municipal Party Committee Propaganda Department "Zhuhai Release", this vaccine was developed by Lizhuzumab Biotechnology Co., Ltd., a subsidiary of Zhuhai Lizhu Pharmaceutical Group, and Institute of Biophysics, Chinese Academy of Sciences. It took two years and 39 days. At present, Lizhu Pharmaceutical Group has built a production workshop with an annual production capacity of 3.5 billion doses of the new crown vaccine raw liquid and an annual production capacity of 1.5 billion doses of preparations.
In Jiang Rensheng's view, the entire industry is working hard now, "the country's policies are getting better and better, and we will always catch up."
On May 10 this year, the "14th Five-Year Plan for Bioeconomic Development" was officially released, which is my country's first five-year plan for bioeconomics. The plan proposes that the focus will focus on drugs, vaccines, advanced diagnosis and treatment technologies and equipment, improve original innovation capabilities, strengthen scientific research on drug supervision, enhance the supply chain guarantee level of high-end biomedical products and equipment, and strongly support disease prevention, control and treatment and response to population aging.
At present, the national immunization program vaccine preventable infectious diseases provided by the Chinese government to residents for free, and the central government has invested more than 4 billion yuan each year. At present, a variety of preventable infectious diseases in my country can reach a historical low. At the same time, more innovative vaccines with independent intellectual property rights are accelerating their launch.
One dose of the vaccine is injecting strong confidence into the blueprint of a healthy China.
