[Text/Observer Network Wang Hui Zhou Yuanfang] "Scientific and technological research should adhere to the problem-oriented approach, and rush to the most urgent and urgent problems. On May 28, General Secretary Xi Jinping stressed at the Tenth National Congress of the Chinese Association for Science and Technology, the academician conference of the two academies, "Practice has proved that China's independent innovation cause is promising, and the vast number of scientific and technological workers in China are promising." ”
The rapid and successful development of a COVID-19 vaccine in China is one of the best examples.
On May 26, the Journal of the American Medical Association, an international medical journal, published the "Evaluation of the Protective Efficacy of Two Novel Coronavirus Inactivated Vaccines for Adult COVID-19 Infection" published by Sinopharm China Biologics. This is the world's first officially published clinical trial results of the phase III clinical trial of the new crown inactivated vaccine, and the first publication of the results of the phase III clinical trial of the new crown vaccine in China. The results showed that 14 days after the two doses of the two inactivated new crown vaccines of China Biology, high titer antibodies could be produced, forming effective protection, and the positive transliteration rate of antibodies in the whole population and antibody reached more than 99%.
Why is it that domestic COVID-19 vaccines, especially inactivated vaccines that use traditional technical routes, can enter the world's first echelon and continue to lead this time? Why does the West not do inactivated vaccines, but instead flocks to mRNA vaccines and adenovirus vector vaccines? In the face of the continuous emergence of mutant strains around the world, why can inactivated vaccines still respond effectively?
With these questions in mind, Observer.com interviewed Yang Xiaoming, chairman of Sinopharm China Biologics, on May 27. Yang Xiaoming confidently pointed out that it is the technological breakthroughs made in many years of deep ploughing of inactivated vaccines, the advantages of our national system, and the dedication of scientists day and night that have achieved the acceleration of domestic new crown inactivated vaccines.
Inactivated vaccines are a traditional technical route, and many people take it for granted that old technology is backward. In this regard, Yang Xiaoming particularly stressed that the new crown inactivated vaccine developed by Sinopharm Group China Biologics is no longer "traditional and backward, we are a new inactivated vaccine." ”
He told the Observer Network: "The breakthroughs in this technical route have only been achieved by China, such as breakthroughs in strain screening technology, inactivation process and evaluation breakthroughs, purification breakthroughs, large-scale cultivation breakthroughs and so on." The West does not make this new inactivated vaccine because there are some aspects where they have not broken through, or have not completely broken through. ”
Yang Xiaoming said: "Domestic inactivated vaccines can still effectively deal with all the mutant strains that have been found so far, because inactivated vaccines use a complete virus, rather than a target, so it has a broad spectrum of protection against global strains, which is a prominent advantage of inactivated vaccines." ”
Yang Xiaoming, Chairman of Sinopharm China Biologics, Source: Sinopharm China Biologics
"Technological breakthrough, we spent 8 years"
Inactivated vaccines are very common, and the hepatitis B vaccine, the inactivated polio vaccine, the inactivated vaccine of enterovirus type 71 (hand-foot-and-mouth disease vaccine), and the DTP vaccine are all inactivated vaccines.
From the name, there seems to be nothing to explain: the live virus is extinguished, the "corpse" is thrown in front of the immune cells in the body, let it remember what the virus looks like, and the next time a similar virus comes, it will immediately generate immunity.
It may sound simple, but every step of vaccine development is not easy. In particular, the covid-19 inactivated vaccine of Sinopharm China Bio group includes a number of technological innovations.
On May 27, Yang Xiaoming introduced the company's six major technological breakthroughs in inactivated vaccines to the Observer Network in an easy-to-understand way.
The first is a breakthrough in the screening of vaccine production strains, and the development of good virus inactivated vaccines begins with excellent vaccine production strains. When a traditional virus inactivated vaccine is made, it takes researchers six or seven months to screen out a suitable production seed. But this time, in the screening of the new crown virus, Sinopharm rushed out of the new speed.
Yang Xiaoming revealed that they created a new method of strain screening, "it only took 16 days to screen the vaccine with good efficacy, high yield, genetic stability and broad antigen spectrum to produce virus seeds." ”
"Sifting through seeds is looking for the one you want in a pile of seeds," he says. There are good and bad seeds in this pile, but the premise of screening is that there is the one you want. Like the big pot of seeds of AIDS, none of them are suitable, and this situation is worse, because even if you check out all the seeds one by one, there can be no one. ”
The second is a breakthrough in inactivation. The key to the inactivation process is inactivation, it is easy to kill the virus, it is difficult to kill it just right, just dead, but it can also stimulate immunity.
"Inactivated or not enough," Yang Xiaoming said, "inactivated, the structure of the virus will be destroyed or crushed, that is, destroy the antigenic activity of the virus, it will not work." The virus has a 'coronary process' on it, and if this nail-like 'process' falls off more than 50%, it is basically ineffective. ”
2019 novel coronavirus renderings Source: US Centers for Disease Control and Prevention official website
Compared with this situation of killing the virus "too dead", it is more dangerous to inactivate it enough.
"Other viruses may not cause major problems if they are not inactivated enough," Yang Xiaoming said, "but the new crown virus is very contagious and pathogenic, and the new crown pneumonia is a class B infectious disease, and it is a respiratory infectious disease." If the virus is not effectively inactivated, it will cause disease, and leakage may cause biosecurity accidents. ”
It's like when we stir-fry, either there's more salt, more water, or it's mushy, or it doesn't taste right. The trick and trick to making a good dish is "just right", and the same is true of the inactivation process.
Yang Xiaoming explained: "The previous (inactivation) operation was to take the virus to a ravage, after the ravage, the virus was indeed inactivated, but it is likely that its structure, antigen molecules and other active ingredients were also destroyed. In this way, the vaccine is not effective, or even has no protective effect. In this case, the easiest way is to increase the antigen content. However, if the antigen is released more, the adverse reactions of the vaccine will increase, for example, the adverse reactions at the injection site include redness, swelling, heat, pain, suppuration, etc., and the whole body has fever, headache, anorexia and so on. ”
"This time our inactivation is based on modern biological technology, which can ensure full inactivation and ensure the antigenicity of the virus after inactivation." In addition, we have established a method to know that the virus will not cause disease to people after inactivation, and it can also retain antigenicity intact. ”
He continued: "This time, the inactivated vaccine of our national medicine has been administered more than 300 million doses, and there are basically no serious adverse effects related to the vaccine. ”
The Observer Network noted that many places in Europe have reported cases of blood clots and even deaths after vaccination with the AstraZeneca vaccine. Subsequently, a number of European countries, including Germany, France, Italy, Denmark, Norway, and Sweden, announced a total or partial moratorium on the use of the AstraZeneca vaccine.
The third breakthrough mentioned by Yang Xiaoming is the purification technology. Purification removes impurities and takes out the most effective ingredients. He introduced: "The early inactivated vaccines did not have this technology, were not much purified, and did not have the indicator of purity 'impurities', and the concentration could be adjusted slightly after inactivation." After 2013, when we studied the inactivated polio virus vaccine, we established the international leading level of inactivated vaccine purification technology. The improvement of purification technology has enabled the 'effective antigen', or 'effectively inactivated intact virus', to reach more than 99%. ”
However, increased purity often has an impact on the scale of vaccine production. Yang Xiaoming said: "In the past, after the purity reached more than 99%, the production of vaccines was often not large. However, this time the new crown inactivated vaccine, we have improved the purification method, so that the speed of purification is greatly improved, and it does not affect the purity. ”
"If we had done 50 million doses before, we wouldn't be able to rest all year round. But now, we can achieve large-scale production with high purity and low impurities, and the production capacity will increase from 1 billion to 2 billion and then to 3 billion. ”
Sinopharm China Biological COVID-19 Inactivated Vaccine Source: Sinopharm China Biologics
The fourth breakthrough is mass cultivation. To achieve mass production of inactivated vaccines, there must first be enough virus before they can be inactivated and purified. Therefore, large-scale (viral) culture is also a key technology.
The new crown virus is not "like a fish in the water" in all cells, and this time Sinopharm China Bio uses vero cells (a kind of monkey kidney cell) to culture the new crown virus. Specific culture cell lines, culture conditions, etc. need to be explored, and ways to make them grow better, grow much longer, and have stable passages.
"When we studied the inactivated polio vaccine, we have already broken through large-scale cell culture technology, and when the new crown comes, we have made a breakthrough on this basis, and the production capacity is greater," Yang Xiaoming gave a very vivid example: "Just like Mr. Yuan Longping planted rice, your family is 500 kilograms, their family is 800 kilograms, Yuan Longping can produce 3,000 kilograms per mu, and our inactivated vaccine is like 'growing 10,000 kilograms'." Otherwise, how can a billion and eight billion vaccines be made? This is also our breakthrough, which has not been mastered abroad. ”
The fifth major breakthrough is in the formulation of vaccines, that is, the composition of vaccines. In addition to the effective antigen as the main component, the vaccine also has a protective agent that maintains and protects the stability of the antigen and temperature tolerance. The difference in the function and nature of the protective agent determines the final characteristics of the vaccine, such as the temperature tolerance of the vaccine, the length of the expiration date and so on.
Here, Yang Xiaoming gave an example of making bread. "The same bread, why is our family delicious and their family not delicious?" Everyone's noodles are the same, rice is the same, but the recipe is different, the proportions and materials are different, so the things made are different. ”
Finally, there is biosafety. Yang Xiaoming said that such a large number of virus cultures, in the process of operation, we must first ensure that the operator can not be infected, and can not be placed in the ordinary environment to operate and produce, because once leaked, it will lead to biosecurity accidents. The research and development of inactivated COVID-19 vaccines must be carried out in the environment of a biosafety protection level 3 (P3) laboratory, and manufacturers must also have biosafety level 3 protection standards.
"The construction of this P3 production facility is also an innovative point," the researchers of Sinopharm China Biologics told the Observer Network, before the domestic vaccine production used P3 laboratories, Sinopharm China Biological New Crown inactivated vaccine production workshop was completed, filling the gap in domestic hardware infrastructure.
At the same time, they also cooperated with relevant departments to compile the first vaccine bio-safety production facility standard and biosecurity system document, filling the gap in the hardware standards and management system of high-grade biosafety workshops for human vaccines in China.
Yang Xiaoming said that Sinopharm China Biologics spent about 8 years to achieve a technological breakthrough in inactivated vaccines, and established a new inactivated vaccine technology platform in 2017. "Through this platform, we have implemented and achieved a breakthrough in the inactivated polio vaccine (iPV vaccine), enabling it to reach a single variety production capacity of 100 million doses."
"In fact, our platform and technology are already ready. When the new crown came, it just collided. It's like having to stir-fry, but there's no dish yet. The new crown is coming, then fry it, and in the process of frying, it has encountered huge demand. And in solving the problem of mass production, we have made some new breakthroughs. From 100 million doses to 3 billion doses, this kind of growth cannot be done if there is no breakthrough in technology and no certainty. ”
Staff in a high-grade bio-safety production workshop Source: Sinopharm Group China Biologics
"Science allows failure, but the people can't afford to wait"
There are three core difficulties in the development of innovative vaccines: long time, high investment, and low success rate. There is a classic summary in the pharmaceutical industry - two billion dollars in twenty years: it takes twenty years and two billion dollars to develop a vaccine.
So, what is the level of Sinopharm China Bio in the vaccine industry?
Yang Xiaoming said frankly: "From the perspective of long history, the number of varieties and the size of the number, there are only five or six giant enterprises in the world, and Chinese biology ranks behind these enterprises. ”
However, in his view, the development of the new crown vaccine is a once-in-a-century opportunity to overtake the curve.
"Our goal of overtaking is the top five or six vaccine companies in the world, and then expanding is a few small innovative companies, that is, to overtake their cars."
He specifically analyzed: "'Overtaking' is also divided into different dimensions. The first is the innovation side, and I think this time we're 'overtaking'. China has laid out a total of 5 technical routes, none of which have stepped on the air, and there has been progress on each route, with the largest number of varieties and innovations in the world. In addition, we are also 'overtaking' in terms of speed and usage. ”
Up to now, Sinopharm China Biologics has been approved for registration and emergency use by about 70 countries, regions and international organizations, more than 100 countries have put forward clear needs, and the vaccination population has covered 196 countries, becoming the most widely used and best-used COVID-19 vaccine in the world.
Yang Xiaoming said: "The inactivated vaccine uses a complete virus, not a target, so it has a broad spectrum of protection against global strains. Broad spectrum means anything to eat, which is the advantage of inactivated vaccines. From the data point of view, sinopharm China Biological's inactivated vaccine is currently effective for all mutant strains in China, the United Kingdom, South Africa and other places, but the protective effect is a little reduced. While our protective effect is a little reduced, some other vaccines have fallen badly. If our inactivated vaccines are ineffective, the vaccines currently being studied and used in clinical studies are basically all ineffective. ”
Before the epidemic, when everyone talked about the research and development, production and supply of vaccines, they would think of some international "vaccine manufacturers". But this time, some companies are absent. In this regard, Yang Xiaoming said: "Maybe it is not that they have not done it, maybe it is not that they have not chosen, and it is not that they have not worked hard. Mistakes were made, and science allowed failure, but Moscow did not believe in tears. You have failed, and the people cannot afford to wait. ”
Recalling the research and development of Sinopharm China Biological's new crown vaccine, Yang Xiaoming specifically mentioned the advantages and assistance of the national system.
"It's something that other countries don't have. For example, the US Food and Drug Administration will not be like our Food and Drug Administration, from the beginning with us to make plans, advice, and then every step after that to help us do a good job of supervision. For another example, we did not have a laboratory at the beginning, we wanted to borrow the professional laboratory of the national research institute, we directly called the vaccine research and development special class of the scientific research group of the joint prevention and control mechanism of the State Council, and then the sample was transferred, without talking about money, it was done directly. ”
"This is the national system, which is our advantage, and this advantage ensures the success and speed of research and development." Our research and development progress has been highly concerned by the party and the state, the State Council joint prevention and control mechanism scientific research group vaccine research and development special class, the Ministry of Science and Technology, the Ministry of Industry and Information Technology, the State-owned Assets Supervision and Administration Commission, the Health Commission, the Food and Drug Administration and its various professional verification and evaluation agencies, Hubei Provincial Government, Beijing Municipal Government and other relevant leaders have come to our research institute for inspection, guidance and coordination, as well as the Institute of Medical Laboratory Animals of the Chinese Academy of Medical Sciences, the Wuhan Institute of Virology of the Chinese Academy of Sciences, the Institute of Virus Disease Prevention and Control of the Chinese Center for Disease Control and Prevention, Beijing Zhaoyan New Drug Research Center and other units have given close cooperation," Yang Xiaoming revealed that in the research and development of this new crown vaccine, as long as they put forward what they need, the country will meet all of them. "In fact, don't even mention it, everything that should be prepared is ready for you."
The covid-19 inactivated vaccine developed by Sinopharm Group China Biological Beijing Institute of Biological Products Source: Sinopharm Group China Biologics
"Before I went to the United States, I knew I was coming back."
Of course, behind the advent of this vaccine is the selfless dedication of scientists. They support china's technological breakthroughs and ensure our technological leadership.
Talent is essential. However, how long does it take to train a senior vaccine scientist?
In this regard, Chairman Yang Xiaoming modestly said: "I may not be a scientist, if so, I have been working for 36 years since I graduated from college." ”
He sighed: "Scientific research is the real big wave of sand. In the process of doing research, some people can't stick to changing positions, some people are not good enough to eliminate, some people make money with a little progress... The scientific researchers who have persisted, without exception, have not forgotten their original intentions. ”
In addition to sighing, Yang Xiaoming told the story of his journey:
"In 1986, I went to Japan just after graduating from college. At that time, in my eyes, Japan was very developed. But international students around me told me that the United States is more developed than Japan. I was young and hadn't been to many places, so it was hard to imagine what the United States, which was more developed than Japan, looked like. So, I made up my mind that I must find an opportunity to go to the United States, see what the United States is like, and see how advanced the Technology of the United States is in our field. ”
"Ten years later, in 1996, I went to the United States and stayed there for 6 years. Looking back, the United States at that time was really more developed than us, and Shanghai, the most developed country at that time, could not compare with New York. But now it's different, and New York is in many ways inferior to Shanghai. ”
"Before I went to the United States, I had an idea: I must bring back vaccine technology well. So, every day in the United States, I try to see as much as possible, learn more, compare more, find more gaps, because I know I will definitely come back. ”
After returning to China, Yang Xiaoming went to Sinopharm Group's China Biologics Wuhan Institute as the executive deputy director in charge of scientific research. In Wuhan, he stayed for 8 years, 6 years as executive deputy director and 2 years as director.
"I come from a scientific research background and have spent time in the same field abroad, and I know the gap better than anyone," Yang Xiaoming said, "so I spent a lot of efforts in Wuhan to reform and introduced various incentive policies and scientific research policies." By the time I left, Wuhan had undergone earth-shaking changes, from the initial backward loss to the top enterprise within the group. ”
He believes that Sinopharm China Biologics can launch the new crown vaccine so quickly this time, which is not unrelated to the internal reforms in the past decade. "Otherwise, we wouldn't have reacted so quickly and inactivated vaccines would have been slower to develop."
He gave an example: "The two inactivated COVID-19 vaccines developed by Wuhan and Beijing came out almost at the same time. At the beginning, they were back-to-back research and development, only I knew their respective progress, and the two did not know each other. In fact, the competition between them also reflects our reforms. It turns out that everyone is engaged in cooperation groups, but once they cooperate, they are afraid of laziness, so they simply come separately. ”
"In addition, there are some different technical details in the inactivated vaccine, and the two formulas are still a little different in detail. At first, no one knew which combination would succeed, but now it all succeeded, and of course it was the best. ”
Sinopharm China Biological Vaccine R&D Team Source: Sinopharm China Biologics
Research and development is important, but in Yang Xiaoming's view, what is more important is the cultivation of talents and the establishment of talent pools. To achieve this, on the one hand, it depends on policy, and on the other hand, it also depends on the efforts of scientists themselves.
He analyzed: "The United States can maintain development for about 100 years by attracting talent. Why so many people from all over the world go to the United States is an important reason. ”
"I've been in the U.S. and I've learned a lot. When I went to the United States, I didn't get involved with my relatives or reasons, so I relied on technology. For example, I will have 5 technologies, and they happen to need these skills, and they will pay me accordingly. When I went, the plane tickets were all bought, and I went with my wife for $100. After you go, as long as you do a good job in these few techniques, you can have a salary, a house, a car, and a rich life. ”
Yang Xiaoming stressed that he told this story "not to praise how good the United States is, but to reflect the Attitude of the United States to talents from this incident." The United States has noticed the importance of talent early on, and then implemented policies to find ways to retain them. The rapid development of China's vaccine industry in recent decades has also relied on talents. There are talents introduced from outside, and there are also talents that we cultivate ourselves. ”
"Our country has also long noticed the importance of talent, which is a change in concept. In addition, we are constantly reforming the system and mobilizing the enthusiasm of scientists. Now in scientific research, our country has the money to do things, can do things, and encourages advancement. The state has introduced many policies and major projects to support scientific research, such as the 863 Plan, the 973 Plan and so on. ”
In Yang Xiaoming's view, all these changes in the system and mechanism are external factors, "internal causes are in the scientists themselves."
"Scientists themselves must also try to improve themselves, to be able to make things, if you are a 'stone', how can you hatch an 'egg'?" Excellent scientists are all trained in the process of trial and error, do not forget the original intention, can bear hardships and stand hard work, willing to dedicate. ”
Sinopharm Group China Biological Institute Beijing Institute of New Crown Vaccine R&D Team Source: Sinopharm Group China Biologics
Sinopharm Group China Biological Institute Wuhan Institute of New Crown Vaccine R&D Team Source: Sinopharm Group China Biologics
Sinopharm Phase III data was released for the first time, "countries without vaccine production capacity can be assured of procurement"
On May 26, the Journal of the American Medical Association, an international medical journal, published the "Evaluation of the Protective Efficacy of Two Novel Coronavirus Inactivated Vaccines for Adult COVID-19 Infection" published by Sinopharm China Biologics.
The results of the study showed that 14 days after the two inactivated doses of the two new crown inactivated vaccines of China Biology, high titer antibodies could be produced, forming effective protection, and the positive transversion rate of antibodies in the whole population and antibody reached more than 99%. The protective efficacy was 72.8% in the WIV04 vaccine group and 78.1% in the HB02 vaccine group. The safety is good, and the adverse reactions are mostly pain at the injection site, which is mild, transient and self-limiting.
This is the world's first officially published clinical trial results of the phase III clinical trial of the new crown inactivated vaccine, and it is also the first time that the results of the phase III clinical trial of the new crown vaccine in China have been published.
The report was completed by Sinopharm China Biologics, the National Joint Vaccine Engineering and Technology Research Center, the Wuhan Institute of Biological Products, the Beijing Institute of Biological Products, research institutions from the United Arab Emirates, Bahrain, Jordan, Egypt and other countries, the Henan Provincial Center for Disease Control and Prevention and other institutions and units, the corresponding author of the State Council Joint Prevention and Control Mechanism Science and Technology Expert Group Member, Director of the National Joint Vaccine Engineering and Technology Research Center, Chief Scientist of the "863" Program Vaccine Project of the Ministry of Science and Technology, Yang Xiaoming, chairman of Sinopharm China Biologics, and others jointly completed.
Prior to this, WHO added the COVID-19 inactivated vaccine developed by Sinopharm Group China Bio-Beijing on the "Emergency Use List" (EUL) on the 7th of this month, which gave the green light for the global promotion of the vaccine.
This is the fifth vaccine to be included on the Emergency Use List after Pfizer, Modena, AstraZeneca and Johnson & Johnson, and the first inactivated vaccine. As a result, these 5 vaccines have formed three technical routes - mRNA vaccine, adenovirus vector vaccine, inactivated vaccine - "three-legged" situation.
WHO's assessment shows that sinopharm vaccines are easy to store and distribute, which is a great benefit for the vast number of developing countries.
Sinopharm vaccine storage conditions are 2 to 8 degrees Celsius, and the existing vaccine cold chain system and even household refrigerators can meet the requirements. In contrast, the Modena vaccine in the United States has a storage temperature of minus 20 degrees Celsius, and the Pfizer vaccine needs to be stored at minus 70 degrees Celsius.
In addition, Sinopharm vaccine is also the first new coronavirus vaccine with a vaccine bottle monitor, and the small label on the vaccine bottle changes color with temperature so that health workers know whether the vaccine can be used safely.
Through a comprehensive assessment, the panel concluded that there was sufficient evidence to demonstrate the safety of the vaccine. Across age groups, the vaccine is estimated to be 79% effective against symptomatic and hospitalized (COVID-19) diseases.
So, what does being included in the "emergency use list" mean for Sinopharm China Biologics?
Yang Xiaoming said that this shows that "the safety and efficacy of this vaccine meet international standards, and countries around the world that do not have vaccine production capacity can be assured of procurement without worrying about quality problems." ”
It is believed that in the near future, more and more domestic COVID-19 vaccines will go international as "public goods" in addition to meeting domestic needs, contributing China's strength in global public health security and jointly building a community of human health.