The history of human development is a history of the fight against infectious diseases. Plague , Malaria , Influenza , Cholera ... Every major infectious disease is a catastrophe. It was not until the advent of vaccines that mankind took the initiative in the fight against infectious diseases. In history, few vaccine developments have attracted worldwide attention like the new coronavirus vaccine .
Two and a half years ago, we were still trapped in the helplessness and fear of a sudden virus attack. Today, the World Health Organization has included 11 vaccines in the "Emergency Use List", becoming a powerful weapon for mankind to fight the epidemic. What makes the Chinese people proud is that in this list, there are many Chinese vaccines - the "national team" Sinopharm China National Biotechnology Co., Ltd. leads the way, and its inactivated vaccine became the first in the world to obtain the WHO The new crown vaccine authorized for emergency use in non-Western countries is also the sixth new crown vaccine to obtain safety, effectiveness and quality verification from the WHO.
One of the main designers of this vaccine is Zhang Yuntao, chief scientist of China National Biotech. For more than 30 years, he has been deeply involved in the field of biopharmaceuticals and is committed to building a solid health defense line for the Chinese people and promoting Chinese vaccines to shine on the world stage. Not long ago, the list of Beijing's "most beautiful scientific and technological workers" in 2022 organized by the Beijing Municipal Party Committee Propaganda Department, Municipal Association for Science and Technology and other departments was announced, and Zhang Yuntao was among them.
The COVID-19 epidemic is still raging, and Zhang Yuntao dare not relax in the face of honor. With responsibility and mission in mind, he is leading the team to continue to race against the virus day and night and promote the clinical research of the Omikron strain new coronavirus vaccine.
Creates Miracles
At the end of 2019, a sudden COVID-19 epidemic broke the joyful atmosphere of people celebrating the festival. For Zhang Yuntao and his colleagues, a protracted battle against the virus began.
"After our diagnostic team sequenced the virus, we found that this virus was not among the four known coronaviruses. Preliminary judgment was that this may be a new infectious disease system, so at the early stage of the epidemic, we decided to make a vaccine Research and development." Zhang Yuntao recalled.
Zhang Yuntao
In fact, this is not a routine move. Although it is generally believed that vaccines are the ultimate weapon against strange "invaders", researchers often develop vaccines after the disease becomes prevalent. As a creative product, the development of a vaccine is extremely risky. In this regard, there is a so-called "Double Ten Rule" in the industry, that is, to make a vaccine, it requires an investment of 1 billion and takes 10 years. How sure are you of success in dealing with this new "invader"?
"A new virus that can cause infectious diseases is as harmful to human beings as a 'world war'. China is a big country with a large population, and we must have our own vaccine!" Zhang Yuntao and his team rose to the challenge.
Zhang Yuntao spent that Spring Festival in battle. "We held a week-long meeting at the Ministry of Science and Technology two years ago, and on the night of New Year's Eve, we were still demonstrating the vaccine." One of the focuses of the demonstration is, which technical route should the new crown vaccine take? Zhang Yuntao explained that the basis for the development of any vaccine is to obtain the immunogen that can stimulate the human body to produce immune memory. The so-called different technical routes refer to different methods of obtaining immunogens.
Taking the new coronavirus vaccine as an example, the inactivated vaccine obtains the immunogen after inactivating the entire virus. The gene recombinant vaccine takes out part of the S protein gene on the outer membrane of the new coronavirus, inserts it into a vector, and then achieves mass reproduction in vitro. The adenovirus vector vaccine takes out the fragment of the target gene and inserts it into a live vector. After the live vector enters the body and reproduces in cells, the adenovirus produced naturally contains the immunogen of the corresponding fragment. The mRNA vaccine injects the mRNA sequence of part of the S protein into the body, allowing the human body to become a "vaccine factory" and produce its own immunogens. The attenuated live vaccine uses modern biological means to weaken the toxicity of the virus strain so that it can be passed down stably and prevent and treat diseases by simulating the process of natural infection.
Among all technical routes, inactivated vaccines are traditional vaccines with mature technology and technology, controllable quality and good safety. They are still the main force in the vaccine market. The vaccines babies receive after birth are all inactivated vaccines. Therefore, inactivated vaccines have also become the focus of research and development by scientific research teams.
has clear goals and moves quickly. The two major biological products research institutes in Beijing and Wuhan under the jurisdiction of China Bio immediately started back-to-back research and development. "Using the same raw materials and seasonings, the dishes made by different people may taste different. The same is true for vaccines. The team's different understanding of vaccines and different research and development accumulation will lead to differences in the vaccine products they make. ." Zhang Yuntao said that the two teams conducted back-to-back research in order to increase "double insurance."
However, the mature technology does not mean that this is necessarily a smooth road. A major risk in the development of
inactivated vaccines is the antibody-dependent enhancement effect (ADE effect), which is a major problem that plagues the development of respiratory inactivated vaccines. Zhang Yuntao explained that the ADE effect means that after the vaccine enters the human body, the antibodies produced may accelerate virus infection. This is a bloody lesson in history. However, a positive sign gives them confidence. At that time, China Biotechnology proposed to collect the plasma of recovered patients to produce specific immunoglobulin for the rescue of critically ill patients. Monitoring found that patients who received this treatment did not experience accelerated infection. "Judging from our technological accumulation, if there is no ADE effect during treatment, it means that the development of a new coronavirus inactivated vaccine is theoretically feasible."
There are still many difficulties that are unprecedented. From the beginning of the research and development of
, China Biotech has made it clear that the construction of production workshops must be synchronized with laboratory research. Only in this way can we ensure that the vaccine can be put into production as soon as possible after it is successfully developed. To produce general vaccines, workshops only need to meet Good Manufacturing Practices (GMP standards); to produce inactivated COVID-19 vaccines, they must meet biosafety protection level three (P3) standards. Before this, our country had never had a P3 production workshop.
built a P3 workshop and invested 1 billion. If the vaccine development is unsuccessful, wouldn’t it be in vain? But in the eyes of Zhang Yuntao and his team, this is both a challenge and an opportunity. "Even if the workshop is built but not used, it can still be regarded as making up for the country's shortcomings." If there are no construction standards, then set your own standards. With the spirit of breaking all boats, the Beijing Institute of Biological Products built China's and the world's first new coronavirus vaccine production workshop in just 60 days, creating a miracle.
What Zhang Yuntao is proud of is that this standard eventually became a national standard, laying the foundation for large-scale production of vaccines.
Inactivated Vaccine R&D Process
Trying the Vaccine on His Own The development of
vaccine is very difficult; but what everyone is most afraid of is not the difficulty, but the lack of time.
"To be honest, there was a period of time when I was very depressed and the psychological burden was heavy." Zhang Yuntao said frankly that it was the first time that he had been under such great pressure for so many years in scientific research. Faced with the raging epidemic, people across the country are looking forward to the vaccine. The entire team is in continuous rotation mode, promoting vaccine research and development at a minute-by-minute pace.
Production process research on fermentation, inactivation, purification, etc., in vivo evaluation of mice, rats, guinea pig, rabbit and other animals, covering quality control of the entire production process, human clinical research... After each step Looking back, it is full of thrills. "Every day I feel like riding a roller coaster." Zhang Yuntao said with a smile that during the research and development process, he always encountered various complex situations.
For example, in the early stages of research and development, the isolated virus must be inoculated into cells to allow the virus to grow and reproduce. One day, researchers discovered that the virus suddenly stopped growing. "At this time, we have to analyze various factors of the growth environment; the most frustrating thing is that after adjusting all factors, the virus still does not grow. Then we can only overthrow them all and start from scratch, making every step more standardized and more efficient. Be careful.”
The process of animal testing is even more full of twists and turns.To put it simply, animal testing is to vaccinate the animal and then inject it with the virus to test whether it will produce antibodies in its body and whether it will be infected with the virus. However, actual implementation is far from that simple. "The experiments on animals are not 'one is one and two is two'. Animals are just like people. For example, if you catch a cold for a few days, the vaccine will not be effective after taking the vaccine." After several experiments, Zhang Yuntao gradually came to a conclusion. "It is normal for the comprehensive antibody data to fluctuate by 20%, and sometimes the results are completely opposite. At this time, we need to look at it in parallel and systematically." Zhang Yuntao said that generally speaking, when doing Animal experiments have been done one by one from childhood to adulthood; but this time, various animals and experiments were carried out at the same time, and the "series" task was changed to "parallel". "Although the workload is large, it also saves a lot of time."
In February 2020, the seven species of animals participating in the test all achieved good immune effects. Zhang Yuntao and his team saw a glimmer of hope. He tensed up a few times. Yue's heart finally relaxed. "There are tens of thousands of known viruses, and only more than 50 have been made into vaccines. Although we have encountered an infectious disease that has never been seen in a century, fortunately, we can still make a vaccine." After
, good news continued to come. The Wuhan Institute of Biological Products collaborated with the Wuhan Institute of Virology of the Chinese Academy of Sciences to develop an inactivated vaccine for the new coronavirus in less than three months. Immediately afterwards, the new crown inactivated vaccine of the Beijing Institute of Biological Products also achieved success. In April, two vaccines were approved to enter clinical trials. Such speed was unimaginable in the past.
"In addition to our accumulation of mature technology and the full support of all departments from the central to local governments, the winning point is that we have a team that is selfless and dedicated." Zhang Yuntao said that developing inactivated vaccines must work with the virus. . At the beginning of 2020, when everyone was avoiding the new coronavirus, scientific researchers wanted to play with the virus "in the palm of their hands." He is always touched by the dedication of team members: the R&D laboratory has a high level of protection. In order to reduce the time of putting on and taking off protective clothing, the scientific researchers try to eat and drink less, and even wear diapers; for more than half a year, almost everyone With the office as home and the sofa as bed, "an extra hour of sleep" has become a luxury. There is an episode in
that Zhang Yuntao rarely mentions to outsiders. Before clinical approval was obtained, many leaders, including him, had already taken the lead in injecting the vaccine in advance to "test the vaccine themselves." "Although the new coronavirus inactivated vaccine was developed in an extraordinary short time, it does not violate scientific laws at all. There are many tests that need to be done, and there is no shortage of procedures that need to be followed. After a lifetime of working on vaccines, I have the confidence and confidence We still have it.”
The subsequent two phases of clinical trials have indeed proven the safety of the vaccine. The 4,064 people vaccinated, ranging from children to the elderly over 70 years old, had no obvious adverse reactions and all produced high-titer immune responses. When
leads the world and
was conducting phase III clinical trials, the team encountered a "proud" problem.
Zhang Yuntao explained that the Phase III clinical trial of the vaccine is to observe the protective effect of the vaccine after vaccinating the popular population in the epidemic area, that is, to "catch cases" in the epidemic area. At that time, the epidemic in my country had been effectively controlled. This also means that the test site must be moved abroad. This is the first time that Chinese vaccines have gone overseas on a large scale.
Doing clinical work abroad involves many factors such as culture, law, social system and economic interests. Our country does not have enough experience, so we have to explore everything. After multiple rounds of negotiations, the United Arab Emirates, Egypt, Bahrain and other countries have become the bases for the third phase of clinical trials. China Biotechnology named this retrograde team the "Great Wall" in the hope that they can build a barrier against the virus as an invader.
On July 9, 2020, the "Great Wall" project team shouldered the heavy responsibility and flew to Abu Dhabi, the capital of the United Arab Emirates . As soon as the plane landed, the rolling heat wave gave the newly arrived team a "death blow". Difficulties such as food and language are still secondary.At that time, the number of people infected with the new coronavirus in the United Arab Emirates, a country with a population of nearly 10 million, had reached four to five hundred per day, and later even increased to more than 1,000 people per day, which meant that they had to face the virus every day.
However, the most challenging aspect is not the difficult environment. "It is difficult to conduct research on protective effects, and the workload is 10 to 100 times that of ordinary clinical research." Zhang Yuntao said that in the United Arab Emirates, 43,000 volunteers participated in clinical trials, half of which were injected with placebo and the other half. Every day, they have to follow up on these 43,000 people, find needles in the haystack among these 43,000 people, catch infected people, and observe the actual effectiveness of the vaccine. There is a strict process for the "confirmation" of a case: first, the endpoint determination committee in the UAE must determine whether it is a case, and then the endpoint committee in China will determine whether the person is a case, and then the data security committee will review and announce the person. Vaccination or not. Zhang Yuntao, the remote control director of
, sets the "highest standards" for team members. He requires that the data on all cases be impeccable and that every data can withstand the test of experts and time. Many young people have cried uncontrollably under great pressure. One night, when the domestic endpoint committee was reviewing the data on a case, it concluded that the data was insufficient. Zhang Yuntao, who rarely loses his temper, lost control of his emotions and reprimanded the person in charge mercilessly. The member on the other end of the video wiped away his tears and then devoted himself to the work of improving the data. What the
team in the United Arab Emirates may not understand is that Zhang Yuntao's anger is actually deeply apologetic. At that time, China Biotechnology invited all well-known infectious disease experts together, and these experts used their breaks to participate in case determination. There was a scene that night that deeply touched Zhang Yuntao: Among the experts involved in the judgment was Li Xingwang, chief physician of the Infectious Disease Diagnosis and Treatment Center of Beijing Ditan Hospital. "Professor Li, it's begun!" Li Xingwang, who was napping on the bed, suddenly got up when he heard the greeting. He waited for a break and then squinted for a while. "Experts work day and night. One of our problems not only means a waste of material and financial resources, but also sacrifices the experts' precious time, which I can't bear to do."
Under his leadership, the overseas clinical team gritted their teeth and Finally, it passed the rigorous review with high scores. On the last day of 2020, the National Medical Products Administration of China approved the conditional marketing of the inactivated COVID-19 vaccine developed by the company in accordance with the law. This is the first COVID-19 vaccine to be launched in my country. After
, Zhang Yuntao led China's vaccine to move overseas more steadily, and actively promoted the addition of China Biotech's new crown vaccine to the WHO's "Emergency Use List."
He still remembers that he still spent the second Spring Festival after the epidemic in battle. On the night of New Year's Eve, he led the team to conduct a video defense. Faced with the tough questions raised by more than 250 WHO experts, Zhang Yuntao answered with reasonable evidence and scientific rigor, which made the vaccine's effectiveness and safety data fully recognized by the experts.
During the May Day holiday last year, after learning that the WHO would send an email with supplementary materials, Zhang Yuntao led the international cooperation, clinical research and other team members to stay in the office until 3 a.m. After receiving the email, he immediately guided everyone to discuss, and on the same day, he responded to questions from WHO. Three days later, the WHO approved the emergency use authorization of China Biotech’s COVID-19 vaccine.
"This not only means that the WHO will provide Chinese vaccines to the world as public goods. It also means that our technical standards and quality standards for the entire research from virus strain isolation to clinical trials are recognized. This is a recognition of the Chinese vaccine people and the Chinese scientists are a huge affirmation of China’s vaccine industry!”
In Zhang Yuntao’s view, eliminating an infectious disease is as glorious as landing on the moon. “I have chosen the field of public health as my lifelong career and will continue to fight for it."
[Release Doubts]
1 China National Biotech is developing the Omicron vaccine. How effective is it? After the Omicron vaccine is launched, can it be mixed with the previously developed COVID-19 inactivated vaccine?
Zhang Yuntao: Judging from the data obtained so far, The Omicron strain new coronavirus inactivated vaccine can induce high-level neutralizing antibodies against the Omicron virus, and can also produce high-level neutralizing antibodies against both the Beta strain and the Delta strain against the BA.1 and BA.2 mutations. The neutralizing antibodies against and induced by the strain are equivalent, with no obvious difference, so they are effective against emerging mutant strains such as BA.2 and Infection with will have obvious effects.
There is no problem in mixing various vaccines with the same technical route. After the Omicron COVID-19 inactivated vaccine is launched in the future, people who have previously been vaccinated with the COVID-19 inactivated vaccine can choose a different manufacturer. The vaccines produced are subject to sequential booster vaccination.
2 Does the virus continue to mutate, does it mean that we have to continuously develop new vaccines?
Zhang Yuntao: Humanity’s knowledge of the new coronavirus is still limited, and we cannot rule out the emergence of new epidemic mutations in the future. The possibility of strains. Once the original vaccine is not effective enough, it does not rule out the possibility of developing a new vaccine. As humans understand the virus more and more, it is possible to develop a vaccine that is suitable for all mutant strains. It is also the direction of efforts of scientists around the world, including me.
(Original title: New Year's Eve Defense - Behind the WHO Emergency Use Authorization)
Source: Beijing Daily Reporter: Niu Weikun
Process Editor: L021
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