Author Cheng Mengchao
Edit Zhang Guo
The Institute of Biological Products adjacent to the East Fifth Ring Road in Beijing is now a cultural and creative industrial park hidden in ivy. A huge white factory has been out of service for a long time, so people will intentionally or unintentionally avoid this desolate building.
Until September this year, a group of middle-aged and elderly people hugging, shaking hands and taking photos were welcomed in front of the building. They have different skin colors and are mixed with Chinese and English when chatting.
30 years ago, this group of people witnessed the birth of the building. It is the product of a cooperation between China and the United States, the birthplace of China's first recombinant yeast hepatitis B vaccine.
, represented by this vaccine, hundreds of millions of Chinese people have received hepatitis B immune protection. The former Ministry of Health said that as of 2010, at least 80 million people were protected from hepatitis B virus infection. The 2014 National Hepatitis B Epidemiological Survey showed that among children aged 1 to 4, the proportion of hepatitis B virus infection was 0.32%, a cliff-like decline from 9.67% in 1992.
After many years, the staff of both sides reunited, and many people could recognize old friends at a glance. A Chinese engineer said that in order to save money, he used a test tube with cracks. American experts were shocked and snatched it to the ground in anger. An American employee suspected that the Chinese people didn't like him for a long time because people said to him, "You don't look very good." It took him a long time to understand that it was the way Chinese people express their kindness.
However, at the end of the recollection, the words summarized by both parties were very similar: after experiencing misunderstandings and even quarrels, they still learned to understand, learn to trust, and become friends.
.12 billion infected
China is a "hepatitis B major country". In the 1970s, the first epidemiological survey of hepatitis B conducted in mainland China showed that the infection rate was above 9%. According to World Health Organization standards, the infection rate of hepatitis B virus is higher than 8%, which is a highly prevalent area with severe epidemics.
Zhuang Hui, an academician of the Chinese Academy of Engineering and professor of pathogenic biology at Peking University, explained to the reporter of China Youth Daily and China Youth Network that before the promotion of vaccination of the hepatitis B vaccine, there were 120 million hepatitis B virus carriers in China, of which 30 to 40 million were caused by mother-to-child transmission. "Adults are infected with hepatitis B virus, less than 10% have evolved into chronic hepatitis B , and the prevalence of neonatal infection is as high as 90%-95%. "
He said that patients with chronic hepatitis B in early years will develop into cirrhosis and liver cancer unless they die from other diseases. In China, Chinese patent medicines such as Schisandra chinensis are used extensively to protect the liver. "Those methods are actually almost ineffective."
Tens of millions of people suffer from misfortune as soon as they are born, and people are "feared when talking about hepatitis B." At that time, all the world champions in many national sports teams suddenly had severe physical strength and ended their careers early because of chronic hepatitis B.
At that time, Zhao Kai, director of the Beijing Institute of Biological Products and now an academician of the Chinese Academy of Engineering, received the task of taking the lead in developing hepatitis B vaccine. This is China's first national specialized agency for the research and production of health and epidemic prevention and serum vaccines.
vaccine is listed as the top priority in the prevention and treatment of hepatitis B. In 1986, the blood-derived hepatitis B vaccine developed by the Beijing Institute of Biological Products and other units was put into production.
"Although blood-borne vaccine is effective, it has three major disadvantages." Zhao Kai said that using the plasma of virus-infected people as raw materials can cause risks such as polluting the environment and injuring production personnel; long-term and large-scale blood collection from the human body will not only harm health, but also cannot guarantee stable supply. The most important thing is that in addition to the surface antigen that is necessary for vaccine production, the plasma may also carry other pathogens.
production capacity is also restricted by the workshop-style production process. "After plasma processing, the antigenic liquid is obtained, first put in a large glass cylinder, and then hand-diluted one by one." Zhao Jingjie, who was once in charge of the production of hepatitis B vaccine at the Beijing Institute of Biological Products, told reporters that some colleagues accidentally scratched their fingers during operation and were infected with the virus.
In the early 1970s, when Tao Qimin and others from Peking University People's Hospital first conducted a blood-derived hepatitis B vaccine trial, due to the lack of foreign exchange, they could not buy the gorillas needed for animal experiments, and even injected them into their own injections instead of animal experiments.
For a long time, China's vaccine production has not had the ability to industrialize and standardize.In 1986, the American Merck company isolated the encoding gene of the surface antigen of the hepatitis B virus and implanted it into the genome of yeast cells that can reproduce in large quantities, which can quickly synthesize a large number of antigens, thus launching the genetically engineered hepatitis B vaccine.
"It is not something that biological workers can do, it involves many engineering issues." Zhao Kai still remembers that he was invited to inspect the US production line on the spot. In the fully enclosed modern workshop, they had never seen glass bottles and hand-hand handling, and replaced them with large metal cans of dozens or hundreds of cubic meters and fully enclosed pipes connecting them. "From culturing yeast to harvesting yeast cells, breaking cells, purifying antigens..., it is all completed on the assembly line, and it is purely industrialized."
In 1987, Zhao Kai and other experts suggested to the former Ministry of Health that they would consider introducing Merck's hepatitis B vaccine. In 1988, after several arguments, China formed a delegation and started a long negotiation with Merck.
Get into a boat
At that time, several independently developed genetically engineered hepatitis B vaccine projects in China were still in progress. Some people said that instead of giving money to foreigners, it is better to continue to support domestic research.
The then Minister of Health Chen Minzhang approved: With his continued support, foreign technology must also be introduced. The hepatitis B epidemic is severe, so there is no need to worry about too many vaccines.
Another problem is the transfer fee. Merck initially hoped to sell finished vaccines to China, with three shots required for a single immunization, with a total price of as low as $100. This was a price that China could not afford at the time. The focus of the negotiations has shifted to one-time technology transfer, with an initial offer of $10 million.
Both parties in the negotiations that year admitted that since then, it would be almost impossible for Merck to make any more money. Vaccine research and development often invests hundreds of millions or even billions of dollars. Merck then-CEO Roy Vagelos, who was determined to promote this cooperation, even had a quarrel with other executives in the company.
"I'm very anxious, time is tight, I want to protect my children from this deadly disease. Newborns in China should be vaccinated within 24 hours of birth..." More than 20 years later, Vagelos recalled in an interview.
in the delegation in the Chinese Ministry of Finance official once told Zhao Kai: The US dollars that the ministry can take out for this are actually at most several million.
Zhao Jingjie participated in several negotiations. In his memory, there was a disagreement between the two sides, and the Chinese representatives would leave the seat collectively and go out to "should a small meeting" in the corridor in order to unify their opinions first. "We who are engaged in hygiene and production hope that the cooperation will be negotiated quickly; but the comrades in charge of foreign trade and finance are more considerate and more cautious..."
In the end, Merck reduced the cost to another $7 million. China has introduced Kangtai Company in Shenzhen and introduced a vaccine production line each with the Beijing Institute of Biological Products. The Ministry of Finance and Shenzhen paid US$3.5 million respectively.
In 1989, Merck signed an agreement with the Chinese delegation to transfer the recombinant yeast hepatitis B vaccine technology to China, charging US$7 million as the cost of training Chinese personnel and paying US participants for labor. In addition, no longer charge patent fees and profits.
At the end of 1990, China sent technicians to the United States to study. 18 months later, a group of U.S. employees came to China again to assist in the production of the vaccine.
Zhao Kai remembers that many years later, Vagelos met him one time and still "complainted" with a smile: The 7 million US dollars that year, trained you two groups, and then paid the salary of our staff, and finally lost a lot!
In 1990, Wu Amei, a Chinese studying in the United States, was recruited to Merck as the US translator for this cooperation project. She looked through the documents of previous negotiations and was surprised to find that Merck once wanted to give up cooperation.
"Money is actually not the key to Merck." To this day, Wu Amei is still very emotional, "The most difficult thing is the difference in mutual trust and cultural."
"For Merck, China was a completely unfamiliar country at that time." Wu Amei recalled that the most discussed internally within the company was the sky-high cost of vaccine research and development. Even if it was transferred to mainland China at a low price, it was still a product that was highly anticipated in the rest of the world.Is this country that has never dealt with before trustworthy? Will they sell vaccines privately in other countries? Can their technical strength ensure product quality? If there is a problem with the vaccine produced in China, it will affect the reputation and prospects of this product and even Merck in the global market.
Looking through the documents of that year, Wu Amei felt that the relevant Chinese departments were also very cautious, leaving room for many statements. Of course, speaking implicitly is also a characteristic of the Chinese. But in the eyes of Americans, many documents are purely "Tai Chi", which is really difficult to understand.
At that time, Merck sent letters to China repeatedly, repeatedly confirming a question: Did Minister Chen Minzhang agree to this resolution? According to American customs, the final effect of the document depends on the personal signature of the project general manager. But it is obviously not the case in China. Therefore, the reply they receive is always a red-headed document stamped with the official seal of a certain department: "We have studied..."
Americans are even more suspicious: Who are we?
China also has many doubts. Merck, who is worried about China's lack of technical capabilities, is only willing to promise to guide the production lines in Beijing and Shenzhen, each with an annual production capacity of 20 million vaccines. However, the annual output of 40 million vaccines is only enough for more than 10 million people to use, which cannot meet the epidemic prevention situation.
In the deadlock, the main leaders of both sides stood up and took a step forward. Zhao Kai explained to the leaders that based on his field investigation at Merck, the annual output of 20 million units is actually Merck's conservative estimate. In the United States, there is no big problem with the exact same production line, an annual output of 30 million units. Americans don’t understand China, so they are worried, so this one can be followed by them.
At one time, Vagelos, who was frustrated, also reorganized his mood. "I began to realize that the national conditions of the two countries are completely different." Under his promotion, Merck relaxed some terms, such as the possibility of exporting vaccines after the introduction of the vaccine, which was changed to "only used in mainland China within 10 years."
As for the quality issues that both sides are very concerned about, a Chinese official said this: After the agreement was reached, we got into the same boat and had the same goal. Everyone should trust, not doubt, and they should step forward together to get ashore.
Winning trust depends on ability
The day of signing was September 11, 1989. When the news reached Shenzhen, the young man Liu Qun was very excited. He will be sent to study at Merck. In his memory, that year, Sino-US relations experienced ups and downs, and people speculated that cooperation might be "pornographic", at least there is no chance for the time being.
Kangtai Company was temporarily created in Shenzhen to undertake the hepatitis B vaccine project. When the first batch of personnel were in place, the factory was still constructed on the wasteland. The office is located in a dormitory. More than a dozen employees who had nothing to do at one time rented a house, so a vigilant police came to check in the middle of the night.
employees sent to the United States, most of the employees from the Beijing Institute of Biological Products are senior technical personnel. The newly established company in Shenzhen, except for the team leader, is almost all young graduates. This has made the US very worried.
One day after Liu Qun arrived in the United States, a manager in charge of the project in Merck asked them, "Are you engineers? I don't think they are engineers, they are engineers!"
Manager pointed to the Beijing team in the distance.
Zhao Jingjie, who also went to the United States, also has his own opinion on the character of Americans: he is not bad and has a very straightforward temperament. Once the document regulations are not followed, it is not uncommon for Americans to throw the document to the ground and turn their heads and leave. However, when we meet again a few hours later, the other party is always chatting and laughing.
"I didn't feel humiliated, maybe the Americans also wanted to inspire us." Liu Qun said that there was no grudge in his heart at that time because it was purely a learning attitude. "It's really not as good as humans. We don't know anything about it."
American companies had already adopted the "standard operating procedures" (hereinafter referred to as SOP in English). The details involved in each link in production were recorded in a thick booklet, whether it was learning or operating. "As long as you follow the steps, it's very simple and standardized, and you won't make mistakes." Liu Qun said, "It's really not too difficult for Chinese people."
As the interaction deepened, the contradictions decreased.Merck's employees began to take turns inviting Chinese people to visit their homes or travel. "The Chinese people win trust depends on their ability. Americans quickly discovered that they are very smart and easy to learn." Wu Amei recalled.
underestimated the difficulty
When the US representative went to China, he also encountered endless challenges.
Wu Amei went abroad in 1984. She thought at the time that 8 years have passed, and the conditions of the top domestic vaccine production institutions should not be too bad. Until she was surprised to find that the engineers were still driving carriages and carrying machinery by hand.
The US realizes that they underestimated the difficulty of the project. "There were two adjacent cold storages at that time, one of which was not low enough. So the Chinese side suggested whether to dig a hole in the wall and use a pipe to transport air conditioning." Merck's engineer Hong Ailin recalled, "I subconsciously wanted to laugh, but I held back. So I said: OK, give it a try. But if it doesn't work, I'd better buy a compressor."
Later she asked many Chinese why they came up with such an idea. Some people say that the funds are tight, so it is stressful to buy another one.
As a yellow man who grew up in the United States, Hong Ailin is curious and unfamiliar with China. She occasionally squeezed onto the buses in Beijing during peak hours with other colleagues, and citizens would rush to give up their seats to foreign faces and ask her to convey her welcome, even though she couldn't understand Mandarin at all.
She gradually felt that China was extremely enthusiastic about foreigners at that time and wanted to show her goodness; but this mentality itself brought barriers to hide those sensitive and hurtful issues.
Hong Ailin settled in China in 2000. She gradually understood that the Chinese people's "no problem" and "don't worry" are actually completely different from the United States, and may have many different meanings in different environments.
"But at that time, a group of 'Americans' did not understand these. They just felt that you said it was okay, but there were problems in reality; if there was a problem, why should we solve it like that - how can we help you solve the problem?" Hong Ailin took a big sip of water and said with a smile.
A middle-level leader of the Beijing Institute of Biological Products couldn't help laughing and talking about the past.
The most impressive thing he was when an expert from the US consulted a drug certification issue. In fact, that problem was still in a blind spot in China at that time. He could only reply "We are still studying" and "Let's think about it." Until the other side could no longer hold back their anger, "Why are you always going around in circles!"
"I can't tell them that our system is not perfect, right?" The leader sighed, "This is really not clear."
It's the Americans' turn to adapt to the environment. In Wu Amei's words, Americans gradually gave up controlling everything and began to adapt to the compromise philosophy of "turning a blind eye".
"Americans soon discovered: Although Beijing's partners refused to say some problems, they could always solve them themselves in the end, and in fact they did not have much impact on the project." Wu Amei's view, in this regard, it is better to say that they have sufficient "understanding" rather than achieving full "trust".
Merck has also made a new assessment of China within: the hardware environment is worse than expected, but the Chinese people's abilities and qualities exceed expectations. They were surprised to find that although old Chinese engineers may not have received formal college-style engineering education and cannot even use computers to draw, they can achieve higher accuracy with pencils and rulers.
"In fact, many Americans never go abroad for the rest of their lives, and don't even have a passport. Their stable and comfortable town is also closed and they don't know much about China." Wu Amei said that fortunately, they realized this and tried to change. Later, she simply made a slide to introduce Chinese culture to them.
is not for money
Because of this cooperation, the Beijing Institute of Biological Products popularized the concept of "SOP" and "modular". "It's shocking and advanced." A young technician at that time recalled that in the past, vaccination often caused side effects such as fever and vomiting, but it was actually because of slight contamination in production. I just can't figure out where the bad is.
After graduating from University, Zhou Yongdong was responsible for quality inspection and verification in the institute.The first time I met an expert from Merck, the other party asked directly: "Are these equipment sterile?"
"Yes."
"How do you know?"
"High temperature of 120℃ was sterilized for 30 minutes." Zhou Yongdong was confused. The high temperature should be able to ensure safety, and everyone has been doing this.
"Then how do you prove sterile?"
"Didn't it say 120℃..."
"What about the evidence of disinfection?"
Zhou Yongdong became angry. Later he realized that the other party’s “difficulty” was actually paving the way for popularizing new consciousness. "In the past, it was said that it was high temperatures and ultraviolet rays were exposed, but if the operator was lazy, his hands were shaking, and which corner was leaked, no one could know."
. The manual brought by the US clearly states that when high-temperature steam is sterilized, observation points must be set up in the corners where the steam is most difficult to touch - a thermometer and color-changing test strips must be placed to confirm that the temperature is high enough to sterilize. After the sterilization is completed, test strips for collecting colonies must be placed in several fixed locations. After the culture, there will be no bacteria to grow, which is truly safe.
A work that Zhou Yongdong was also involved in at that time was to translate the SOP manual into Chinese. Due to the rare attempts to standardize the field of biomedicine, many professional terms have confused this graduate of the biology department of the top university. Among the few references, in addition to the Tsinghua University chemical engineering dictionary, it also includes information on the "two bombs and one satellite" project.
"There are many terms in the Chinese Pharmacopoeia now, and they were also left behind at that time." Zhou Yongdong, who was middle-aged, was quite proud.
"I have to wear shoe covers when entering the factory. Some people always forget to wear them when they go in, and some people leave when they get off work." Hong Ailin recalled with a smile, she had to be at the door and reminded her one by one.
But as an American, she did not realize in the early days that some employees did not like to change. In her memory, some Chinese employees often say: You are rich in the United States and can afford to drive Cadillac . It would be nice if we have a bicycle!
The implication is that Merck hopes to completely copy the industrialization standards of American factories to ensure the reliability of the project. But in the eyes of some Chinese people, SOP and fully automatic machinery are good and wasteful; many parts can be replaced by slightly worse but cheaper ones, which can save a lot.
In the view of many Chinese witnesses, Merck's experts came to China as mentors, but were repeatedly questioned by "students", and they were inevitably sensitive. Some people discovered that the project encountered difficulties later, and the US experts always subconsciously stated that "it was not our fault" before considering the solution.
An interesting story is that an expert from Merck once chatted with an old Chinese engineer and asked in English: "Do you know why I came to China across the ocean?"
But the old engineer has poor English and has limited vocabulary. He was anxious for a long time and only came up with one word: "For...for money (for money)?"
The expert's face suddenly changed drastically and he slammed the door and came out. I returned after a few minutes, and still had a expressionless face.
Until a few days later, facing the old engineer again, the expert said seriously: "I still have to declare that I participated in this project because Chinese children need protection, not for money..."
Another time, Merck Headquarters suspected that the project was not implemented properly and asked the person in charge to return to the United States to report. Many participants remembered that the person in charge was shocked at the time and kept muttering, "It's over, it's over, it's going to be unemployed" and "Let's get off forever." This man loves shooting and cuts the footage he usually records into a short film. After seeing this, Merck's senior management felt that the project was progressing well, so they turned the crisis into safety.
htmlFor more than 0 years, when it comes to promoting this project, China and the United States will mention a name - Eugene Wapler. As the patent holder of some core technologies of genetically engineered vaccines, he is a scientist with a standout position in Merck and is about to retire, but he strongly demands to join this "hard" cooperation.He also has a name called "Wang Jinde". He was born in a farm in Shanxi in 1935. His father was a missionary and a "agricultural expert" mentioned by fellow Shanxi villagers, and his mother was a nurse.In the next 10 years, the Wopler family and many refugees were displaced on the battlefield, avoiding the threat of war and helping the Chinese as much as possible.
"China is another motherland of mine." Eugene Wopler said during his lifetime.
In Beijing, the tall and thin old man used to wearing a white coat and beige pants, shaking his empty pants legs. During his break, he likes to hold a carton of letters and a pile of cookies, greet young Chinese people and play word spelling games together.
Hong Ailin remembers that a young Chinese technician once asked Wopler seriously, "You said that if the vaccine will be better when you put it on your feet? Because the acupuncture points on the soles of the feet control the internal organs."
, watching her, thinking: It's too embarrassing, too ridiculous, how can you answer this?
Wopler's answer was very serious: I don't know, because there was no trial. Maybe it's worth a try in the future.
He didn't smile.
"I suddenly realized that taking it for granted that others are stupid is a kind of ignorance, because you don't know the other person's culture and experience." Hong Ailin said.
Just like the Chinese in the United States that year, they finally gained trust, and Chinese employees also clearly remember that tall and strong Merck engineers would get into narrow instruments for inspection; they often worked overtime with the Chinese until late at night, and then rushed back to their far-distance residence by rushing back to their trucks.
After more than a year of running-in in Beijing, the Merck team went to Shenzhen to complete the same work, only half of the time. "In Shenzhen, everything went smoothly for no reason," said Liu Qun.
Not profitable but the best business decision
In October 1993, the recombinant yeast hepatitis B vaccine workshop of the Beijing Institute of Biological Products was officially put into production. Vagelos, who came from the United States, could no longer remember much details about that grand inauguration. He remembered two Chinese kids greeted him on the red carpet, both of whom were very cute.
html After 2009, China began to provide free hepatitis B vaccine for all newborns; in 2005, the only remaining vaccination fee was completely waived; from 2009 to 2011, the country successively re-injected hepatitis B vaccine for children under the age of 15.The proportion of newborns in China who received the first dose of hepatitis B vaccine in a timely manner was only 22% in 1992 and rose to 91% in 2013. The incidence of acute hepatitis B in people under 20 years old dropped from 51,400/100,000 in 2005 to 0.88/100,000 in 2016.
To this day, this vaccine derived from Merck's technology is still the main product of hepatitis B in China due to its low cost and high reliability. Shenzhen Kangtai is the company with the largest supply of hepatitis B vaccine in China. When signing the contract 30 years ago, Vagelos predicted: "This project will help China eliminate hepatitis B in 50 years."
He later said that although there is no profit, it is one of the best business decisions Merck made in the 20th century, and it hopes to save lives, more than anything the company has done in the past.
Thanks to the hepatitis B vaccine, it is difficult for newborns in China to be infected with the hepatitis B virus again, but the historical "debts" of 120 million people have not been completely resolved. The National Health Commission's 2014 estimate data states that there are about 90 million hepatitis B virus carriers nationwide. More than 300,000 people die every year from hepatitis B and a series of diseases caused.
Academician Zhuang Hui, who has been dealing with hepatitis for a lifetime, said that the price of hepatitis B antiviral drugs that used to cost thousands of yuan a month had dropped to more than ten yuan due to the inclusion of medical insurance. However, due to concepts and other reasons, one of the obstacles in the current treatment of hepatitis B is still difficult to achieve standardized diagnosis and treatment.
According to him, among the 80 to 90 million hepatitis B virus carriers, less than 20% of them were diagnosed and found out that they were carrying the virus. Among the 28 million people who develop hepatitis B patients, only two or three million people receive regular treatment.
In the vaccine field, China is still catching up. More than 90% of the global vaccine market is still occupied by four giants, Merck, GlaxoSmithKline, Pfizer and Sanofi . The R&D expenses of the four companies account for 17% of their operating income, while the figure for Chinese pharmaceutical listed companies is only 2.8%. There is still a shortage of independent vaccines.
30 years later, there are not many people who go to the forgotten vaccine workshop in Beijing to go nostalgia.But Zhao Jingjie remembered that many domestic units sent people to inspect the market at that time, and the market was crowded with people. "This project has brought the overall level of our vaccine manufacturing to a new level," said Zhao Jingjie.
The current Sino-US cooperation has different opinions on the project. Some people think that the two sides have more and more worries; some people think that increasingly powerful and mature Chinese companies have more channels for exchanges with foreign countries and are able to directly hire foreign experts, making it easier to cooperate.
But everyone admits that as the product of a spontaneous friendly cooperation, the impact of the hepatitis B vaccine project has left traces on many aspects of history.
Merck has won global praise through this cooperation with China. The Chinese market also rewarded the company. In 1992, Merck established a China branch.
After that cooperation, Wu Amei was determined to "do a bigger project for China's public health" and stayed at Merck, and once became the director of the China Vaccine Division of the company; Hong Ailin is now an executive of an investment bank, responsible for investing in the medical field in China; Liu Qun stayed at Kangtai and became the vice president.
Many of them have been communicating for 30 years. Reunited in the park where I worked in the past, people sat together and looked at the old photos, and soon there were endless stories and jokes. Someone took the lead in humming a few words, and the group of people sang the songs they learned together back then.
In 2011, Liu Qun also went to Merck headquarters again to discuss the technology transfer of another vaccine. From a business perspective, it was a less successful meeting.
Before returning home, he decided to visit Eugene Wapler. He was surprised to find that there was a pair of Chinese calligraphy hanging in Wopler's house, which was a gift he gave many years ago.
"I will leave this world later, and my child doesn't understand calligraphy. You should bring it back to China." Before saying goodbye, Wopler said, "This is what belongs to you."
Liu Qun's eyes suddenly became wet. Everything seems to be back in the past.
But time will only move forward in a hurry. Eugene Wopler, who did not catch up with the party in Beijing 30 years later. On April 24, 2019, he died of illness in the United States.
The vaccine he participated in is still in China. Many of the children who were vaccinated with it have started their own families and businesses. According to the cooperation plan set 30 years ago, their next generation was given such a vaccine within 24 hours after they were born.
This article is independently produced by China Youth Daily and was first published on the China Youth Daily client and headline account to join the Tree Project.
