Pioneers of Covid-19 Vaccine Development

On a hot morning in July 2020, Liang Hongyang, deputy director of the No. 6 Vaccine Office of the Beijing Institute of Biological Products (BJIBP) under China National Biotec Group (CNBG), a subsidiary of China National Pharmaceutical Group (Sinopharm), rushed into the lab working on the COVID-19 vaccine. When he left the BJIBP building, Liang saw tents were pitched and people were waiting in a long queue to get vaccinated. He overheard someone say, “I finally feel safe after getting vaccinated.”

Liang felt quite relieved to hear that. He has been a core member of the R&D team for the COVID-19 vaccine since the beginning of 2020. The development and successful trials of the vaccine could only happen thanks to the hard work of the whole team.

Call of Duty

Spring Festival 2020 was special because of the COVID-19 outbreak.

Zhao Yuxiu is the director of the No. 2 Vaccine Office of the BJIBP. Zhao received a call from Wang Hui, general manager of the BJIBP, while she was celebrating the Chinese New Year with her family. “Start collecting materials and information on the coronavirus immediately and prepare to research a COVID-19 vaccine,” Wang told Zhao on the phone. “I went back immediately to discuss the vaccine plan,” recalled Liang, who was also called back by Wang. Several other researchers returned to work quickly too.

The researchers are all seasoned experts with experience in researching and developing the polio vaccine. Some excel at the upstream process like reactor culturing, while others focus on the downstream process. Some are adept at verification and some has expertise in animal experiments. These experts in their respective fields formed a temporary research team, working against the clock to formulate plans to produce a COVID-19 vaccine.

COVID-19 is a Class B infectious disease alongside other diseases such as SARS and AIDS, but infection prevention and treatment of COVID-19 cases is practiced according to the standard of Class A infections like diarrhea and plague. Since a P3 biosafety laboratory is necessary for developing an inactivated vaccine from an active virus, they borrowed a P3 lab from the Chinese Center for Disease Control and Prevention (CDC).

Zhao Yuxiu and Zhang Ying were among the first scientists to enter the P3 lab. Zhang Ying had been working in the BJIBP since 1990 and had participated in R&D of multiple vaccines, making her a veteran expert at testing, developing, and producing vaccines. On the second day of the Chinese New Year, Zhang began sending cell samples to the lab for pre-stage isolation of strains and various verifications. Zhang was forbidden to enter the P3 lab before taking systematic training on both theory and practice such as how to correctly put on and take off protective outfits and masks to avoid exposure to the virus. Zhang passed the strict examinations and was finally cleared to enter the lab. “During training, our teacher put phosphorus on our protective gowns and made us take them off from the inside,” she recalled. “Then the teacher would use fluorescent light to check for shiny powder on our bodies. We passed only after we could do it without getting contaminated by fluorescent powder.”

The COVID-19 vaccine production workshop at CNBG’s Beijing Institute of Biological Products. (LIU RONG)

“I was nervous the first time I entered the P3 lab because no one knew much about the virus,” she continued. “But my teacher had already been in there, and he did not flinch from the unknown danger. So I followed.” Zhang’s nephew also became involved in production of the COVID-19 vaccine. She burst into tears the moment she was informed that she needed to develop coronavirus strains. She was afraid the virus would get her.

“We were scared, but when the first dose was ready, we got excited and took photos with the vaccine,” Zhao recalled.

Compared to the labs at the BJIBP, the P3 lab has stronger negative pressure, so the maximum time researchers can stay and work continuously in the lab is four hours. “Every time I left the negative-pressure environment, my legs felt weak and my body exhausted,” said Liang. “Because of the low oxygen levels in the lab, I felt drained, and my response to the environment was slowed.”  Putting the protective outfits on and off was quite time-consuming, so researchers tried their best to avoid eating and drinking to negate the need to use the restroom for as long as possible.

CDC is a scientific research organization, so generally virus culture strains can be placed in test tubes and beakers, and its maximum culture capacity is 1,000 milliliter of virus solution. However, the BJIBP specializes in application studies including producing vaccines and cultivating viruses, so scientists had to use reactors, and the minimum volume of its culture tanks is 10 liters. Moving such big tanks into the P3 lab of CDC was a dangerous task because a virus leak would have disastrous consequences. So Liang and Zhao first did simulation experiments using the polio virus and passed multiple risk assessments. The equipment was finally allowed to enter the P3 lab after the experimental design and operation was proved totally safe. “We were extremely cautious on the simulation experiment,” Zhao said. “CDC researchers were surprised that it was possible to culture viruses like that.”

The day before the cells were injected with the COVID-19 virus, Liang could barely walk due to pain in his left angle from serious gout. Gout sufferers need to drink a lot of water to guarantee good metabolism and relieve pain, but Liang could not drink much water because of the suit and work. To perform the insertion experiment as planned, Liang took a lot of painkillers. “The number of researchers allowed in the lab was quite limited, so I had to help Zhao carry heavy reactors into the lab,” said Liang. “I couldn’t drop the baton at such a critical moment.”

The pain did not let up on the day of the experiment, but Liang decided to cope with it and put on his protective outfit while leaning against the wall. “I tried to use my right leg to hold my weight, and it felt like I was standing on broken legs.” Liang eventually succeeded in moving the reactor into the lab with his teammates.

Liang’s colleagues consider him outgoing, humorous, and quick-witted. He can become quite communicative about his work. But Liang couldn’t hold back tears when recounting his experience in the P3 lab. Since leaving home during the Spring Festival, he never mentioned these stories to his family. “My father is a member of the Communist Party of China, and he always says that when the country is in need, we must always be ready to help and never back down.”

Mission Possible

The most critical step of developing the COVID-19 vaccine was to inactivate the coronavirus and make it lose its pathogenicity while maintaining its immunogenicity. The COVID-19 virus was new to the researchers, so scientists had to engage in extensive cell experiments to confirm the amount, concentration, and temperature of the inactivating agent. To develop the vaccine as soon as possible, the R&D team increased the number of experiments while ensuring the accuracy of the operation. About two weeks later, the scientists finally solved key problems.

As the coronavirus started ravaging the world and killing thousands daily, developing the vaccine became a race against death. Every second became precious, and the whole team had to manage enormous pressure. The researchers entered the P3 lab in the morning and afternoon each day, and after work in the lab was completed, they would communicate with colleagues at the BJIBP’s P3 biosafety workshop about scale production of the vaccine. At about 10 o’clock every night, they would gather to analyze the results of the day’s work and adjust the direction of experiments for the next day.

To ensure plans proceeded as scheduled, researchers worked from 7 p.m. to nearly 4 a.m. the next day for a time. To avoid staying in the P3 lab for more than four hours continuously, they would exit the lab briefly and then return after putting the protective suit back on. The team seized every available moment to develop the vaccine. “Every researcher worked seven days a week, and we were often too tired to say a word when we got off,” said Bai Jiang, a researcher at the No. 5 Vaccine Office.

Normally, it takes about eight to 10 years for scientists to develop and scale-produce vaccines, but the BJIBP team managed to develop a COVID-19 vaccine in just three months. They did not skip a single experiment or miss any processes. They obeyed every scientific rule, and the inactivated vaccine was still developed in such a short time and special situation.

On April 27, the inactivated COVID-19 vaccine developed by the BJIBP was approved by the National Medical Products Administration for clinical trials, and phase I/II clinical trials were launched simultaneously. On July 22, 2020, the two inactivated vaccines from Sinopharm CNBG were approved for emergency use.

“Everything was completely consumed by the vaccine and we conquered daunting challenges one after another,” said Wang Hui. “Each of us knows how much hard work we did and that we will probably not have such an experience again in our lives.”

After the vaccine development was completed in June, the R&D team left the CDC and returned to the BJIBP to work on scale production in high-level biosafety workshops.

The official launch of the vaccine has brought back the pressure on the BJIBP’s team. “We are under pressure from biosecurity, increasing production, and personnel management,” said Liang. “The year 2021 will be another challenging one.”

The production capacity of the existing workshop of the BJIBP is 120 million doses per year, but completion of a second workshop will empower it to produce a billion doses a year. While domestic demand for COVID-19 vaccines remains huge, Chinese vaccines will also be provided to other countries as global public goods. Taking it abroad requires scientists and researchers to expand vaccine production while ensuring biosafety.

The COVID-19 outbreak has changed ways of living and thinking for many people. Members of the team gained a deeper understanding of their profession and work. “We are guardians protecting our people’s health, and we must construct a defense against disease with our own hands and minds,” continued Liang. “The sense of accomplishment from this process is something money can never buy.”

By Yuan Yanan, Zhang Chunxia

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