The battle of the six-member CNBG COVID-19 vaccine task force
The last day of 2020 marked a milestone in the research and development of inactivated vaccines to fight COVID-19 in China. At a December 31 press conference organized by the State Council Joint Prevention and Control Mechanism Against COVID-19, the National Medical Products Administration announced that it granted conditional emergency usage authorization for an inactivated vaccine for COVID-19 developed by Beijing Institute of Biological Products Co., Ltd. (BJIBP), a subsidiary of China National Biotec Group (CNBG) under China National Pharmaceutical Group (Sinopharm). It was the first COVID-19 vaccine authorized for emergency use in China.
Usually, it takes 10 years and a US$1 billion investment to develop an inactivated vaccine. Just feasibility studies for a certain project can take a whole year. Furthermore, vaccines are creative products, so successful development is never guaranteed. However, BJIBP succeeded in developing a vaccine in a mere 10 months without taking shortcuts or cutting corners in procedure. How did they do it?
Upon learning about the novel coronavirus outbreak in Wuhan in early January 2020, Wang Hui, then deputy director of BJIBP, suspected that her Chinese New Year (Spring Festival) holiday would bring long working days. On January 19, she received a call from Yang Xiaoming, president of CNBG and chief scientist of the vaccine project under the “863 Program,” a national high-tech R&D initiative.
“Get going,” said Yang succinctly.
As expected, the Spring Festival was extremely busy for Wang, who was appointed chief executive of BJIBP’s COVID-19 vaccine project. She visited the Division of Infectious Disease Prevention and Control (DID) of the Chinese Center for Disease Control and Prevention to get information on isolating the first novel coronavirus strain before setting up a task force for the R&D of a COVID-19 vaccine.
New Year’s Eve is when most Chinese families reunite for dinner. Zhao Yuxiu, director of BJIBP’s Vaccine Research Unit II, was about to eat with her family when she received a phone call from Wang. “Collect all the information on the novel coronavirus and prepare for vaccine research,” said Wang. Shortly after dinner, Wang called again: “Come to the institute immediately for a meeting on vaccine development.”
Liang Hongyang, deputy director of Vaccine Research Unit VI, returned to Beijing overnight after learning of the outbreak. Early on the first day of the Lunar New Year, he got a similar call from Wang to prepare for vaccine development.
On the first day of the 2020 lunar year, a vaccine development task force of six was organized. Members were Wang Hui, Zhao Yuxiu, Liang Hongyang, and Zhang Jin, who had previously been a key member of Wang Hui’s IPV (inactivated poliovirus vaccine) task force, Li Na, the institute’s youngest QC (quality control) manager, and Ding Ling, an animal lab specialist.
Due to the urgency of the task, each of the members of the task force was supported by a group with special expertise for the research and development of an inactivated vaccine against COVID-19.
Smallpox and polio were both eradicated in China through the efforts of the CNBG in the development of inactivated vaccines. To research and develop a COVID-19 vaccine, the company invested 2 billion yuan (US$30.8 million). To ensure success, they decided to simultaneously develop two types of vaccines: an inactivated vaccine and a recombinant protein vaccine. Inactivated vaccines are a fairly mature and reliable technology with a good safety record, playing a major role in today’s vaccine market. The recombinant protein vaccine is a newer technology. A recombinant yeast hepatitis B vaccine was already in the vaccine market, while an 11-valent HPV vaccine (Human Papillomavirus) and a Norovirus vaccine were in clinical trials.
“We formulated detailed strategies and strict vaccine development schedules,” said Wang Hui. “From experimental design, quality control, and process flow, to workshop construction, we did our best to consider every detail of each step according to international and national standards. We did that through our experience accumulated over the decades and a world leading technology platform.”
Wang Hui set up her “command post” in a meeting room of BJIBP’s office building. At 10 p.m. every day, the six members of the task force would meet there. “There were two large white boards in the meeting room,” explained Wang. “Each of us would write data on the boards as well as tasks accomplished that day for analysis and discussion. Based on the data, we would draw up plans for new experiments and design new strategies. We would make strategic adjustments according to the results of the day’s experiments. We had to move forward steadily every day with tens of thousands of simultaneous experiments involving hundreds of participants without mistakes.”
The heavy workload made it impossible for the team to go home after work. All of them worked and lived in their offices and labs, sleeping on an air mattress or sofa after working a dozen hours, and then getting up again for new experiments.
Pushing Forward Steadily
The COVID-19 vaccine task force received unprecedented support from other departments of the company, which devoted all available human, material and financial resources to the project.
“Research and development of the vaccine went so rapidly because of involvement of the production department throughout the process,” said Zhao Yuxiu. “When the resources and technological advantages of each department were pooled together, we made great collective strides.”
The task force had to face various unknowns, thrills, and challenges every day. Wang Hui cited trials with monkeys. Vaccines must pass pre-clinical studies before clinical trials, including challenging studies with monkeys. Researchers would vaccinate monkeys and then try to infect them with target pathogens. If they did not get infected, it evidenced that the vaccine was producing the desired immune response. If they did get infected, the vaccines would have to be reworked.
“Those experiments were very challenging,” said Wang. Because of the time constraints, the vaccine development team shifted the original serial experiment structure into parallel experiments by dividing 80 serial experiments into four parallel groups of 20 experiments, all of which went on simultaneously.
The experiment program had to meet global standards. The task force members worked night after night on each and every detail of the experiments, such as counting pathogens on throat and anal swabs of monkeys, comprehensive analyzing monkeys’ physiology, and measuring antigens for the monkeys.
“Any deficiency or imperfection in the program could lead to the failure of experiments,” said Wang.
“After the monkeys were injected with the candidate vaccine, we kept our eyes on them every day for signs of efficacy,” recalled Wang, “Facing the unknown, we were often worried. Fortunately, experiments proved successful. Even the monkeys injected with small doses of the candidate vaccine got fairly good protection.”
Alongside successes, Wang and the other members of her team also experienced setbacks, failures, and despair. More often than not, they had to experiment with 10 programs before continuing with one or two mature ones. They had to consider all possibilities for their designed program, even if it tripled the workload.
“We had a lot of pressure,” said Liang Hongyang. “Each and every step had to go perfectly.”
According to Zhang Jin, the inactivated vaccine against COVID-19 was developed with the same approach as the IPV vaccine. “We made improvements to the original production process,” said Zhang. They consulted medical literature to solve problems in the process and built a more solid theoretical basis for the smooth development of the vaccine.
“The samples from the candidate clinical vaccine we developed within a month all passed the probation assessment by the National Institutes for Food and Drug Control,” said Zhang.
The most challenging period for the BJIBP task force stretched from early February to the beginning of phase-I and phase-II clinical trials on April 28.
On June 28, the results of the clinical trials were released, which showed that high titre antibodies had been produced in those inoculated with the candidate vaccine without any significant adverse reaction.
On July 22, two inactivated vaccines for COVID-19 developed by CNBG were authorized for emergency use by government departments. Outbound travelers, medical workers, epidemic prevention and control personnel, border control officials, and urban basic service providers were among the first to be inoculated. So far, 3 million doses have been injected for emergency use without severe adverse reactions.
“It was the result of the concerted efforts of a group of people dedicated to the same cause,” said Wang Hui on the success of the COVID-19 vaccine development.
Shortly after Spring Festival, Zhao Yuxiu began to conduct research at the DID’s P3 laboratory. She was one of the first to get involved with coronavirus research. Thanks to full support from the DID, she conducted research in isolation for nearly two months. Under layers of a protective suit, she studied the transgenerational adaptation of strains for vaccine production, storage construction, virus inactivation conditions, and other factors in a negative pressure lab. To save the time wasted in putting the protective suit on and off, she tried to eat and drink less and even wore adult diapers.
In the wee hours of the morning, she would remove her protective suit, return to her dorm and check her phone for messages from her son. The situation was similar to her involvement in IPV vaccine development. Due to her busy work day and night, her son has grown up without her most of the time.
Liang Hongyang was among the second group of researchers to work under the same conditions in the P3 lab. The day before his research entered the stage of virus inoculation on cells, Liang’s persistent anterolisthesis flared up. He couldn’t walk due to unbearable pain in his left ankle. His doctor urged him to drink more water to get better, but he was stuck in the protective suit all day, unable to drink anything.
To continue his research, he took large doses of painkillers. Recalling that episode, Liang, who is usually optimistic, couldn’t help but choke up.
“It is still painful to think about that experience,” said Wang Hui. “During our months racing against the coronavirus, every member of the team teetered on the brink of collapse both physically and mentally at one time or another.”
“During the most intense period of vaccine development, I was so exhausted that I couldn’t walk 100 meters,” said Wang, who had always felt physically fit and energetic before. It was the most exhaustion she had felt in a dozen years.
“But it was worth it,” she added. “I am happy about what we accomplished.”