The road to the first domestic HPV vaccine
◎Our reporter Fu Xiaobo
【Innovation Story】
In the middle of the night, the campus is completely silent, but the oval building of Xiamen University is brightly lit—this is an ordinary day at the National Engineering Research Center for Diagnostic Reagents and Vaccines for Infectious Diseases.
Working 6 days a week and more than 12 hours a day is the normal work of Professor Xia Ningshao and his team members.
They work against the clock, and an important task is to race against HPV (human papillomavirus).
When it comes to HPV, I believe many people are no strangers.
Cervical cancer threatens women's health, and persistent HPV infection is the core cause of this disease.
For a long time, although the HPV vaccine has been available, the domestic penetration rate has been very low due to the monopoly price and limited supply of imported vaccines.
In 2019, Xinkening, the first domestic HPV vaccine (commonly known as cervical cancer vaccine) developed by Xia Ningshao's team and Wantai Biotech, was launched on the market, breaking the long-term monopoly of imported vaccines and making China the No. 1 vaccine in the world after the United States and the United Kingdom. 3 countries with independent supply of cervical cancer vaccine.
What's even more rare is that the total cost of 3 injections of domestic HPV vaccines is only more than half of the price of imported vaccines.
Locking down E. coli to produce vaccines for humans
This 18-year vaccine battle has been arduous every step of the way.
Previously, eukaryotic cells such as yeast cells, insect cells, or mammalian cells were used as the expression system for vaccine preparation in mainstream genetically engineered vaccines in the world, because they are close to human cell structure, which is technically convenient for gene expression and protein modification of pathogens that infect humans .
However, this method has high technical barriers, and the core technology is monopolized by foreign countries.
How to find a new way to stand out from the encirclement?
Countless attempts, countless failures.
Through a lot of repeated experiments, Xia Ningshao's team finally found a chance of success. They set their sights on a well-known bacterium-Escherichia coli.
"Different from generic drugs, we have opened up a brand new technical line. It not only bypasses the patent barriers of international pharmaceutical giants, but also contributes a high-quality and low-cost choice for vaccine research and production around the world." Talking about Xinke Ning's innovation, Zhang Jun, a key member of the vaccine development team and deputy director of the National Infectious Disease Diagnostic Reagent and Vaccine Engineering Technology Research Center of Xiamen University, proudly told the Science and Technology Daily reporter.
The key to the team's breakthrough in vaccines is to use Escherichia coli as an engineered cell for human vaccine production, and to create the world's first prokaryotic expression virus-like particle vaccine technology system.
Zhang Jun introduced that Escherichia coli has unique advantages as an expression system, such as simple preparation and low cost. Although the threshold for research and development is high, once a technological breakthrough is achieved, it is easy to reproduce and produce on a large scale, which can greatly improve the accessibility of vaccines.
In the early days of vaccine development, many people in academia and industry looked at the research conducted by Xia Ningshao’s team with suspicion, especially when they learned that they would use Escherichia coli to express complex HPV proteins, thinking that it was “almost impossible”.
"Innovation must take a path that no one has gone before. Of course, our persistence is not blind. A series of pre-experimental data that meets expectations has strengthened our determination to go along this route." Zhang Jun said.
Every link has gone through countless trial and error
Can E. coli be used to produce human vaccines?
This is the fundamental question that makes the team questionable.
Recombinant protein expression is a key link in the production process of genetically engineered vaccines.
Researchers need to transfer a gene fragment containing a pathogen into a suitable cell to express a protein antigen, and then purify it to produce a vaccine.
Escherichia coli is a prokaryotic organism, and it is very difficult to modify the gene and purify and refold the protein in the later stage.
There are hundreds of types of HPV, and the protein structure is complex.
The antigens expressed by E. coli need to be assembled into virus-like particles similar to natural viruses in order to play the role of vaccines.
The key to preparing the antigen is to accurately pair multiple cysteine residues of the candidate antigen protein, and form correct disulfide bonds and pentamers with correct conformation.
The team has been groping for 15 years before breaking through the key technology of the whole chain from candidate antigen protein to virus-like particles.
Li Shaowei, a team member, recalled that they spent several months cloning the HPV L1 gene for vaccine development from patients with cervical lesions in a hospital in Xiamen, and then expressed it in Escherichia coli to obtain HPV virus-like particles. , significant progress has been made.
However, in the process of vaccine process development, one of the "price" production process problems was encountered.
The students who participated in the research got stuck at key points, "broke down and cried", and then "silently put away their emotions" to continue the experiment.
"In the first few years, our team rarely published important papers, but everyone paid willingly regardless of personal gains and losses." Zhang Jun introduced that based on rigorous experimental data and scientific demonstrations, the team shielded the "noise" and studied quietly , adhere to the use of Escherichia coli prokaryotic cell system as the research object.
"In the stage of vaccine development, every link has gone through countless trials and errors. Everyone is frustrated, lost, and then regroups. There is no myth in innovation. Only by presenting solid scientific data and truly solving technical problems can we win the recognition of peers." Zhang Zhang Jun said.
The first HPV vaccine to go abroad
Those in the elliptical building are called "progressive" and "innovative".
Tens of thousands of volunteers, medical staff, and researchers participated, tens of thousands of experiments, failed and tried again... In this way, the HPV vaccine has gone through 18 springs and autumns from the establishment of the project to the final launch.
Today, Xinkening has not only achieved domestic mass production, but also obtained the PQ certification of the World Health Organization and the marketing authorization of Morocco and Nepal, becoming the first HPV vaccine to go abroad.
Based on this set of independent innovative technical lines, China is expected to develop more and more complex vaccines in the future.
Xia Ningshao led the team to continuously break through numerous technical challenges.
Looking back on the road we have traveled, the research and development process of each vaccine has spanned more than 10 years, but the team's footsteps have never stopped.
"Imported vaccines are expensive, and high-quality and cheap domestic HPV vaccines are a major livelihood demand in our country." Xia Ningshao said, "Some people may think that we can always grasp the frontier, but our current achievements do not rely on talent. It’s about patience and perseverance.”
At present, the second-generation nine-valent cervical cancer vaccine is undergoing phase III clinical trials, and the third-generation cervical cancer vaccine (twenty-valent) has achieved a technological breakthrough...
The report of the 20th National Congress of the Communist Party of China pointed out that we must adhere to the frontier of world science and technology, the main battlefield of the economy, the major needs of the country, and the life and health of the people, and accelerate the realization of high-level scientific and technological self-reliance and self-improvement.
"Facing the country's major needs and people's lives and health is our team's consistent original intention of scientific research." Talking about the next step, Xia Ningshao said, "There are many choices on the road to innovation, and every project we choose will be It is a protracted battle. Supporting our spiritual beliefs is the ideal of seeking health and well-being for the people, as well as the inexhaustible exploration of the road to virus immunity!"