Global competition for new crown vaccine development
"China News Weekly" reporter / Peng Danni
Published in the 964th issue of China News Weekly on September 14, 2020
In 2009, at a family gathering in a spacious backyard in Toronto, Canada, a group of Chinese vaccine experts with senior positions in multinational pharmaceutical companies talked about the vaccine problem that China has long lagging behind developed countries.
This year, four of them left Canada and returned to Tianjin, China to establish CanSino.
Due to the close relationship with Canada, the company's English name (CanSino) is a joint writing of Canada and China.
However, in addition to an Ebola vaccine developed in cooperation with the Chen Wei team of the Chinese Academy of Military Sciences as a national emergency reserve, it was granted conditional marketing approval in 2017. So far, although this vaccine company has 16 vaccines under development, There is still no product on the market, with a cumulative loss of about 470 million yuan.
Now, relying on a new crown vaccine developed in cooperation with Chen Wei's team again, on August 13, Cansino was listed for trading on the Science and Technology Innovation Board, with a market value of more than 100 billion yuan, and it has become the domestic "first new crown vaccine."
The four major global vaccine giants are GlaxoSmithKline in the United Kingdom, Pfizer and Merck in the United States, and Sanofi Pasteur in France. They account for 90% of the global vaccine market.
At the beginning of the new crown epidemic, they did not actively participate.
Vaccine research and development is an industry that requires huge capital and is full of uncertainty.
But this has not prevented more and more vaccine manufacturers, biotech companies and scientists from investing in.
The list of vaccine research and development projects for the new crown virus is constantly growing.
At the beginning of March this year, there were about 64 new crown vaccine projects in the world. By the beginning of September, more than 175 new crown vaccine candidates were being developed worldwide, of which more than 30 were already in clinical trials.
This big race to find an effective vaccine is not only about the health of billions of people around the world, it will also bring billions of dollars in revenue to successful developers and manufacturers.
The public's expectations and confidence in the new crown vaccine have also continued to rise with the new developments in the research from time to time.
But if you carefully examine these vaccine technologies and clinical trial results, you will find that they either have a history of risky research and development, or are new technologies that have never been verified.
At present, this global vaccine research and development competition is advancing to the final sprint at an unprecedented speed. This scientific, technological, commercial, and political contest is approaching the most critical moment.
A new battlefield for old rivals
In February 2014, Yu Xuefeng, one of the founder and chairman of Cansino, obtained a technology license for adenovirus amplification from the Canadian National Research Council, which has become an important part of supporting Cansino's adenovirus vector technology.
In this year, Chen Wei, a researcher at the Institute of Bioengineering of the Academy of Military Medicine of the Chinese Academy of Military Sciences and an academician of the Academy of Engineering, cooperated with Cansino to develop an Ebola vaccine and cooperated with the Canadian National Microbiology Laboratory to conduct cooperative research and evaluate vaccines. .
What they developed at that time was the same type 5 adenovirus vector vaccine as today's new crown vaccine technology route.
A phase II study of the vaccine showed that the vaccine produced an antibody response 4 weeks after injection.
Although the Phase II clinical trial did not prove that this vaccine can prevent Ebola infection, in 2017, China approved the vaccine for marketing, but it is only used for emergency use and national reserves. This is the only vaccine approved by the company at present .
In contrast, the Jenner Institute of Oxford University, the world's largest university vaccine research institute, was not so lucky in that infectious disease.
In 2014, the institute led the first clinical trial of an Ebola vaccine, but in 2015 it was overtaken by Merck & Co. of the United States. The latter took the lead in verifying its vaccine candidate in Guinea, Africa, where Ebola is still prevalent. At the end of last year, it was approved by the US and European regulatory agencies for listing.
That failed experience made the Oxford team understand the importance of speed.
"Throughout the process, we are very clear that a one-week difference may lead to different fates for the two vaccines." said Adrian Hill, director of the institute.
Speed is related to public health, it is also related to the availability of funds, whether suitable subjects can be successfully recruited, and so on. It is ultimately related to success or failure.
"Government funds will be given priority to vaccine manufacturers that run fast." Dr. Yu Li, the chief vaccine officer who once worked at the US FDA, told China News Weekly.
For example, the US Biomedical Advanced Research and Development Agency (BARDA) has invested more than 12.3 billion U.S. dollars in companies including Oxford vaccine partner AstraZeneca and Moderna, one of the “seed players” in the United States; the European Union has invested in German biotechnology. The company CureVac issued a loan of more than 75 million euros and a 100 million euro loan to another German vaccine manufacturer BioNtech.
Both companies belong to vaccine contestants that have entered the clinical trial stage.
Today, the two R&D teams that once participated in the vaccine competition during the Ebola epidemic-China's Chen Wei team and the UK's Oxford team have met again in the new crown epidemic and have become the fastest and most watched vaccine team in the world Two of them.
As at the time, the technology they used this time is still an adenovirus vector vaccine.
On March 17, just one day after Moderna in the United States started the world's first clinical trial of a new crown vaccine, the new crown vaccine jointly developed by Chen Wei's team and Kangsino also officially launched clinical research, which is China's first new crown vaccine to enter the clinical stage.
Less than a month later, on April 12, the vaccine's Phase II clinical trial was launched in Wuhan, and a total of 508 subjects were recruited.
But then, among all the research and development teams, the most "radical" schedule was the Oxford team vaccine.
Adrian Hill, director of the Jenner Institute, and Sara Gilbert, head of the research and development of the new crown vaccine at Oxford University, have been studying vaccine technology based on chimpanzee adenovirus vectors for many years.
After Ebola, this technology was once again used in the development of MERS vaccines in 2018.
Therefore, when COVID-19, which is also a coronavirus, came, the team was already prepared.
"As early as mid-January when we learned the gene sequence of the new coronavirus pneumonia virus from China, we were able to quickly introduce the gene sequence into our vaccine technology and design a vaccine candidate." Hill said.
On February 17, they began to inject vaccines in mice. By April, when the collaboration with AstraZeneca was finalized, the team had resolved issues such as funding and vaccine production for clinical trials.
On June 4, the vaccine recruited participants to enter the Phase III trial, including 10,000 participants from the United Kingdom and 30,000 participants recruited by AstraZeneca in the United States. On June 2, Brazil also approved the vaccine for local clinical trials. The trial plans to include 2,000 volunteers.
This vaccine became the first in the world to enter Phase II/III clinical trials.
The inactivated vaccine from China Kexing and the two mRNA vaccines from the United States announced that they entered Phase III in late July.
Until August 9, Saudi Arabia announced that it would cooperate with Cansino to carry out a phase III clinical trial of an adenovirus vaccine and plan to recruit 5,000 subjects.
On August 17, Pakistan stated that it would also conduct phase III clinical trials of Cansino vaccine.
In addition, Cansino also launched Phase III in Russia on August 14.
Sara Gilbert, the head of Oxford Vaccines, has great confidence in her vaccine.
In an interview with Bloomberg Businessweek, she believes that the Oxford vaccine has an 80% chance of effectively preventing vaccinators from contracting the new coronavirus, and this result will be announced in September.
She said: "We know the circumstances of the adverse event, we know the dose that needs to be used, because we have done it many times."
However, on September 8, AstraZeneca announced that it had voluntarily suspended the Phase III clinical trial of the new crown vaccine in cooperation with the University of Oxford and accepted the review of the safety data by an independent committee. The reason was that a British subject had a suspected serious Adverse reactions.
AstraZeneca said in a statement, “This suspension is a routine action. As long as an unexplained underlying disease appears in a trial, such action must be taken during the investigation to ensure Maintain the integrity of the trial.” It also stated that it is working to speed up the review of this single incident to minimize any potential impact on the trial schedule.
Whether the adverse event was caused by the vaccine or the subject still needs to be investigated.
Qin Yuan believes that if there are serious adverse reactions such as 5%-10%, it means that the vaccine does have a safety problem, but this case is only present, and it is likely to be an accident.
"I think the vaccine will restart after an objective evaluation (Phase III clinical trial)."
A person familiar with the matter said in an interview with the American medical media STAT that the volunteer is expected to recover.
But it is still unclear about the nature and time of its adverse reactions.
Also on this day, the CEOs of 9 pharmaceutical companies, including AstraZeneca, BioNTech, Moderna, and Pfizer, jointly signed a commitment stating that they will strictly abide by high standards of ethical requirements and solid and reliable science in the development and testing of the new crown vaccine. in principle.
Not only these two teams, but for most participants in this vaccine race, especially those who run ahead, the development of the new crown vaccine does not start from scratch.
"The vaccine research and development path of each manufacturer is carried out on their own existing platform technology and production conditions. There is no need to open another path, so they are familiar with the road." Yu Li said.
New and old technologies compete in the same field
In addition to advising the US government’s anti-epidemic policy, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID) under the National Institutes of Health, is also one of the leaders in the development of the new crown vaccine.
For Fauci and others, in addition to knowledge accumulation, rapid vaccine development for emerging infectious diseases also depends on technological innovation.
In 2018, two scientists from the NIAID Vaccine Research Center in the United States and their "boss" Anthony Fauci wrote in the Journal of the American Medical Association that the traditional vaccine development method using fully inactivated viruses or viral proteins, each Each response to a new virus requires a separate design, and new technologies, including the platform vaccine technology using DNA or mRNA that has been rapidly developed in the past decade, only need to replace a part of the vaccine each time, which can act on multiple viruses at the same time. Heralds a new era in which vaccines respond more quickly to emerging infectious diseases.
Since 2003, based on these new technologies, the time from obtaining a new virus sequence to phase I human testing has been shortened from 20 months to more than three months.
NIAID and Moderna have cooperated in the research and development of the MERS vaccine.
On January 11, one day after the new coronavirus gene sequence was released, the two parties decided to partner again; on January 13, they had already set the gene sequence for a new coronavirus vaccine named mRNA-1273.
On March 16, they injected the first shot into the subject, becoming the world's first new crown vaccine to enter clinical trials and a key vaccine in the United States.
mRNA (messenger ribonucleic acid) is essentially a code, similar to the 0 and 1 of a computer.
For the new coronavirus, an mRNA vaccine instructs the cells of the human body to produce the S spike protein of the new coronavirus to help the immune system remember the new coronavirus.
Nucleic acid vaccines have the advantages of fast preparation and simple ingredients, so they are favored.
In the list of new coronavirus vaccines under development by the World Health Organization at the end of August, 10 nucleic acid vaccines have entered clinical trials, accounting for 1/3 of all vaccines entering clinical trials.
However, no matter whether it is a DNA or mRNA vaccine, there is currently no human vaccine approved for marketing. This is still a hope that has yet to be verified.
Moderna currently has 8 mRNA vaccines under development, and 6 of them are in clinical phase I, but none of them successfully managed to reach the market all the way.
On the other side of the Pacific Ocean, the technological path adopted by China's "national team" Sinopharm Group China Biotechnology Co., Ltd. (hereinafter referred to as "Sinopharm Zhongsheng")—inactivated vaccines, in the term of "Science", is a time-tested technology.
In the history of vaccines, at first, most of the vaccines that appeared in the world were inactivated vaccines.
According to public reports, on January 5, the Wuhan Institute of Virology of the Chinese Academy of Sciences isolated the new crown virus strain, and the new crown inactivated vaccine began to be developed.
On January 19, Sinopharm Zhongsheng organized the research and development of three vaccines: Zhongsheng Wuhan Institute and Wuhan Institute of Virology, Zhongsheng Beijing Institute and China Centers for Disease Control and Prevention, respectively responsible for the development of two inactivated vaccines, genetic engineering sub-units The vaccine is led by the China Institute of Biotechnology.
According to an official article of Sinopharm Group, compared with other types of vaccines, inactivated vaccines have advanced research and development technology, mature production processes, controllable quality standards, and good protection effects. Zhongsheng has already developed mature inactivated vaccines. Platform, with experience in the research and development of inactivated SARS virus vaccines, and large-scale production capacity, with an annual production capacity of 700 million doses of various vaccines.
It can be seen from Zhongsheng's vaccine product line that the company mainly focuses on attenuated live vaccines and inactivated vaccines.
Beijing Kexing Zhongwei Biotechnology Co., Ltd. from China has a similar experience. The company developed an inactivated vaccine during the SARS epidemic 16 years ago, but it stopped in phase I clinical trials.
A vice president of Kexing said, "(When the new coronavirus pandemic) we immediately restarted our known methods."
Qin Yuan, an authoritative vaccinologist in China, analyzed that compared with China, because inactivated vaccines are used less in foreign countries, there are no conditions for manufacturing inactivated vaccines. In addition, foreign R&D technologies are more advanced than domestic ones. The third-generation vaccine technology is relatively mature.
Unlike the previous concerns of Fauci and others, traditional technology is also going very fast.
In fact, among the 8 vaccines currently entering clinical phase III in the world, inactivated vaccines from Sinopharm Beijing Institute of Biology, Sinopharm Wuhan Institute of Biology and China Kexing Company account for 3 seats.
The two inactivated vaccines of Sinopharm Wuhan Institute and Beijing Institute of Biosciences received clinical trial approval documents issued by the UAE Minister of Health on June 23. Phase III clinical trials were launched in the UAE, and 15,000 people are expected to be enrolled; August 21 In Japan, Sinopharm Zhongsheng and Argentina launched a phase III clinical trial cooperation. The day before, the vaccine was approved for clinical trials in Peru and Morocco.
On July 21, China Kexing’s inactivated vaccine entered Phase III, and a clinical trial was launched in Brazil. It is the third vaccine in the world to enter the Phase III trial. About 9,000 people are expected to participate in the trial.
On August 11, Kexing's inactivated vaccine began to carry out phase III clinical trials in Indonesia, involving 1,620 subjects.
"The difference in the choice of technical routes is actually related to the scientific research strength and industrialization conditions of different countries. If China makes mRNA vaccines, the progress will definitely slow down." said Jin Xia, director of the Vaccine and Immunization Research Center of Shanghai Public Health Center.
The progress of domestic nucleic acid vaccines is indeed slower than that of the United States.
On June 19th, the mRNA vaccine jointly developed by the Academy of Military Sciences, Yunnan Watson Biology and Suzhou Aibo Biological Company was approved to enter clinical trials. It was China’s first clinically approved nucleic acid vaccine; around July 20th, Ai Diwei The DNA vaccine jointly developed by Xin and Inovio of the United States, and the mRNA new crown vaccine of Shanghai Fosun Pharma and BioNTech entered phase I clinical trials in China at the same time.
In contrast, on July 27, the two mRNA vaccines in cooperation between Moderna and NIAID, Pfizer and BioTech in Germany have started phase III clinical trials on this day.
Be cautious about those positive results
Vaccines are important because the best defense against pathogens is still the ancient guards in our body: T cells and B cells. T cells are responsible for killing virus-infected cells, and B cells can secrete a variety of Some of the antibodies that can directly neutralize the virus are called neutralizing antibodies.
Jin Xia, director of the Vaccine and Immunity Research Center of the Shanghai Public Health Center, told China News Weekly that the protection of a vaccine depends on the level of neutralizing antibodies and the quality of T cell responses.
Therefore, the titers of neutralizing antibodies can indirectly reflect the immunity of the vaccine.
Tal Zaks, Moderna's chief medical officer, cares about time because the company needs to be able to prove the potential or "expected benefits" of the vaccine before this summer.
According to the "New Yorker" report, on May 15th, Tal Zaks received the initial report of his new crown vaccine in his mailbox. Although only 8 of the 45 subjects in Phase I were analyzed, the results were enough to allow the company's executives and collaborators Excitement: After two administrations, 8 subjects in the low-dose group and the middle-dose group all produced neutralizing antibodies, and their titers reached or exceeded those in the serum of convalescent patients. At the same time, The vaccine is generally safe and well tolerated.
Three days later, Moderna disclosed this data in a company press release and informal paper.
Although this was questioned by the scientific community because of its lack of rigor, this information immediately boosted investors' confidence, and Moderna's stock price rose by nearly 20% that day.
This summer, a number of vaccines have successively disclosed preliminary clinical trial data. Almost every week, people can hear "hopeful" data about vaccine reports.
Qin Yuan explained that because many previous vaccines used inactivation technology, this kind of vaccine induces a weak T cell response, so in the past, the level of neutralizing antibody was usually used to judge the immunogenicity of the vaccine.
However, it is not clear how effective this indicator is.
The flu vaccine has been used for many years, but it is still uncertain how protective the neutralizing antibody titer is.
On July 14, the complete clinical data of Moderna's mRNA vaccine phase I was published in the New England Journal of Medicine.
The data showed that on the 43rd day after vaccination, the neutralizing antibody titers detected by the participants were 339.7 and 654.3 in the 25 and 100 microgram dose groups, respectively. On August 12, the German biotechnology company BioNTech and Pfizer jointly developed The mRNA vaccine also published its Phase I/II clinical trial data in the journal Nature.
Volunteers vaccinated with doses of 10 micrograms and 30 micrograms of vaccine had their average titers of neutralizing antibodies peaking at 168 and 267 on the 7th day after the second vaccination.
On July 20, two adenovirus vector vaccines were catching up step by step: Chen Wei’s team’s type 5 adenovirus vaccine (Ad5-nCoV) phase II clinical trial data, and the chimpanzee adenovirus new crown vaccine jointly developed by Oxford University and AstraZeneca The data of the Phase I/II clinical trials were published in The Lancet.
In the neutralization test of the Oxford University vaccine that can reduce the infection rate of the new coronavirus by 50%, at 28 days of vaccination, the subjects all activated the neutralizing antibody, with an average titer of 218.
However, in the phase II clinical trial, the average titers of neutralizing antibodies in the high-dose and low-dose groups of the Chen Wei team vaccine were 19.5 and 18.3, respectively.
Similar to the results of Phase I: 28 days after vaccination, the levels of activated neutralizing antibodies in each dose group did not exceed 40.
In general, these vaccines have activated antibodies, especially neutralizing antibodies, 2 to 4 weeks after vaccination.
But experts emphasize that these data are difficult to compare directly.
"Without a third-party independent organization that evaluates these vaccines under the same experimental conditions, it is difficult to really draw conclusions." Jinxia said.
T cell responses are equally important, but only the data on T cells of this Oxford University vaccine impressed scientists.
Xu Jianqing said that there are 856 and 424 T cells in one million cells of the Oxford vaccine at 14 days and 56 days respectively. For comparison, at 28 days, there are about 100 T cells among the million cells in Cansino vaccine. In other words, Even the data at 56 days of vaccination with Oxford vaccine is 4 times higher than that of Cansino.
On August 13, the inactivated vaccine of Sinopharm Wuhan Institute published specific test results in the Journal of the American Medical Association.
In phase I clinical, 14 days after three vaccination, the average titers of neutralizing antibodies in the low, medium, and high dose groups were 316, 206, and 297, respectively; in phase II clinical trials, the average titers of neutralizing antibodies were 316, 206, and 297, respectively; 14 days after the dose of the vaccine, the neutralizing antibody titers were 121 and 247, respectively.
The incidence of adverse reactions of this vaccine is not statistically different between the vaccine group and the placebo group, which is lower than the currently published data of other vaccine clinical trials.
However, Xu Jianqing said that because this type of vaccine uses the entire inactivated virus to stimulate the human immune system, the types of activated antibodies are very broad, including a large number of non-neutralizing antibodies. If the patient is reinfected, the risk of symptoms will increase (ie The ADE phenomenon cannot be ruled out at present, so the subsequent safety remains to be tested in large-scale clinical trials, especially when the vaccinators are exposed to the virus again.
The recombinant protein vaccine of Novavax, a US biotechnology company, also published the results of a phase I/II clinical trial in the New England Journal of Medicine on September 2. The neutralizing antibody titers induced by it reached 4 of those in convalescent COVID-19 patients. Times.
The trade-off between efficiency and speed
In the 18th century, the British doctor Edward Jenner used vaccinia to prevent smallpox and was called the "father of vaccines."
A century later, scientists realized that people can be exposed to inactivated viruses to teach the immune system to deal with the virus.
Since the 1980s, vaccine giants have generally adopted recombinant subunit protein vaccines. Nucleic acid vaccines are the third-generation vaccine technology developed in the past 30 years. These technologies have a common purpose, that is, how to "deceive" human immunity. System to remember what the pathogen looks like.
To achieve this goal, vaccines can be prepared from weakened viruses, inactivated viruses, partial viral proteins, viral proteins implanted on harmless viruses, or even just mRNA encoding the viral protein code.
Vaccination is actually similar to experiencing a viral infection in the human body without a health hazard.
At the beginning of the year, China laid out five technical routes for the development of new coronavirus vaccines, including inactivated vaccines, genetically engineered subunit vaccines, adenovirus vector vaccines, attenuated influenza virus vector vaccines, and mRNA and DNA-based nucleic acid vaccines.
These routes almost cover the mainstream research and development technology of the new crown vaccine.
Dave O’Connor, a virologist at the University of Wisconsin-Madison, told China News Weekly that when vaccines are comparable in immunogenicity, other factors, such as ease of production, cost, side effects, and frequency of delivery, etc. Consideration may be more important, which is why multiple candidate vaccines need to be promoted at the same time.
From this perspective, the vaccines of each technical route have their own advantages and disadvantages.
A team led by Chen Zhiwei, director of the Institute of AIDS, Li Ka-shing School of Medicine, University of Hong Kong, is developing a DNA nucleic acid vaccine against the new coronavirus.
He told China News Weekly that as a cutting-edge technology, human-use nucleic acid vaccines have not been approved for marketing, which means that the industrialization is immature, and it is difficult to meet the application of thousands of large-scale populations in the future.
However, if this bottleneck can be broken, he believes that nucleic acid vaccines are fast and have no advantages in pre-existing immunization, and may become a better technology to lead future vaccines.
Yu Li explained that mRNA vaccines can neither be produced by machines nor produced in E. coli. They can only be subjected to in vitro polymerase reactions in test tubes, making mass production difficult.
Right now, even Moderna, the world's most advanced technology in this field, has no experience in mass production.
China has neither technical intellectual property rights in the field of mRNA vaccines, nor does it have the capacity for mass production.
Unlike DNA vaccines, mRNA is very unstable in the environment. One technical difficulty is how to ensure the stability of the product, and there are still many bottlenecks in storage and transportation technology.
At present, Pfizer's mRNA vaccine must be stored at minus 70°C, while Moderna's vaccine must be stored at minus 20°C.
Melanie Saville, Head of Vaccines at the Alliance for Epidemic Prevention and Innovation (CEPI), pointed out that whether the vaccine needs to be stored at minus 70°C or 4°C is a completely different matter. If a nucleic acid vaccine needs to establish a -70°C cold chain, it will greatly increase the cost. And the complexity of things.
Qin Chengfeng, a researcher at the Chinese Academy of Military Sciences, and others reported on "Cell" at the end of July the mRNA vaccine developed by this institution and local enterprises, emphasizing that the vaccine has three major advantages, one of which is that it can be stored at room temperature for a week or at 4°C for a long time. , The cold chain cost is low, and it is easy to achieve large-scale population vaccination.
But right now, the most likely vaccine to be marketed in China is an inactivated vaccine.
Sinopharm said that its inactivated vaccine may be launched at the end of this year or early next year as soon as possible.
"But if you consider the production cost and potential safety risks, the fastest runners may not be the best ones. They are just candidates before other vaccines are on the market." Qin Yuan said.
In terms of convenience, Melanie Saville said there is a key difference between one dose or two doses.
The ideal vaccine should be a dose of vaccine, so that there can be faster protection, and patient compliance is much higher.
In low- and middle-income countries, single-dose vaccination may be more successful than two-dose vaccination because it is much cheaper.
The current plan for a single injection is two adenovirus vaccines from the Oxford team and Cansino.
Professionals explained that the ability of inactivated vaccines to activate T cell immune response is relatively poor, and the latter is an important immune function to prevent secondary infections. Therefore, inactivated vaccines need to be vaccinated repeatedly.
Adenovirus vector vaccine does not have these shortcomings, but it also has its own inherent defects, that is, "pre-existing immune effect."
Human-derived adenovirus type 5 widely infects humans and causes the common cold.
For those who have been infected with the adenovirus, vaccines that use this virus as a vector will neutralize the virus vector by the body's pre-adenovirus antibodies before the human body has an immune response to it, thereby affecting the vaccine effect.
"The type 5 adenovirus vector is basically not used abroad. Except for the case of Merck’s HIV adenovirus vaccine failure due to pre-existing immunization, other studies have also proved that the positive rate of type 5 adenovirus antibodies in the population is very high. The highest proportion can even reach more than 90%, which will not only weaken the immunological effect of the vaccine, but also have a high adverse reaction rate." Qin Yuan said.
Even if the chimpanzee adenovirus of Oxford University has not been infected before, if it is used this time, the effect will be greatly reduced when the human body is vaccinated again in the future.
In the phase II clinical trial of the Chen Wei/Kangsino vaccine, more than half of the 508 subjects included have a higher pre-existing immunity to the vector, and the level of activated neutralizing antibodies in this part of the population is approximately higher than the pre-existing immunity People with low power are twice as low.
Melanie Saville said, obviously, we want these vaccine candidates to have the best overall performance.
"If a vaccine that needs to be stored at -70°C but has a degree of protection of 90% is compared with a vaccine that can be stored at 2°C to 8°C but has a degree of protection of only 10%, I would rather choose the former. It is necessary to put all the factors together Consider to achieve the best balance."
Not just a scientific question
In a July 30 review of China’s new crown vaccine in Nature, US President Trump said that he is willing to cooperate with any country that can develop an effective new crown vaccine.
However, China's vaccines have long been excluded from the list of US$10-billion-dollar funding for the "Variate Speed" program.
In this pandemic, vaccines have gone beyond the scope of health and disease, and have carried many political demands.
Lawrence Gostin, professor of global health law at the Georgetown University Law Center, said: "I have never seen (other) medical products have such a big political stake. Behind the political symbolism of the new crown vaccine is the superpower. They have been regarded as a symbol of showing their country’s scientific strength and a means to prove the superiority of the political system."
In February of this year, the World Health Organization (WHO) stated that it does not expect to have a new crown vaccine available within 18 months.
In the past, the birth of a vaccine usually took 7 to 12 years.
However, only 6 months after the WHO published the above views, domestic and foreign vaccine research and development companies have successively announced the time points for the large-scale production of the new coronavirus vaccine, some of which claimed to be delivered as early as October this year-this is a short distance from the new coronavirus gene sequence. The announcement has only just passed 8 months.
Chen Zhiwei has been researching HIV vaccines since 2003, and it took them 6 years to go from the laboratory to phase I that year.
He said that if some new crown vaccines can complete clinical phase III trials by around November this year, it will undoubtedly be a milestone in the history of human vaccine research.
But for politicians, there is no fastest, only faster.
In early August, Trump said: "I think in some cases it is possible to develop a new crown vaccine before November 3 (U.S. Presidential Election Day). (The vaccine is on the market) earlier, much earlier than before the end of the year." On August 22, Trump wrote on Twitter again: We must focus on speed to save more lives!
Those who stand in the way of the FDA deliberately make it difficult for pharmaceutical companies to recruit enough people to test the new crown vaccine, thus delaying the pace of the new crown vaccine.
In the US-Soviet space race in the middle of the 20th century, in 1957, "Sputnik 1" became the first man-made satellite successfully developed and launched into space, making the Soviet Union the top spot.
Now, a new crown vaccine called "Sputnik-V" also represents Russia's participation in this vaccine race.
Russia announced its "win" competition in a unique way: On August 11, Russian President Vladimir Putin announced that the world's first new coronavirus vaccine was registered in Russia and production may start as early as September.
This vaccine uses two adenoviruses Ad5 and Ad26 as carriers. Volunteers are first vaccinated with Ad26 vector vaccine, and after an interval of 21 days, they are vaccinated with Ad5 vector-based vaccine.
The vaccine was developed by the Russian National Research Center for Epidemiology and Microbiology "Gamaleya", and the Phase III clinical trial has not yet been completed.
On September 4, the vaccine's Phase I/II Phase II clinical trial results published in the "Lancet" showed that the vaccine showed good safety.
In terms of immunogenicity, at 42 days after vaccination, the level of neutralizing antibodies was close to the average level of recovered patients from COVID-19, with specific values ranging from 45 to 49.
In fact, China has approved some vaccines conditionally.
On June 25, the Health Bureau of the Logistics Support Department of the Central Military Commission issued an approval document for military special-needed medicines, which approved the adenovirus vector new crown vaccine jointly developed by Cansino and the Academy of Military Sciences to be used in the military. The validity period is one year, but the scope of vaccination cannot be expanded.
Zheng Zhongwei, director of the Science and Technology Development Center of the National Health and Construction Commission and the leader of the vaccine research and development team of the Joint Defense and Joint Control Mechanism Research Team of the State Council, introduced on CCTV on August 22 that China has officially launched the emergency use of the new crown vaccine on July 22. It did not disclose which vaccine it was.
On September 6, China's two new inactivated vaccines for the new crown were exhibited at the China International Trade in Services Fair in Beijing. The two vaccines were from Sinopharm Group, China Biotech and Kexing.
According to CNBC, the New York Times and many other US media reports in early September, the CDC sent a letter to the governors of 50 US states on August 27, urging the public health officials of all states to do a good job or distribute the new crown in late October or early November. Administrative preparation of vaccines.
The letter did not specify which of the two vaccines were distributed, only vaccine A and vaccine B were the code names, but the media speculated that the most likely to be distributed are the two mRNA vaccines of Pfizer and Moderna.
More like a marathon
Although Oxford Vaccine is already far ahead of a vaccine, when asked by the media about the most worrying thing, Sara Gilbert, the head of research and development and professor of vaccinology at Oxford University, said that as the virus spreads around the world, the epidemic slows down. , It will be difficult to prove that the vaccine is effective.
"(Phase III) trials must be conducted at the right time and at the right place, which is why we plan to conduct multiple trials in multiple countries."
In the Phase III clinical trial, subjects were divided into two groups: one group received a placebo and the other group received a vaccine.
Then, researchers must wait for people to accidentally come into contact with the virus or become infected. Once a large number of cases appear in the placebo group and the number of vaccinated subjects is very low, then statistical differences begin to show the effectiveness of the vaccine. .
Therefore, if the population infection rate in the natural state is higher, the study can be ended sooner.
If compared with the control group, the vaccinated test group reduces the infection rate by 50%, then a vaccine has 50% protection.
On July 9, the International Association of Drug Regulators (ICMRA) agreed on the standards for the Phase III efficacy test of the new crown vaccine.
China currently does not have a standard in this regard. The WHO proposes that ideally, the protective efficacy of vaccines should be at least 70%, and the minimum standard is 50%.
The US FDA standard is lower, and the vaccine protection rate exceeds 50% before it can be approved for marketing.
Sara Gilbert still has this concern. For China, where the number of new domestic cases is close to zero every day, it is almost impossible to carry out a phase III trial in the country.
Therefore, in Brazil, in the United States, in Saudi Arabia...in those countries where the new crown virus is still raging, a new crown vaccine is coming or is about to arrive, competing for as many eligible subjects as possible.
Right now, when the fastest-growing vaccine is still in Phase III clinical trials, many national governments and pharmaceutical companies have begun to deploy vaccine production lines and formulate their own purchase and sales plans.
In this regard, Anthony Fauci pointed out in an interview with the Journal of the American Medical Association on June 8 that what is happening now is a very unique situation in the history of vaccine development: vaccine scientists and these companies, as well as the US federal government, Taking risks, because people start producing vaccines even before they know whether they will work.
So, which vaccine under development has received consistent or more recognition in the industry?
"I think this vaccine from Oxford University is still promising. Compared with Moderna's immune effect, it may not be much worse. But from the perspective of preparation cost, it must be the low cost of Oxford University vaccine." Qin Yuan said.
Yuli is also more optimistic about the Oxford vaccine, because the vaccine not only has antibodies, but also has a good T cell response, and it runs very fast.
As early as when the Oxford University vaccine disclosed the results of animal experiments, Xu Jianqing was optimistic about the potential of this vaccine.
Regarding the domestic new crown vaccine, he also has several vaccines that he thinks are good, although they are being advanced step by step, they are not among the fastest research and development.
CEPI, a multilateral cooperation mechanism established in 2017 with the support of the Gates Foundation, the Wellcome Foundation of the United Kingdom, the World Economic Forum in Davos, the Norwegian government and other institutions, is the new crown vaccine development. It is an important international organization in China, which selected vaccine players that it believes has potential for funding.
Melanie Saville, head of research and development at CEPI, said, “We make selections based on three key criteria: speed, scale and accessibility to ensure that the most promising vaccines continue to develop.”
These vaccines are: DNA vaccine of Inovio of the United States, mRNA vaccine of Moderna of the United States, mRNA vaccine of CureVac of Germany, measles virus vector vaccine of Merck & Co., Ltd., chimpanzee adenovirus vector vaccine of Oxford University/AstraZeneca, and attenuation of the University of Hong Kong Live vaccines, recombinant protein vaccines from Novavax, a US pharmaceutical company, "S-trimer" protein vaccines from China Clover, and molecular clamp vaccines from the University of Queensland, Australia.
Jin Xia believes that if the vaccines that I think are good now, in another half a year or a year, when the Phase III data comes out, you may see different results. It is risky to bet all the "treasures" on the fastest vaccine. of.
Peter Hotz, a vaccine scientist at Baylor University School of Medicine in Houston, USA, said that the first batch of vaccines may not be the best.
They may be partially protective, and over time they will be replaced by better vaccines.
"Maybe you can call it a race, but it's more like a marathon."
(At the request of the interviewee, Qin Yuan is a pseudonym in the text)
China News Weekly, Issue 34, 2020
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