What is the hope for the global preliminary vaccine R & D "preliminary competition"?
China News Weekly Reporter / Peng Danni Huo Siyi
Published in the 2020.6.01 total issue 949 "China News Weekly"
According to the statistics of the World Health Organization, as of May 22, there are currently more than 120 candidate new crown vaccines, of which 114 are in the preclinical evaluation stage, 10 vaccines have entered clinical trials: 5 of them are from the Chinese team, the rest Five models were developed by American and British scientists. In the vaccine development "contest", the runners who ran fast have taken the lead in the Phase II clinical trials. But who is more promising? There is still no definite answer. However, at the level of immune response, animal or human test data released by several teams have initially shown different potentials.
Behind the first human clinical trial report on vaccines
On the evening of May 22, the world's top medical journal "The Lancet" published the results of the Phase I human clinical trial of the adenovirus vector Ad5-nCoV vaccine developed by the team of Chen Wei, a member of the Chinese Academy of Engineering and a researcher at the Institute of Military Medical Research, Academy of Military Sciences This is also the world's first human clinical data report of the new crown vaccine.
A vaccine developer close to Chen Wei's team told China News Weekly that the human clinical trials of the vaccine are mainly divided into three phases: Phase I is to understand the initial safety of the vaccine, and Phase II is in a larger sample size Investigate the safety of the vaccine and determine the optimal immunization dose. Phase III will apply this dose to a large sample population to evaluate the effectiveness.
The results of the Phase I clinical trial of the vaccine of Chen Wei's team showed that during the period from March 16 to March 27, 2020, 108 healthy adults aged 18 to 60 were injected with vaccines and found that the volunteers were on the 14th day after vaccination. A specific T cell response begins. The titer of neutralizing antibody reached its peak on the 28th day after inoculation.
The main and secondary measurement indicators of this study were the adverse reactions within 7 days and 28 days after vaccination, respectively. The results showed that the overall number of adverse reactions accounted for 81%, the severity of most adverse reactions was mild or moderate, and the grade 3 adverse reaction rate was 9%. The research team said that serious adverse reactions were transient and self-limiting, but based on the results of this assessment, the high-dose group was eliminated in the phase II clinical trial.
The 108 subjects of the research team were divided into three groups: low dose (0.5ml), medium dose (1ml) and high dose (1.5ml), 36 persons in each group. Inducing antibodies that have a strong neutralizing ability against the new coronavirus is an important goal of the new corona vaccine. In this test, 28 days after vaccination, the average value of the low-dose group was 14.5, the middle-dose group was 16.2, and the high-dose group was only 34.
Xu Jianqing is the director of the Institute of New and Reproducible Infectious Diseases of Shanghai Public Health Clinical Center, and is also the main head of the new crown vaccine research and development team of the institution. He told "China News Weekly" that the neutralizing antibody titer after vaccination should be at least more than 40, and 40 is the bottom line indicator. In general, the higher the neutralizing antibody concentration, the better. The ideal vaccine is conservatively estimated to be around 1,000.
In addition to looking at the absolute number of neutralizing antibodies, Xu Jianqing pointed out that there is a relative indicator, that is, before and after vaccination, the neutralizing antibody titer has increased by at least 4 times. In the three dose groups of Chen Wei's team, on the 28th day, when the number of neutralizing antibodies reached the peak, only half of the subjects in the low and medium dose groups were able to achieve a four-fold increase in neutralizing antibodies. The ratio is 75%.
Tao Lina, a former immunization planning physician at the Shanghai Center for Disease Control and Prevention, also pointed out that the results in the report are not ideal. The 4-fold growth rate of neutralizing antibodies should reach more than 90% at 28 days. However, since effective antibody standards are not determined, and cellular immunity is equally important, the current results do not yet explain the problem.
Despite some uncertainties, the Chen Wei team started a Phase II human clinical trial in Wuhan on April 12. Compared with the non-random design of Phase I, Phase II adopts a randomized, double-blind model and introduces a placebo control group, which not only expands the sample to 500 people, but also introduces volunteers over 60 years old for the first time, with a maximum age of 84 years. According to sources familiar with China News Weekly, the preliminary results of the Phase II trial have been reported to the State Drug Administration for review on May 16, and the results are expected to be announced around June.
In this study, 44% to 56% of volunteer subjects had an immune response against adenovirus. This group of subjects had high adenovirus neutralizing antibody titers before, and the number was significant after the vaccine was given. improve. Zhu Fengcai, the first author of the paper and the Jiangsu Provincial Center for Disease Control and Prevention, said that the high level of adenovirus type 5 immunity may have a negative impact on the sustainability of the immune response caused by the vaccine.
The root cause of this problem is related to the technical route of the vaccine: it is constructed using genetic engineering methods and uses the replication-deficient human adenovirus type 5 as a vector to express the new coronavirus S antigen. Xu Jianqing explained that, theoretically, about 80% of Chinese people are positive for adenovirus type 5 antibodies, which means that most people have already been infected. When the adenovirus enters the body again, the adenovirus antibodies in the body will attack the carrier instead of it. The expressed S protein, which renders the vaccine ineffective, is often referred to as a carrier blocking effect, or pre-existing immunity. This is also the main reason why many vaccines using this technology route have failed previously.
For the weakening of immunity brought about by adenovirus, one solution is to adopt a heterologous priming-strengthening strategy, that is, to inject different types of vaccines to strengthen the immune response in the body, and the first vaccine to help the body establish a priming immunity; The second vaccine is used to strengthen the immune system again. Chen Wei's team also pointed out that some previous studies have proved that this heterologous priming-strengthening strategy can induce a stronger and longer-lasting immune response in people with high pre-existence. The Ebola vaccine used this scheme.
Oxford vaccine is not really a failure
The new crown vaccine ChAdOx1 nCoV-19 based on the chimpanzee adenovirus vector at the Jenner Institute of Oxford University has long been expected. However, its recently published animal test data has been directly pointed to as "failure" by some domestic and foreign media, but it is not the case .
Xu Jianqing explained that chimpanzees types 1, 26, 35, and 68 are adenovirus vectors commonly used to develop human vaccines. Although the vaccines of Oxford University and Chen Wei team are both adenovirus vector technology, adenovirus type 5 is a weak common cold virus, many people have been infected, so there will be pre-existing immunity, and chimpanzee adenovirus vector has never been No one has been infected. The vaccine being developed by Zhang Linqi, director of the Global Health and Infectious Diseases Research Center at Tsinghua University, also uses chimpanzee adenovirus as a carrier. He pointed out that its pre-existing immune response is very low in the human body, so there will be some advantages in terms of dosage and side effects.
On April 23, scientists from the National Institutes of Health's Rocky Mountain Laboratory in Montana injected six rhesus monkeys with a single dose of Oxford University vaccine. After vaccination, to simulate a pandemic environment, these monkeys were exposed to a large number of viruses. The control monkeys in the laboratory continued to develop infections, but 28 days later, the vaccinated monkeys were still healthy. Compared with the control group, the viral load in the tracheal-alveolar lavage fluid and airway tissues of the experimental group was significantly reduced, and no symptoms of pneumonia were observed. More importantly, the vaccinated rhesus monkeys did not have immune-enhancing diseases, which proved the safety of the vaccine to a certain extent.
But three days later, the discussion reversed. William Haseltine, a former professor at Harvard Medical School and a well-known expert in AIDS research, published an article in Forbes on May 16 that the Oxford vaccine cannot prevent rhesus monkey infection. After the challenge test, the new coronavirus RNA data in the nasal secretions of rhesus monkeys showed that both the experimental group and the control group were infected, and the neutralizing antibody titer caused by the vaccine was extremely low. He said, "It is very clear that the vaccine did not prevent infection in the challenge test-this is the gold standard for vaccine evaluation, but he may provide some protection."
Some vaccinologists compared the results of Oxford University with the data of animal studies on inactivated vaccines published by Chinese researchers in early May, and believed that the latter seemed to be more immunogenic. On May 6th, the results of the first international animal experiment cooperated by the Qinchuan team of the Institute of Medical Laboratory Animals of the Chinese Academy of Medical Sciences and Kexing were published in Science. The results of the study showed that on the 7th day after the 4 rhesus monkeys were reinfected in the high-dose group, no virus was detected in the throat, anus, and lungs; the pharyngeal, anal, and lung specimens on the 7th day after the infection in the middle-dose group The virus was partially detected by Zhongneng, but the viral load was reduced by about 95% compared to the control group.
However, the head of the Oxford University research team said that it is unfair to compare Oxford University with Kexing ’s monkey test because the animal test used to infect animals with a very high dose of virus, much higher than the Kexing team, and the infection There are also multiple ways of delivery, so viral genetic material appeared in the nasal cavity of monkeys in the experimental and control groups-but this infection did not cause pneumonia.
Xu Jianqing explained that the effectiveness of the vaccine should be viewed from two dimensions, prevention of infection and prevention of pathogenicity, the latter may be understood as reducing pathogenicity. Preventing infection, which means that the virus cannot enter the body at all, is indeed the gold standard, but in fact, most human vaccines cannot do this, but can only reduce the pathogenicity. For example, Kexing's vaccine uses a tracheal intubation to directly attack the lower respiratory tract, but if inhaled by nebulization, Xu Jianqing said that even if the concentration of the neutralizing antibody activated by the vaccine is high, it will be in the nose Virus detected.
Dong Chen, dean of the School of Medicine at Tsinghua University and an expert in immunology, read the test results of several vaccines that have been officially published and told "China News Weekly" that the scientists who conducted animal experiments at Oxford University are "veteran at first glance." Compared with several other trials, this study can't pick out faults in trial design, and the trial design and measurement indicators are very comprehensive. Xu Jianqing also said that the results of the Oxford vaccine are credible. These data show that this vaccine has room for improvement and supports the continued advancement of clinical research.
Right now, the Oxford team is advancing clinical trials as scheduled. At the end of April, ChAdOx1 nCoV-19 began a phase I clinical trial, recruiting a total of 1100 people. Before the end of June, the clinical trials II and III will be carried out simultaneously, and the subject size will reach 5,000.
Preliminary examination of other technical routes
Internationally, currently, in addition to the Moderna mRNA vaccine, the United States also has the DNA vaccine INO-4800 of the pharmaceutical company Inovio, which has entered Phase II clinical trials. On April 23, the German biotechnology company BioNTech and the American pharmaceutical company Pfizer jointly developed The mRNA vaccine has begun clinical trials in Germany. Novavax's recombinant nanoparticle vaccine in Maryland, USA, also launched a Phase I clinical trial in May.
The five globally recognized new vaccine design routes are: nucleic acid vaccines (including mRNA vaccines, DNA vaccines), recombinant genetic engineering (protein recombinant) vaccines, inactivated vaccines, attenuated influenza virus vector vaccines, and adenovirus vector vaccines. Nucleic acid vaccines, especially the mRNA vaccine technology, are favored by researchers and capital in this vaccine competition. Three of the five vaccines currently in clinical trials abroad are mRNA vaccines, but domestic mRNA candidate vaccines are still No one has entered this stage.
However, there are currently no officially published results of animal or clinical trials on this technical route. On May 18, Moderna disclosed a "positive" mid-term clinical data for the Phase I study in an unofficial paper in a company press release. Moderna said that after the vaccine was given, all 45 participants produced antibodies. After two doses, all 8 subjects in the low-dose group and the medium-dose group produced neutralizing antibodies, and the titers reached or exceeded the titers of neutralizing antibodies in the serum of patients in the recovery period. Safety and tolerance are good.
This information immediately boosted investors' confidence, and Moderna's stock price rose nearly 20% that day. However, insiders are skeptical of these data. A researcher from Vanderbilt University in the United States wrote that compared with the data disclosed by Moderna, it should pay more attention to the part that was not disclosed. For example, how did the remaining 37 subjects respond to neutralizing antibodies? What are the specific values of neutralizing antibodies that have been observed?
The company only said in general terms that these detected antibody levels are a good sign, "If it reaches the antibody level of the recovered person, it will be enough." However, little is known about how high the antibody level can save the recovered from reinfection. However, mRNA-1273 has been approved by the US Food and Drug Administration for the Phase II study on May 6, and Phase III is expected to begin in July.
The aforementioned vaccine scientist who did not want to be named said that Moderna ’s mRNA technology is the most advanced in the world, but in the past the company has been using this technology in the development of therapeutic vaccines such as tumors, because this technology is not yet mature enough to be large-scale in the short term It is very expensive to produce, and the vaccine itself is very expensive. Even if the United States has greatly reduced its cost, it will cost $ 600 to 1,000 per dose. However, China has neither technical intellectual property rights in the field of mRNA vaccines, nor the capacity for mass production.
On the technical route of adenovirus vectors, the Chinese Chen Wei team and the Oxford University vaccine that have been running ahead have been born. Some people in the industry believe that the doubts caused by the Oxford University vaccine will affect the prospects of domestic adenovirus vaccines. Kang Xinuo recently launched the mRNA vaccine, which was interpreted by some people as an alternative to adenovirus vector vaccine.
In addition to the vaccine of Chen Wei's team, the other four domestic clinical trials are inactivated vaccines, which are respectively from China National Pharmaceutical Group China Bio-Wuhan Biological Products Research Institute, Beijing Kexing Zhongwei Biotechnology Co., Ltd., and China Bio-Beijing Biotechnology Research Institute. , Chinese Academy of Medical Sciences participated in research and development. The five vaccines are expected to complete phase II clinical trials in July.
Unlike foreign countries that tend to adopt emerging vaccine technologies, several other domestic vaccines that have entered clinical trials are traditional inactivated vaccine technologies. Judging from the animal test results of Kexing, Xu Jianqing said that the data of activated antibodies in primates are good, but the vaccine uses a whole inactivated coronavirus to stimulate the human immune system, so the type of activated antibodies is very broad. Including a large number of non-neutralizing antibodies, so the subsequent safety is still to be tested in clinical trials. "Adenoviral vectors and mRNA and other new vaccine technologies have given great promise, but there has been no successful vaccine as a support before. New and old Both methods can and should be developed at the same time, there is no need to choose between the two. "Dave O'Connor, a virologist at the University of Wisconsin-Madison, said that when the vaccine is comparable in immunogenicity, other factors Considerations such as ease of production, cost, side effects, and frequency of delivery may be more important, which is why multiple candidate vaccines are required to advance simultaneously. He also said that a large number of vaccine candidates for the World Health Organization are steadily advancing, and most will be tested first in Syrian hamster or non-human primate models. These data may be gradually released this summer.
Although the candidate vaccines on the track are still far from Phase III, the fact that the domestic pandemic has generally passed has become a "difficult" for domestic vaccine research and development. Xu Jianqing said that Europe and the United States have always allowed challenge tests in influenza vaccine research. The so-called challenge test is to use a virus to challenge the vaccinated subjects to understand how protective the immune response generated by the vaccine is.
After the outbreak of the new crown epidemic, Europe and the United States soon began to discuss whether to allow human virus attack trials. Because if the vaccine is vaccinated on young adults, even if the vaccine protection fails when the virus is attacked, the pathogenicity is controllable, so Xu Jianqing believes that such tests should be allowed to be conducted in a specific population to really speed up the vaccine research. And better judge the protection of the vaccine.
China News Weekly Issue 19, 2020
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