Who’s more hopeful of the world’s more than 120 new crown vaccine candidates?

According to the World Health Organization, as of May 22, there are now more than 120 candidates for new crown vaccines, 114 of which are in the preclinical evaluation phase, 10 vaccines have entered clinical trials: 5 from the Chinese team, the remaining 5 by American and British scientists. In the vaccine development “competition”, the fast runner has been the first to enter the Phase II clinical trial. But who’s more hopeful? There is still no definitive answer. However, at the level of immune response, animal or human trial data published by several teams initially showed different potential.

Behind the First Vaccine Human Clinical Trial Report

On the evening of May 22, The Lancet, the world’s top medical journal, published the results of human clinical trials of adenovirus vector Ad5-nCoV vaccine Phase I, developed by Chen Wei, a member of the Chinese Academy of Engineering and a researcher at the Institute of Bioengineering of the Military Medical Research Institute of the Academy of Military Sciences, which is also the world’s first human clinical data report on the new corona vaccine.

A vaccine researcher close to Chen Wei’s team told China Newsweek 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, Phase II to examine the safety of the vaccine in a larger sample size, and determine the optimal immune dose, Phase III will be applied to the large sample population to assess the effectiveness.

The results of The Phase I clinical trial of The Vaccine by Chen Wei’s team showed that between March 16 and March 27, 2020, 108 healthy adults aged 18 to 60 were vaccinated and found that volunteers began to experience specific T-cell reactions on the 14th day after vaccination. The titer of neutralizing antibodies peaks on the 28th day after vaccination.

The main and secondary measures of the study were adverse reactions within 7 days and 28 days after vaccination. The results showed that the overall proportion of adverse reactions was 81%, the severity of most adverse reactions was mild or moderate, and the rate of level 3 adverse reactions was 9%. The team said severe adverse reactions were transient and self-limiting, but based on this assessment, the high-dose group was eliminated in Phase II clinical trials.

The 108 subjects in the research team were divided into low-dose (0.5 ml), medium-dose (1 ml) and high-dose (1.5 ml) groups of 36 people. Inducing antibodies with strong neutrality of the new coronavirus is an important goal of the new coronary vaccine. In this trial, 28 days after vaccination, the average of the low-dose group was 14.5, the medium dose group was 16.2, and the high-dose group was only 34.

Xu Jianqing is the director of the Institute of New Hair and Reproduction Infectious Diseases at the Shanghai Public Health Clinical Center and the main person in charge of the research and development team of the new crown vaccine. He told China Newsweek that the level of neutralizing antibody titer after vaccination is at least 40 or more, the bottom line indicator. Overall, the higher the concentration of neutralizing antibodies, the better, the ideal vaccine conservative estimate to reach about 1000.

In addition to the absolute number of fancy and antibodies, Xu Jianqing pointed out that there is a relative indicator, that is, before and after the injection of the vaccine, neutralizing the antibody titer 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 peaked, only half of the subjects in the low and medium dose groups were able to achieve 4 times the promotion of neutralizing antibodies, compared with 75% in the high-dose group.

Tao Lina, a former immune program physician at the Shanghai Center for Disease Control and Prevention, also pointed out that the results in the report were not ideal, with a four-fold growth rate of neutralizing antibodies that would have been more than 90% in 28 days. However, since effective antibody standards are not determined, and cell immunity is equally important, the current results are not telling.

Despite some uncertainty, Chen Wei’s team opened Phase II human clinical trials in Wuhan on April 12. Compared to the non-randomized design of phase I, phase II adopted a randomized, double-blind model, introducing a placebo-controlled group that not only expanded the sample to 500 people, but also introduced volunteers over 60 years of age for the first time, with a maximum age of 84. The preliminary results of the Phase II trial were reviewed by the State Drug Administration on May 16 and are expected to be released around June, a person familiar with the matter told China Newsweek.

In the study, 44 to 56 percent of volunteer subjects had an immune response to adenoviruses, which had previously had higher adenovirus neutralizing antibody titages, and the number significantly increased after the vaccine was given. Zhu Fengcai, the first author of the paper and a director of the Jiangsu Provincial Center for Disease Control and Prevention, said that the high level of adenovirus adgenion immunity may have a negative impact on the continuity 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 built by genetic engineering method, to replicate the defective human type 5 adenovirus as a carrier, can express the new coronavirus S antigen. Xu Jianqing explained that, in theory, about 80% of Chinese have a type 5 adenovirus antibody positive, meaning that most people have been infected, when adenovirus re-entertherand, the body’s adenovirus antibody will attack the carrier instead of the S protein it expresses, so that the vaccine will fail, which is often referred to as the carrier obstruction effect, or pre-existimmunity. This is also the main reason why many of the previous vaccines that have used the technology route have failed.

One solution to the immune weakening of adenoviruses is to adopt an hetero-boosting strategy, which is to strengthen the immune response in the body by injecting different types of vaccines, the first vaccine to help the body establish first-time relief, and the second vaccine to re-strengthen the immune system. Chen Wei’s team also noted that previous studies have shown that this heterogeneous-enhanced strategy can induce stronger and longer-lasting immune responses in populations with high pre-existing levels. This scheme was used in the Ebola vaccine.

Who's more hopeful of the world's more than 120 new crown vaccine candidates?

On April 10, staff displayed samples of the new coronavirus inactivated vaccine at the China Bionew Crown Vaccine Production Base of China Pharmaceutical Group. Picture/Xinhua

Oxford vaccine is not a real failure

The New Corona vaccine ChAdOx1 nCoV-19, based on chimpanzee adenovirus vectors at Oxford University, has been highly anticipated, but its recently published animal test data has been described as a “failure” by some media at home and abroad, but this is not the case.

Xu Jianqing explained that chimpanzees type 1, 26, 35, 68 are commonly used to develop human vaccine adenovirus vector. Although both Oxford University and Chen Wei’s team vaccine are adenovirus vector technology, but 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 infected people. The vaccine being developed by Zhang Linyi, director of Tsinghua University’s Center for Global Health and Infectious Diseases Research, is also based on chimpanzee adenoviruses. He points out that its pre-existing immune response is very low in the human body, so there are some advantages in terms of dosage and side effects.

On April 23, scientists at the National Institutes of Health’s Rocky Mountain Laboratory in Montana injected six rhesus monkeys with a single dose of the Oxford vaccine. After the vaccination, the monkeys were exposed to a large number of viruses to simulate a pandemic environment, and the control group in the lab continued to develop the disease, but after 28 days, the vaccinated monkeys remained healthy. Compared with the control group, the viral load in the trachea alveolyceous irrigation fluid and respiratory tissue in the experimental group was significantly reduced, and no symptoms of pneumonia were observed. What’s more, the vaccined rhesus monkeys did not develop immune-boosting diseases, which is partly evidence of the safety of the vaccine.

But three days later, the discussion reversed. William Haseltine, a former professor at Harvard Medical School and a leading expert in AIDS research, wrote in Forbes magazine on May 16 that the Oxford vaccine would not stop rhesus monkeys from contracting. After the attack 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 very low. “It is very clear that the vaccine does not prevent infection in the test – it is the gold standard for vaccine evaluation, but it may provide some protection,” he said. “

Other vaccineists compared the results of Oxford University with animal test data from Chinese researchers in early May, saying the latter appeared to be more immunogenic. On May 6, the first international animal test results, published in the journal Science, were published in the journal Science, in collaboration with the Qinchuan team of the Institute of Medical Experimental Animals of the Chinese Academy of Medical Sciences, in collaboration with Kexing and others. The results showed that the 4 rhesus monkeys in the high-dose group were not detected in the throat, anus and lungs on the 7th day after reinfection, and the virus was partially detected in the pharynx, anus and lung samples on the 7th day after the mid-dose group infection, but the viral load was reduced by about 95% compared to the control group.

However, the head of the Oxford University research team said it was unfair to compare oxford university with the Monkey Trials in Kirching, which had a very high dose of the virus used to infect the animals, much higher than the Coching team, and the delivery of the infection was carried in multiple ways, so the virus gene material appeared in the nasal cavity of the experimental and control group monkeys – but the infection did not cause pneumonia.

Xu Jianqing explained that the effectiveness of the vaccine should be seen from two dimensions to prevent infection and prevent pathogenicity, the latter may be understood as reducing pathogenicity. Preventing infection, that is, keeping the virus completely out of the body, is a gold standard, but in fact, the vast majority of human vaccines can not do this, but only to reduce pathogenicity. For example, Kexing’s vaccine, the test used the detection path is the trachea intubation directly attack the lower respiratory tract, but if inhaled by atomized way, Xu Jianqing said, even if the vaccine activated neutralizing antibody concentration is higher, the virus will be detected in the nose.

Dong Chen, dean of Tsinghua University’s School of Medicine and an expert in immunology, told China Newsweek after reading the results of the trials of several vaccines that had been officially published, that the scientists who conducted the animal trials at Oxford University were “a good old hand” and that compared with several other trials, the study had no problems in the design of the experiments, and that the test design and measurement indicators were comprehensive. Xu also said the results of the Oxford vaccine are credible, and the data show that there is room for improvement in the vaccine to support the continuation of clinical research.

For now, the Oxford team is on track to move on with clinical trials. At the end of April, ChAdOx1 nCoV-19 began its Phase I clinical trial, recruiting a total of 1,100 people, and by the end of June, the Phase II and III clinical trials will be conducted simultaneously, with a trial size of 5,000.

Early examination of other technical routes

Internationally, in addition to Moderna’s mRNA vaccine, the U.S. has the PHARMACEUTICAL company Inovio’s DNA vaccine INO-4800, which has entered phase II clinical, and on April 23rd, the mRNA vaccine developed jointly by BioNTech, a German biotech company, and Pfizer, a U.S. pharmaceutical company, began clinical trials in Germany. The recombinant nanoparticle vaccine from Novavax, Maryland, usa, also launched its Phase I clinical trial in May.

The five new crown vaccines are globally recognized for their design: nucleic acid vaccines (including mRNA vaccines, DNA vaccines), recombinant genetic engineering (protein recombination) vaccines, inactivated vaccines, virus vector vector vaccines and adenovirus vector vaccines. Nucleic acid vaccine, especially the mRNA vaccine technology, in this vaccine competition by researchers and capital favor, foreign currently entering clinical trials of the five vaccines, three belong to the mRNA vaccine, but the domestic mRNA candidate vaccine is still not one into this stage.

However, there are no official animal trials or clinical trial results on this technical route. On May 18, Moderna released “positive” interim clinical data from the Phase I study in an informal paper in a company press release. After being vaccinated, all 45 participants produced antibodies, Moderna said. After two administrations, neutralizing antibodies were produced in the bodies of 8 subjects in the low-dose group and the medium-dose group, and the titer reached or exceeded the neutralizing antibody titer in the serum of the patients in the recovery period, while the vaccine was generally safe and well tolerated.

The message immediately boosted investor confidence, with Moderna’s shares up nearly 20 per cent on the day. However, industry insiders are sceptical about the data. A researcher at Vanderbilt University in the United States wrote that the more important focus should be on the undisclosed part than the data disclosed by Moderna, for example, how did the remaining 37 subjects respond to neutralizing antibodies? What is the specific value of neutralizing antibodies that have been observed?

The company simply said in general terms that these detected antibody levels bode well, “if they reach the antibody level in the recovering person, that’s enough.” But little is known about how high antibody levels can save recovering people from reinfection. However, mRNA-1273 was approved by the U.S. Food and Drug Administration on May 6 for Phase II research, which is expected to begin in July.

Moderna’s mRNA technology is the most advanced in the world, but in the past the company has used it in the development of therapeutic vaccines such as tumors, which are not yet mature enough to be produced on a short-term scale, and the vaccine itself is expensive, even though the U.S. has significantly reduced costs, costing $600 to $1,000 a dose, said the vaccine scientist, who asked not to be named. China has neither technical intellectual property rights nor the capacity to mass produce in the field of mRNA vaccines.

Who's more hopeful of the world's more than 120 new crown vaccine candidates?

On March 28, researchers at the University of Pittsburgh conducted a vaccine study. Figure/University of Pittsburgh Medical Center

The adenovirus vector technology route has been born ahead of the Chinese Chen Wei team with Oxford University vaccine. Some in the industry believe that the Oxford University vaccine raised questions will affect the domestic adenovirus vaccine prospects. Consino’s recent launch of the mRNA vaccine has been interpreted by some as an alternative plan for adenovirus vector vaccines.

In addition to Chen Wei’s team’s vaccine, the remaining four domestic clinical trials are inactivated vaccines, which are developed by China Biobiological Wuhan Biological Products Research Institute of China, Beijing Kexing Zhongwei Biotechnology Co., Ltd., China Biological Beijing Institute of Biological Products, and the Chinese Academy of Medical Sciences. All five vaccines are expected to be phase II clinical trials in July.

Unlike foreign preferences for emerging vaccine technologies, the remaining vaccines entering clinical trials in the country are traditional inactivated vaccine technologies. From the animal test results in Kexing, Xu Jianqing said, primates activated antibody data results are good, but the vaccine because of the use of the entire inactivated coronavirus to stimulate the human immune system, so the type of activated antibody is very broad spectrum, including a large number of non-neutral antibodies, so how safe the follow-up, still to be tested in clinical trials “adenovirus vector and mRNA and other new vaccine technology gives a huge commitment, but no previous success of the vaccine as a support.” Both old and new methods can and should be developed at the same time, there is no need to choose between the two. When vaccines are comparable in immunogenicity, other factors, such as ease of production, cost, side effects and frequency of delivery, may be more important, which is why multiple candidate vaccines are needed to advance at the same time, said Dave O’Connor, a virologist at the University of Wisconsin-Madison. He also said that the World Health Organization’s large number of vaccine candidates are progressing steadily, most of which will be tested first in Syrian hamster or non-human primate models. The figures are likely to become public this summer.

Although the candidate vaccine on the track is still a long way from Phase III, the fact that the domestic pandemic as a whole has passed has become a “difficult” for domestic vaccine development. Xu Jianqing said that Europe and the United States in the study of influenza vaccine has been allowed to attack tests. The so-called attack test, that is, the use of virus attacks inoculated subjects to understand how protective the vaccine produces immune response.

After the outbreak, Europe and the United States soon began to discuss whether to allow human-induced virus attack testing. Because if vaccination is in young adults, even if the vaccine protection fails when the virus attacks, the pathogenicity is also controllable, Xu Jianqing believes that such tests should be allowed in certain populations in order to really speed up vaccine research and better judge the vaccine’s protection.