Bill Gates said in a speech in 2015: “when I was a child, we were most worried about nuclear war. But in the future, if there is something that can kill tens of millions of people, it is more likely to be a highly infectious virus. “
A novel coronavirus outbreak in just a few months swept the globe, infected nearly fifty million people, and claimed about one million lives. At present, with the northern hemisphere entering winter, the world ushered in the second wave of outbreak. To avoid the recurrence of the tragedy caused by the last wave of the epidemic, all countries have taken strict epidemic prevention and control measures, and some European countries even made the decision of “closing cities” again. The epidemic has seriously affected people’s normal life. The whole world is looking forward to overcoming the virus as soon as possible and has high hopes for vaccine research and development.
At present, the progress of vaccine research and development has become the focus of attention. At the same time, the public has many doubts about the new crown vaccine. Understanding the scientific knowledge behind vaccine research and development is helpful to correctly understand the new crown vaccine, grasp the advantages and disadvantages of various vaccines, and formulate scientific anti-epidemic policies.
The basic principle of the new coronal vaccine
In 1796, British doctor Jenner gave an 8-year-old boy an injection of the serous from the blisters of a milking woman infected with cowpox to prevent smallpox, announcing the birth of the first vaccine in human history. After that, the vaccine quickly became one of the most effective means to prevent viral infectious diseases. Different from the natural virus, a virus vaccine is a kind of processed virus or virus component. Because it loses the infectivity or pathogenicity of wild virus, after the vaccine is injected into the human body, it will not cause disease, but also activate the immune system to fight against the virus. The human immune system has the ability of memory, which can rely on long-lived immune memory cells to produce long-term resistance. When the “exercised” immune system resists the enemy again, it can react quickly and strengthen its resistance to the virus quickly. The core of this resistance is the neutralizing antibody, which can inhibit virus infection. These antibodies can bind to the surface protein of the virus, block the binding of the virus to cells, or inhibit the key conformational changes in the process of virus entry, to block the virus infection.
For novel coronavirus, a good vaccine should induce the body to produce an effective neutralizing antibody. Many studies have shown that the most effective neutralizing antibody often targets the receptor-binding region (RBD) of viral spike protein, which is the key region for binding to ACE2 on the cell surface. These antibodies can effectively prevent the virus from entering the cells (Fig. 2). The core task of the coronavirus vaccine is to provide an effective antigen of the receptor-binding region and stimulate the body to produce a protective neutralizing antibody. There are many ways to provide this epitope, and the vast majority of vaccine research and development routes are designed around this goal.
Main routes of new crown vaccine research and development
According to the way of providing virus antigens, vaccines are usually divided into live attenuated vaccines, inactivated vaccines, subunit vaccines, viral vector vaccines, and nucleic acid vaccines (Fig. 2).
Live attenuated vaccine is a kind of attenuated mutant virus, which is obtained by passage, mutation, artificial gene knockout, or natural screening, but retains its natural antigenicity to a great extent. The disadvantage is that the vaccine has the potential of virulence recovery, and can cause disease in the case of immune deficiency.
An inactivated vaccine is a kind of vaccine prepared by culturing and amplifying the virus in cells or animals, then inactivating it physically or chemically and purifying it. Compared with the live attenuated vaccine and genetic engineering vaccine, its preparation process is relatively simple. An inactivated vaccine has the advantages of a short development cycle and safe use. The disadvantage is that the culture cost is high, the immune effect is relatively poor, and it often needs multiple vaccinations.
Subunit vaccine is a kind of vaccine which can obtain high antigenicity virus protein subunit (such as protein, polypeptide, or polysaccharide) using chemical decomposition, protease hydrolysis, chemical synthesis, and biosynthesis. With the development of modern biological technology, we can mass produce these protein subunits by genetic engineering methods, and make subviral particles or virus surface protein display nanoparticles by self-assembly or fusion of nanoparticle skeleton. This kind of vaccine has the advantages of simple antigen composition, noninfective, high safety, and relatively easy mass production. Its disadvantage is that the antigenicity of virus subunit monomer is low, and it often needs to be enhanced by self-assembly or protein vector to form a polymer
Recombinant viral vector vaccine is also a new type of vaccine based on modern genetic engineering technology. By using some viruses without obvious pathogenicity, virulence genes, or replication defects as vectors, the antigen encoding the target virus (such as spike protein or RBD) is inserted into the viral vector for expression, so that the modified chimeric virus can effectively display the target virus antigen, but there is no target virus The virulence of the virus. The common vectors are adenovirus, influenza virus, vesicular stomatitis virus, Newcastle disease virus, and so on. This method integrates the advantages of live attenuated vaccine and subunit vaccine, but the technical requirements are relatively high.
The nucleic acid vaccine is another new type of vaccine, which can be divided into the DNA vaccine and RNA vaccine. These two kinds of nucleic acids carry the sequence encoding the main antigen of the virus, which can be transcribed and translated into viral antigen after entering the cells, and stimulate the body to produce a protective immune response. The difference is that DNA vaccine is more stable and needs to be transcribed into the nucleus to produce viral antigen protein, while RNA vaccine is less stable and needs to rely on effective delivery means, but it can be directly translated into the cytoplasm to produce protein. The advantages of these two vaccines are simple preparation, easy mass production, relatively low cost, convenient storage and transportation, and good immune effect. The disadvantages are that nucleic acid itself is easy to induce an autoimmune response, and depends on effective delivery means, and DNA has a certain risk of integration into the human genome. Although several nucleic acid vaccines have entered the clinical research stage, the current technology maturity is not as good as the above vaccines, so there is no large-scale market application of products.
The mechanism and preparation process of the above vaccine research and development directions are different, and the advantages and disadvantages are obvious. There is no perfect and universal new vaccine research and development direction. In addition to the safety risk of the live attenuated vaccine, other routes can be tried. It is worth noting that before the outbreak, there was no vaccine against coronavirus on the market in the world, which shows that the research and development of a new coronavirus vaccine is facing considerable difficulty
Research and development status of the new crown vaccine
Global new crown vaccine research and development is in full swing. According to the statistics of the World Health Organization, as of November 3, 2020, there are more than 200 kinds of vaccines under research and development in the world, covering almost all research and development routes. Among them, 47 vaccines have been in clinical trials, and 10 vaccines have entered phase III clinical trials (Fig. 3). China and the United States are the two leading countries in vaccine research.
According to the National Health Commission, China’s scientific research team is promoting the vaccine research work along the five technical routes of inactivated vaccine, genetically engineered recombinant subunit vaccine, adenovirus vector vaccine, attenuated influenza virus vector vaccine, and nucleic acid vaccine. At present, 13 vaccines have entered the clinical stage in China, of which 4 vaccines, including the inactivated vaccine and adenovirus vector vaccine, have entered the phase III clinical trial stage. Phase III clinical trials need a specific environment, that is, to evaluate whether the vaccine can really protect the susceptible population and how high the protection rate is in the population in the epidemic area. The success of phase III is the last and most important step for the successful marketing of the vaccine. To promote the phase III clinical research, China officially launched the emergency use of the new crown vaccine on July 22. At present, several candidate vaccines in phase III clinical research have shown good safety. At the same time, China is also making efforts to promote the development of international multi-center clinical trials and accelerate the validation of vaccine effectiveness under international rules. The two inactivated vaccines from the Beijing Institute of biological products and the Wuhan Institute of biological products, affiliated to China National Pharmaceutical Group, are in phase III clinical trials in 10 countries. As of October 21, 2020, a total of about 60000 subjects were vaccinated, and no serious adverse reactions were reported.
The third phase clinical trials of vaccines abroad are also advancing rapidly, among which the progress of mRNA vaccines has attracted much attention. On November 9, 2020, Pfizer announced the first results of phase III clinical trials of bnt162b2, a new mRNA crown candidate vaccine developed by Pfizer in cooperation with biotech in Germany. The results showed that the effective rate was more than 90%, much higher than the expected 50% – 60%. However, due to the small number of samples and a short time, whether it can reflect the actual protection effect and whether it can provide lasting protection still need further observation and analysis.
Usually, vaccine research and development is a complex and long-term process. It usually takes 7 to 10 years from the start of research and development to the completion of all clinical trials until approval. However, some vaccines have not been successfully launched for more than 10 years. It is estimated optimistically that in the first half of next year, the new crown vaccine is expected to be approved and put on the market, among which there is likely to be a vaccine independently developed in China, and the speed of research and development is unprecedented in the history of vaccine research and development. Such a rapid R & D speed is not only related to the huge demand for vaccines in the context of global epidemic deterioration, the concentration of resources by the whole society to tackle key problems, and the progress of vaccine R & D and preparation technology but also related to global competition and policy green light. In the process of catching up with the schedule, the time of R & D and clinical trials has been greatly compressed, which brings challenges to the evaluation of vaccine effectiveness and safety.
Safety and efficacy of Nueva vacuna corona
A good vaccine must be both safe and effective. The advent of drugs or vaccines should be checked and verified at all levels. Hidden dangers should not be left in any link. If they fail to meet the preset goals or requirements, they should be stopped. There have been many lessons in history about the huge public health problems caused by the rush to launch products. For example, in 1961, thalidomide, a drug used to relieve pregnancy reaction, caused thousands of teratogenesis. The new crown vaccine has a huge audience, although its approval and promotion are urgent, it must not reduce the standard in terms of effectiveness and safety.
The so-called effectiveness refers to the ability of vaccines to effectively induce neutralizing antibodies to resist virus infection or significantly reduce symptoms. It is not enough to induce neutralizing antibodies only. Only to reach a certain titer can we effectively fight against virus infection and have a significant protective effect. How long the neutralizing antibody can last and how long it will take to add the neutralizing antibody for continuous protection are also important factors affecting the effectiveness. Also, whether the vaccine is effective for the mutated virus and whether the vaccine can protect people of different ages are also issues worthy of attention. The new coronavirus belongs to an RNA virus, and its recombination and mutation ability is stronger than the DNA virus. There is no successful coronavirus vaccine on the market, and its effectiveness remains to be confirmed. However, from the current progress of phase III clinical in China and abroad, the effectiveness of the new vaccine is optimistic.
Safety is another important issue. In addition to the side effects of vaccination itself, and antibody-dependent enhancement (ADE) is often mentioned in the field of vaccine research and development. The mechanism is that the vaccine induces some antibodies with poor neutralization activity. These antibodies can not inhibit the virus infection, but mediate the virus into the cells through the Fc receptor on the surface of immune cells, thus aggravating the virus infection. This effect is an important reason for the failure of many viral vaccines, such as a respiratory syncytial virus (RSV), dengue virus (DENV), human immunodeficiency virus (HIV), Ebola virus (EBOV), and so on. It has also been reported in other coronaviruses including SARS. Therefore, whether there is ade effect is an important consideration for the safety of the new crown vaccine. It is gratifying that up to now, there is no report of the ADE effect in clinical trials of candidate vaccines.
In the context of the global spread of the new coronavirus, the epidemic not only impacts the political system, economic system, and cultural exchanges on which the survival and development of human society depend, but also refreshes our understanding of the virus, health, and freedom. At present, China has effectively controlled the epidemic through strong isolation, tracking, detection, and other measures, but the pressure of imported foreign defense is huge. The early development of the new coronavirus vaccine is the key to establish effective mass immunization, restore normal life and international exchanges; and scientific understanding of the principle of the new coronavirus vaccine and its precautions is the key to correctly evaluate the vaccine, use the vaccine, and formulate relevant policies.