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How long will the new coronal vaccine come out
Time: 2020-6-11 9:52:19
    Against the background of the global new epidemic situation becoming more and more serious, vaccine is expected to end the epidemic completely. In March, vaccine research in China and the United States was announced to enter the clinical stage almost at the same time. Now, more than 100 new crown vaccine studies are being carried out in the world.

    Although the World Health Organization has stressed more than once that vaccine development is difficult to complete within 18 months, many teams are still eager to make history. This article will take you to see what approaches are available to these teams, what are the difficulties in each of these approaches, and if there is any way to make the arrival of vaccines faster.

Different vaccine development routes have their own

 advantages and disadvantages

    For the development of the new coronavirus vaccine, different research teams in many countries have different strategies, some of which are traditional and some are new.


Live attenuated vaccine to domesticate wild horses into mounts


    This kind of vaccine is no stranger to us. The sugar pill for the prevention of poliomyelitis is a live attenuated vaccine. As the name suggests, a live vaccine refers to a vaccine that uses an active virus, but after modification, the toxicity is weakened, and it is usually not pathogenic. It's like a wild horse that has been domesticated and become an obedient mount, but the function of running is still there.
    In addition to live attenuated polio vaccines, mumps and chickenpox, as well as the first Japanese encephalitis vaccine exported overseas with independent intellectual property rights, are live attenuated vaccines. The biggest advantage of live attenuated vaccine is that the effect of live virus infection on human body is close to that of natural infection. Generally speaking, the immune effect is good and the immune response speed is fast. Vaccine production costs are not high, easy to mass production. However, the disadvantages of live attenuated vaccine are also very obvious, that is, it needs to produce the strain with the right virulence, the research and development time is long, and there is a very low probability of disease risk.
    In terms of the current state of emergency, the conventional development route of time-consuming and labor-consuming for live attenuated vaccine is not urgent at present, and no potential candidate vaccine strains have been identified.


Inactivated vaccine, animal specimens


    Corresponding to sugar pills, polio vaccine also has the option of completely inactivating the activity, that is, inactivated virus vaccine. This technology can also be used to produce new coronal vaccines. The specific method is to heat or use chemical reagents to kill the virus and make it lose its pathogenicity. However, because the protein on the surface of the virus still exists, injection into the human body can also trigger the immune response.
    Here the virus is like a wild animal. It has been made into specimens, but it is still intact in form. Rabies vaccine, influenza vaccine and hand foot mouth disease vaccine are all of this kind of vaccine. The research and development of inactivated vaccine is relatively mature. As long as the applicable strains are screened out and can be produced in large scale, generally speaking, the safety of inactivated vaccine is better than that of live attenuated vaccine. In addition, as long as the key parts of proteins on the surface of the virus that can trigger immune response are not damaged, the effectiveness of the vaccine is not a problem.
    The rapid amplification of production may be the short board of inactivated vaccine; at the same time, inactivated vaccine often needs to be vaccinated many times to produce enough protective antibody, which is also insufficient when used as emergency vaccine. The common difficulty of inactivated vaccine and live attenuated vaccine is that the research and development and production involve virus culture, which requires relatively high biosafety and has biosafety risk.
    At present, three domestic institutions have prepared inactivated vaccine samples and submitted them to the National Institute for food and drug control for registration inspection, namely, Wuhan Institute of biological products / Wuhan Institute of virus, Beijing Kexing company, and Institute of medical biology, Chinese Academy of Medical Sciences (Kunming Institute). The first two of them have been approved by the State Food and drug administration, and the first inactivated vaccine was inoculated in Wuzhi County, Henan Province on April 12.
    As the production of inactivated vaccine requires high level of biosafety, Wuhan Institute of biology of China and Beijing Kexing company have started to build P3 (Biosafety Level 3) inactivated vaccine production workshop. Once clinical research is completed and positive results are obtained, inactivated vaccine production can be put on the market as soon as possible.

Recombinant protein vaccine, direct use of animal fur


    If the first two are the classic vaccine development methods, recombinant protein vaccine is the hot direction of vaccine research and development recently, because of its good safety and low cost.
    This method of vaccine research and development does not need to isolate the virus strain at all, but only needs to express a large number of virus antigen proteins according to the sequence of the virus and make the vaccine. In other words, the vaccine is injected directly with proteins that trigger an immune response, just like using the fur of a wild animal. Hepatitis B, cervical cancer and hepatitis E vaccines are all products of this approach. The S protein on the surface of the new coronavirus can be used as the target protein for synthesis.
    The biggest advantage of recombinant protein vaccine technology route is high safety, because it does not need to operate virus directly, and it is easy to scale up. However, this technique is not enough to express the same protein sequence as the virus. The difficulty is that the protein also needs to fold into the same structure as the virus. For example, the recombinant protein can be self-assembled into a virus like particle, or vaccine adjuvant can be used to assist the effect of the vaccine.
    GSK, a pharmaceutical giant, has announced that it is jointly developing vaccines along this route with Chengdu clover, Xiamen Wantai and Sanofi, another vaccine giant. GSK provides adjuvant system and partner provides recombinant protein antigen. In addition, Anhui zhifeilong Kema / Institute of Microbiology, Chinese Academy of Sciences, Zhejiang Pukang biology / Institute of Virology, Hangzhou Medical College, and Novavax, a well-known US vaccine company, are also carrying out such vaccine research.
    If the novel coronavirus can not really disappear soon, perhaps the safety and accessibility of the recombinant protein technology route can really make the recombinant protein new crown vaccine a regular vaccine instead of an emergency vaccine.

Virus vector vaccine, "sheep in wolf skin"


    The essence of this technology is "sheep in wolf's skin". Put the protein on the surface of the new coronavirus and find a way to install it on the surface of other viruses with no power. The "vector" here refers to the virus that has lost its power, namely "sheep". The virus used for sheep includes the adenovirus which has repeatedly appeared in recent news.
    At present, there are not many vector virus vaccines on the market, and none of them have been applied on a large scale. For example, dengue fever vaccine with attenuated yellow fever virus as vector, and Ebola vaccine with recombinant vesicular stomatitis virus (VSV) as vector; recombinant Ebola virus vaccine has also been developed in China, which uses adenovirus as vector.
    The advantage of viral vector vaccine is that the vector can often induce a strong immune response, so there is usually no need for additional adjuvants. In addition, there are various ways of inoculation, including intramuscular inoculation, intradermal inoculation or oral inoculation. The short board is that some vector viruses may still be integrated into the human genome, which needs to be carefully evaluated during research and development. Moreover, if the vector is a virus that can infect people, such as measles, influenza and adenovirus, the protection effect of the vaccine may be affected because the vaccinator already has antibodies.
    Adenovirus vector is one of the most commonly used viral vectors. The novel coronavirus outbreak has occurred in Chinese and foreign countries. Many research teams have developed targeted vaccines based on adenovirus, such as Johnson's Yang Sen pharmaceuticals, the PLA Academy of Military Sciences / Kang Xi, the Guangdong provincial science and Technology Department, Zhejiang science and Technology Department, Tsinghua University team, Tianjin University team and so on. Among them, the novel coronavirus / Kang HNO team adenovirus vector vaccine entered the clinical I phase in March 16th, and has completed the initial safety observation of the vaccinated subjects. It entered the stage of clinical II in April 13th and is currently the world's first new coronavirus vaccine to enter the clinical II phase.
    Wuhan bowo will cooperate with American biotechnology company to develop a new coronal vaccine using a replication deficient vaccinia virus Ankara strain (MVA). Using attenuated influenza virus strains as vectors, the team of Yuan Guoyong of the University of Hong Kong is developing a new coronal vaccine that can be used for nasal spray. The research and development of the new coronavirus antigen gene expressed by the modified measles vaccine strain by Pasteur Institute in France is also in progress.

Nucleic acid vaccine (DNA vaccine / mRNA vaccine), the human body synthesizes animal fur by itself


    This method is different from the method of recombinant protein, which is directly injected into the human body with the coding nucleic acid of the virus antigen protein, and then the human cells synthesize the virus antigen protein to produce the immune response. The same does not involve any virus operation, equivalent to directly play the "fur" effect, but this time even the fur is made of human body itself.
    Nucleic acid vaccine is divided into DNA and mRNA. Among them, DNA vaccine has been used in the development of HIV, influenza virus, malaria, hepatitis B virus and other vaccines, and has entered the stage of clinical trials. Some DNA vaccines have been approved for animal use, but no one has been approved for marketing. Most of the mRNA vaccines are only in the clinical stage, and have considerable advantages in cancer vaccines, influenza, HIV and other highly variable virus vaccines.
    The advantages of nucleic acid vaccine method are that the production process is easy to standardize, the raw materials of vaccine can be synthesized by chemical synthesis, and it is relatively easy to make large-scale production by using existing general equipment. All of these advantages can play an important role in the new outbreak. The disadvantage of DNA vaccine is that the sequence may exist in the body for a long time, may be integrated into the host chromosome, and the protection effect may be limited. The mRNA vaccine does not enter the nucleus, and there is no risk of integrating the host genome. However, mRNA molecules also have disadvantages. They are not as stable as DNA. The internal environment of the human body is complex. Whether the mRNA delivery system is effective is also a challenge.
    The CEPI is funding novel coronavirus DNA vaccine INO-4800 developed by Inovio. Clinical trial database network( clinicaltrials.gov )On April 6, inovio has enrolled 40 healthy subjects to carry out the phase I clinical trial of ino-4800. The first batch of candidate mRNA vaccine, mrna-1273, was developed by Moderna company, and the clinical phase research was started on March 16. Fosun Pharmaceutical announced on March 13 that it had paid 85 million US dollars to obtain the exclusive development license for the mRNA vaccine of German biontech company in the region. In addition, novel coronavirus vaccines have been developed by CureVac AG, Germany, Pfizer Inc, Tongji University, Dongfang Hospital, Shanghai microbiology, Shanghai public health clinical center, Fudan University and Shanghai Blue Magpie bio.


The process of vaccine development is long and complex,

 and every step is full of uncertainty


    Although the technology upgrading is shortening the vaccine development time, the vaccine development cycle is still very long after the indispensable steps such as finding antigen, evaluating safety and selecting the best candidate vaccine, clinical development, registration and approval, and production are completed. If any step is not smooth, it will slow down or even end the whole R & D process.


Looking for antigens


    The search for antigen is a process of development and change.
    At first, Pasteur invented the first generation of inactivated vaccine by heating and drying the spinal cord of animals died of rabies. The inactivated rabies virus is the effective antigen. Later, live attenuated vaccines using different methods to reduce the virulence of the virus emerged. For healthy people, live attenuated virus, which is not pathogenic but can provide immune protection, is an effective antigen.
    For viruses that are not easy to be cultured in vitro, such as hepatitis B virus, the development of recombinant protein / genetic engineering technology makes the S protein of hepatitis B virus expressed in Saccharomyces cerevisiae, and can form virus like particle structure, and become a safe and effective antigen. For the new coronavirus, generally speaking, the main route to find the antigen is to create a safe and effective antigen for the candidate vaccine according to the nature of the virus itself, as the main effective component of the candidate vaccine. At the same time, the selection of antigens is also the design and validation process of technical routes that different research teams are good at.

Safety assessment is not the best candidate vaccine

    Vaccine is a special drug for healthy people, and its safety evaluation is a long process through non clinical trials, clinical trials and post marketing evaluation.
    If we only look at the preclinical research stage, we mainly use different animals to verify the long-term toxicity, acute toxicity, local irritation, allergy and reproductive toxicity of the vaccine (if women of childbearing age have vaccination consideration). The safety evaluation of vaccines is usually carried out in specialized laboratories, which usually takes several months or more. Therefore, the vaccine developed by using mRNA, DNA, virus vector and other platform technologies can not only shorten the development time, but also shorten part of the safety evaluation time by using similar preliminary safety evaluation data.
    The work of selecting candidate vaccines, in fact, is the verification of preclinical studies on the effectiveness and protection of vaccines, which is often carried out before the safety evaluation, or partially synchronized with the safety evaluation test.
    Specific to the research and development of new coronavirus vaccine: for the recombinant protein vaccine, the expressed protein antigen should be able to detect the binding with the viral serum of convalescent new crown patients; for the mRNA and DNA vaccine, the effective expression of the target protein in the animal body must be detected; for the recombinant virus vector vaccine, the effective packaging of the virus must be able to be detected by the viral serum of the convalescent new crown patients It is different from the above-mentioned virus neutralization vaccine, which is different from that of inactivated vaccine.
    Finally, if these vaccines can protect the existing new coronavirus model organisms from disease after the new coronavirus attack, let alone have no antibody dependent enhancement (ADE), they can be used as a truly effective candidate vaccine. At present, the new coronal vaccines approved in China have been verified by a series of model animal experiments (ACE2 transgenic mice and rhesus monkeys). Moderna's mRNA vaccine did not undergo animal attack toxicity test and entered the phase I clinical study directly, which makes many vaccine R & D professionals inevitably worry about the results of its clinical trial effectiveness.


Clinical development (phase clinical trials)


    Clinical trials of vaccines are generally divided into four phases.
    Phase I trial focuses on safety and clinical tolerance. The observation objects are generally healthy adults, usually in a small range, and 20-30 people are generally designed in China.
    The purpose of phase II trial is to observe or evaluate whether the vaccine can obtain the expected effect and general safety information in the target population. The minimum sample size required in China is 300 cases. Many vaccines that have been verified to be effective in animal experiments often fail because phase II trials cannot verify their effectiveness.
    The purpose of phase III trial is to comprehensively evaluate the protective effect and safety of the vaccine, which is the basis for obtaining registration and approval for marketing. According to the different nature of vaccines and the diseases they prevent, the design of phase III trials of different vaccines is very different. For rabies vaccine, which has already been put on the market, the phase III trial is generally designed for hundreds or thousands of people. HPV vaccine needs to be designed for stage III clinical trials of tens of thousands of subjects, and regular follow-up of 50-80 months is required. Even if some vaccines are developed in an abnormal sequence, it will take 5 to 10 years, which is often the time required for phase III clinical trials.
    For new coronavirus pneumonia, a new and sudden infectious disease, it may be necessary to carry out phase III clinical trial in its epidemic area to observe the difference of virus infection between the control group and the experimental group. Given the novel coronavirus pneumonia outbreak and control in China, the possibility of the new phase III vaccine in China is very small. It is possible that only the subjects in the new crown virus epidemic area in foreign countries will be selected for III phase clinical study. If the epidemic situation in foreign countries is well controlled and there is no suitable population for phase III clinical study, the new coronal vaccine which has completed phase II clinical work can also be used as national reserve vaccine in the future.
    Phase IV clinical trial is a comprehensive evaluation of the safety and effectiveness of the vaccine after it is registered and marketed.
    In China, vaccine clinical trials are basically implemented by vaccine R & D or production enterprises as sponsors and provincial centers for Disease Control and prevention as researchers. It is different from common drugs which are often used for clinical research in hospitals.


Registration approval and production of the first batch of vaccines


    After the completion of preclinical research and preclinical safety assessment, the vaccine enterprises will submit relevant materials for clinical trials; after approval, the vaccine enterprises will conduct clinical studies in various phases, and only when the clinical results and reports meet the expectations can they be approved for marketing.
    After that, the vaccine enterprises generally need to produce three batches of qualified vaccines continuously under the supervision of the drug administration to obtain the vaccine production license, so as to ensure that the production process of the enterprise is stable.
    Each batch of vaccines finally produced on the market, as well as the vaccines previously manufactured for clinical use, must pass both the self inspection of the enterprise and the verification of the CFDA before release. The national inspection for the release of marketed drugs is called batch issuance.


Production (quality control)


    Generally speaking, the quality control of vaccine can be divided into three stages. The first is the quality control of vaccine raw materials, the second is the quality control of production process, and the third is the inspection and testing of intermediate products and final products of vaccine production. This is an important part of quality assurance.
    All raw materials used in vaccine production must have reliable sources. In addition to the most important sources of antigen components such as bacteria and viruses, cell matrix, and other materials, such as culture medium, buffer solution and utensils, should be strictly managed. Especially for animal raw materials, if it is clearly stipulated in China, the source of BSE epidemic area should be excluded.
    The quality of vaccine products is determined by a series of factors in the whole process from the input of raw materials to the delivery of products. Therefore, the quality of vaccines is produced, not verified, and the verification only objectively reflects the quality level of vaccines under supervision.
    The vaccine production process is required to comply with GMP (good manufacturing practice) and relevant provisions of Chinese Pharmacopoeia. GMP of vaccine is a grand and complicated content, but I will not repeat it here. The general principle is that when the personnel in the workshop match the requirements of vaccine production, the whole production process conforms to the approved production process, operates in strict accordance with the standard operating procedures, and controls every link of the whole production process to the greatest extent, so that the products can meet all quality requirements.
    Finally, it should be emphasized that vaccines are special drugs for healthy people. Each batch of products requires batch issuing inspection, which is higher than that of ordinary drugs.

How far is the new coronal vaccine from us


    According to the traditional process, it may take 5 to 10 years for the vaccine to be developed and put into market, which is obviously unacceptable to the current people.
    In the current emergency situation, it is not impossible to find a "shortcut" for vaccine research and development in policy. Saturated research investment, all-round resource tilt, multi line work at the same time, the hard work of researchers day and night, and the continuous rolling review and approval of the review organization are the basis for the rapid development of new crown vaccine.
    At present, nucleic acid vaccine and virus vector vaccine are relatively rapid technical routes. However, even with the fastest speed to complete the process, it will take more than a year. In view of the severe situation of new coronavirus (NCV) spreading all over the world, some companies are trying to make clear the safety data of candidate vaccines through phase I clinical trials (or seamless design after the combination of phase I and II clinical trials) which are relatively complex and have more subjects. At the same time, the dosage, administration scheme and its effectiveness can be clearly defined as soon as possible. In this way, it may be possible to apply for exemption from phase II clinical practice and quickly enter phase III clinical practice.
    In my opinion, in view of the urgency of the current epidemic situation, if a vaccine is verified to be effective through phase I and II clinical trials (under the premise of ensuring safety), we may consider carrying out a relatively large-scale single arm (no control group, all experimental vaccines) phase III clinical design under the state of emergency. First, the medical staff, epidemic prevention personnel and other vulnerable groups were given the greatest possible protection, and then the infection data of the uninoculated area were compared and analyzed to determine the actual results of phase III clinical.
    As an emergency use, the speed advantage of early development of nucleic acid vaccine and virus vector vaccine enables them to enter the runway one body first. However, as the traditional technology route with relatively slow research and development speed, inactivated, attenuated and recombinant protein vaccine can be adjusted continuously according to the development of the epidemic situation. Perhaps in the future, the global demand for vaccines will be astronomical; at the same time, vaccines that are safer, more effective and easy to produce, transport and vaccinate will also be needed, and there will be higher requirements for the production cost and mass production capacity of vaccines. Vaccines with different technical routes are likely to stand out in the future at different stages of the epidemic.
    During the SARS epidemic in 2003, several research teams had carried out research and development of SARS vaccines with various technical routes. However, the epidemic situation was quickly controlled. When the research phase of relevant vaccines was promoted to clinical trials, there were no subjects at all, which made the relevant research and development a "dragon killing technique" and ended up with nothing.
    If the new epidemic can be successfully controlled after the vaccine is developed, we should also pay attention to the experience and lessons learned from this epidemic. While paying attention to the improvement and establishment of public health defense system and emergency response system, we should do a good job in the research and development platform of general coronavirus emergency vaccine, general respiratory virus emergency vaccine research and development platform, and even the general infectious disease pathogen emergency vaccine research and development platform, including its related emergency clinical plan and emergency use plan, so as to truly avoid the vaccine slow down in the face of epidemic situation again An urgent situation.

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