Analysis of the novel coronavirus pneumonia in the severe situation of different types of vaccine research progress

Background < br / > at present, the new crown epidemic situation presents different development trends at home and abroadOn the one hand, the decisive control measures in China after the outbreak of the epidemic have enabled the domestic epidemic to be effectively controlled and enter a new stage of epidemic prevention and control; on the other hand, when foreign countries carry out epidemic prevention and control in China, they have missed the precious time our country has won for the world because they have not taken active response measures, making many countries successively fall into the disaster area of the epidemic, The number of infected people in foreign countries has far exceeded that in China< br / > with the global outbreak of the new crown epidemic, compared with the current measures, vaccine is the best measure for virus prevention and controlAfter the outbreak, a number of domestic and foreign enterprises and scientific research institutions began the research and development of the new crown vaccineAs of March 24, there are no less than 106 companies and research institutions around the world, and at least 73 new coronavirus vaccine projects are under developmentThe projects are mainly in China and the United StatesThere are 37 related projects under research in China, including 9 joint R & D projects with foreign countries; 17 joint R & D projects in the United States, including 9 joint R & D projects with foreign countries< br / > Table 1 regional analysis of global vaccine research and development < br / > common vaccine types and characteristics < br / > with the continuous development of vaccine technology, currently the widely used and mature vaccines are mainly inactivated virus vaccines, attenuated live vaccines and subunit / recombinant protein vaccinesIn recent years, the emerging virus vector vaccines and nucleic acid vaccines are also in rapid development and validation due to their unique advantagesThe sudden outbreak of this outbreak highlights the importance of the application of new technology vaccine< br / > 1Whole bacteria vaccine (whole virus vaccine) < br / > whole virus vaccine can activate immune response by inactivating virus or reducing virus virulence< br / > the inactivated virus vaccine can treat the virus by chemical (usually formalin), heating or radiation, so as to make the virus lose toxicity, but it can still activate the immune response of human body by retaining its main antigen characteristicsCommon whole virus vaccines include polio vaccine, hepatitis A vaccine, rabies vaccine and some influenza vaccinesThe immunogenicity of inactivated virus vaccine is lower than that of live attenuated virus vaccine, which usually requires multiple vaccinations to activate sufficient immune response< br / > live attenuated vaccine is a non pathogenic virus strain obtained by screeningUsually, the method of virus passage in non natural host cells is used to screen live attenuated vaccine In order to survive and infect the non natural host cells, the virus will mutate and adapt to replicate in the new host cells After multiple generations, the virus will not be able to reproduce normally in the natural host Common live attenuated vaccines include yellow fever vaccine, measles vaccine, mumps vaccine, rotavirus vaccine and smallpox vaccine < br / > live attenuated vaccine has a high similarity with natural pathogens, so it can induce a strong and sustained immune response, which can provide lifelong immunity through one or two vaccinations However, vaccination of individuals with insufficient immunity, chronic diseases or organ transplantation may lead to diseases The storage and transportation conditions of live attenuated vaccine are strict, and it needs to be refrigerated to maintain the vaccine activity In rare cases, live attenuated vaccines have the risk of mutation and atavism leading to disease < br / > the whole virus vaccine has a long history of application, with a large number of mature products, but many defects also limit its long-term development, especially in response to emergencies, it can not meet the needs, which will be discussed in combination with the epidemic situation below < br / > 2 Subunit vaccine < br / > subunit vaccine can separate virus protein by chemical decomposition or protein hydrolysis, screen and retain some of the fragments with immune activity Common subunits such as typhoid vaccine The side effect of subunit vaccine is small, but the technology of antigen epitope screening is not mature, and the protein isolated may be denatured, leading to the weak immunogenicity, so it needs adjuvant to enhance the immunogenicity < br / > 3 Recombinant protein vaccine < br / > recombinant protein vaccine uses gene engineering recombinant technology to express the immunogenic protein in the virus shell through bacteria or yeast and other vectors, so as to induce the immune response of the body Common applications include hepatitis B vaccine and influenza virus vaccine Recombinant protein vaccine can be produced on a large scale by introducing gene sequence of expressed protein into yeast and other microorganisms This kind of vaccine uses the most immunogenic part of the virus to make vaccine, which can induce strong immune response, but because only a single protein component is used, sometimes it needs to strengthen immunity to maintain immunity The recombinant protein vaccine has no pathogenicity and can be used in the vaccination of individuals with immune deficiency or chronic diseases < br / > 4 The principle of virus vector vaccine is the same as that of gene therapy It uses non therapeutic virus as the carrier, recombines protective antigen gene into virus, generates vaccine in human body, activates immune response and obtains immunity Virus can express antigens in specific parts or organs of human body, and it has immunogenicity and can activate immune response The gene delivery efficiency of virus vector vaccine is high, but there are high technical requirements for the selection of vector, and strict requirements for the operation and production of virus vector < br / > usually selected virus vectors are replication defective virus vectors, which retain the complete structure and infectivity, but lose the self replication function, and need the help of specific transformed cells or auxiliary viruses to reproduce, so that the human body can generate effective immunity; the other is replication capable virus vectors, They can be used as carriers of foreign genes to maintain self infectivity At present, the main viruses used as vectors are adenovirus and poxvirus, as well as the approved and listed attenuated influenza vaccine < br / > at present, the most mature application is adenovirus vector The transformation of adenovirus vector has been fully studied Adenovirus vector has the advantages of stable genome, wide host range, and not integrated into human genes In terms of production capacity, it is also easy to realize industrialization through 293 cell culture However, adenovirus is a common respiratory pathogen, and neutralizing antibodies of adenovirus commonly exist in human body These pre-existing neutralizing antibodies will reduce the immune response induced by adenovirus vector vaccine At the same time, adenovirus is highly infectious, so recessive infection caused by adenovirus should be avoided in the preparation of vector, which is a problem faced in the development of adenovirus vector vaccine < br / > at present, the world's approved virus vector vaccines include Tianjin kangxinuo's Ebola vaccine with adenovirus 5 as the carrier, which was approved in China, and Merck's Ebola vaccine with VSV as the carrier, which was approved in FDA There are many CMO enterprises that can meet GMP standard in China DNA vaccine, including DNA vaccine and mRNA vaccine, is a new type of vaccine, which is rising in recent years It can produce vaccine by injecting DNA or mRNA encoding vaccine into human body directly, and then use human cells to produce vaccine, so as to cause human immune response The preparation of nucleic acid vaccine is simple, but the large-scale production capacity needs to be tested At present, there is no approved product in the world < br / > DNA vaccine is the DNA expressing viral protein After being delivered to the cell, DNA enters the nucleus, transcribes into mRNA, and then translates into protein in the cytoplasm The protein is presented to the cell surface to activate the immune response DNA vaccines are easy to produce and store The efficiency of DNA entering cells by electroporation or liposome membrane fusion remains to be demonstrated In addition, DNA vaccine needs to go through the process of entering nucleus, transcription and translation, and the effect is slow < br / > the basic principle of mRNA vaccine is similar to DNA vaccine, but mRNA does not need to enter the nucleus, and can be translated quickly in the cytoplasm, and mRNA itself can be used as an immune adjuvant to further promote the immune response MRNA will be degraded through physiological metabolism, with little side effects and no risk of genome integration MRNA production is simple and fast, and transportation cost is low However, mRNA is easy to degrade and needs to be modified to improve its stability Large-scale production requires nano liposome technology to protect mRNA At present, there are few companies that have this technology and can carry out large-scale production, only the biontech, Moderna and curevac as well as the domestic microorganisms have it The rapid progress of mRNA vaccine has entered clinical stage II, such as CMV mRNA vaccine mrna-1647 of Moderna In addition to the previous several kinds of current research and application, some new vaccines, such as therapeutic vaccines and cellular vaccines, have also made great progress < br / > therapeutic vaccine: different from preventive vaccine, therapeutic vaccine is used to induce specific immune response of the body when the body has been infected with pathogenic microorganisms or has been sick, so as to achieve treatment or prevent disease deterioration In recent years, the hot HIV therapeutic vaccine, HPV therapeutic vaccine, hepatitis B therapeutic vaccine and so on all belong to this kind of vaccine < br / > cellular vaccine: it uses cells as carriers to express the target protein of the virus on the cells, avoiding the pathogenicity of the virus itself This time, Shanghai public health clinical center will use human cell as carrier to develop human cell vector vaccine < br / > Table 2 Comparison of the characteristics of different types of vaccines < br / > types and development trends of new coronavirus vaccines < br / > according to the research and development projects of new coronavirus vaccines, 48 disclosed information projects involve 59 published types of vaccines, of which the nucleic acid vaccines are the most, 18 are under research, accounting for 30.5%, followed by subunit / recombinant protein vaccines and virus vector vaccines, 16 and 13, respectively, However, the number of live attenuated vaccine and inactivated vaccine is very small, which fully shows the role of new technology in rapid vaccine development < br / > the recombinant protein vaccine has become one of the main anti epidemic forces because of its mature application, rapid development and preparation, and clear mechanism However, recombinant protein vaccines usually target virus S protein with high mutation rate Once s protein mutates, such vaccines will be ineffective Therefore, the development of multivalent vaccine can effectively make up for this defect, and virus vector vaccine and nucleic acid vaccine can also avoid this problem by expressing multiple antigens at the same time Although the < br / > mRNA vaccine is not mature, its explosive application in this epidemic is mainly due to its short development and production cycle However, the most traditional inactivated vaccine and live attenuated vaccine have been largely replaced by new technologies The inactivated vaccine needs to cultivate a large number of viruses before it is processed, while the cultivation and operation of new coronavirus need to be carried out in the BSL-3 laboratory, the vaccine R & D enterprises do not have the corresponding conditions, and the industrialization of products has a great challenge; the live attenuated vaccine needs to pass through multiple generations to select the appropriate virus strains, and the R & D cycle is too long, so it is difficult to deal with sudden outbreaks < br / > Figure 1 proportion of new coronavirus vaccine types < br / > in the future vaccine research and development trend, subunit / protein vaccine / polypeptide is still the mainstream form, while nucleic acid vaccine will catch up and become the new mainstream vaccine form, and become more and more mature Due to the high efficiency and the special advantages of targeting specific organs, virus vector vaccine is a better choice in dealing with certain viruses < br / > the 48 projects with more detailed information disclosure are mostly focused on a single technology path, and there are 6 projects with more than two paths at the same time < br / > Table 3 multi technology path project < br / > 1 Nucleic acid vaccine < br / > is the most popular vaccine in current research projects, research enterprises and research institutions Nucleic acid new crown vaccine is to inject s protein gene of new crown virus directly into human body, express s protein in human body, and cause immune response of human body Compared with other types of vaccines, the overall development speed is faster Among the 18 nucleic acid vaccine projects under study, there are 12 mRNA vaccines and 6 DNA vaccines, of which 1 is in clinical research, 6 are in animal trials, and 3 are expected to enter clinical research in April < br / > February 26, Shanghai 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