At present, the research and development of Pan coronavirus vaccine are basically in the pre clinical and clinical stages. Just as no universal influenza vaccine has been developed so far, there are many difficulties in the research and development of the pan coronavirus vaccine, and there is still a long way to go before it goes public. Since the outbreak of COVID-19, novel coronavirus (sars-cov-2) has coexisted with humans for more than 3 years. During this period, the new crown vaccine became a powerful weapon for human beings to protect their own health. At present, the new crown vaccines that have been listed include inactivated vaccine, mRNA vaccine, adenovirus vector vaccine and recombinant subunit vaccine. However, the cunning novel coronavirus is also engaged in an "arms race" with us. It constantly mutates to avoid vaccines and natural immunity induced by natural infection. Recently, the natural review of drug research and development issued an article indicating that public health researchers are exploring the path to deal with the long-term threat of novel coronavirus, and using influenza vaccine as a model, they are trying to develop a universal coronavirus vaccine - Pan coronavirus vaccine, which can finally be injected once a year to deal with the future variants of novel coronavirus, provide lasting protection for humans and help to end the new coronavirus epidemic. It is difficult for the existing R & D path to achieve "extensive protection" of vaccines Although the term "Pan coronavirus vaccine" frequently appears in various reports on vaccines under development, its specific meaning is not clear. Wang Tao, a professor at the school of life sciences of Tianjin University, believes that the so-called "Pan vaccine" concept should include three levels. First, it is an advanced vaccine that can resist various mutant strains of novel coronavirus. This kind of vaccine may be called the pan sars-cov-2 variant vaccine. Second, the pan coronavirus vaccine should eliminate or weaken the threat of sars-cov-1, mers CoV and novel coronavirus (sars-cov-2) to human beings at the same time. Third, for vaccines that are designed to be more inclusive, the pan coronavirus vaccine should be able to protect vulnerable populations threatened by the four seasonal coronaviruses that cause the common cold. The project leader of the epidemic prevention Innovation Alliance (CEPI) also defined the vaccine. He said that the fuzzy definition of cross branch coronavirus for human protection triggered many "painful discussions". They finally chose "extensive protection" to describe any vaccine against multiple coronaviruses and "mutant targeting" to describe the next generation of sars-cov-2 vaccine. At present, there are four main routes for the new crown vaccine: inactivated vaccine, mRNA vaccine, adenovirus vector vaccine and recombinant protein subunit vaccine. However, it is difficult to develop a pan coronavirus vaccine with broad protective ability through these paths. "Inactivated vaccine is to kill the complete novel coronavirus and inject it into the body to trigger the immune response in the body." Wang Tao said that according to current standards, inactivated vaccines require 3-5 micrograms of total viral protein per dose. If the inactivated vaccine is used as the "Pan vaccine" line, seven coronaviruses need to be inactivated and injected into the body at the same time. Each virus is 3-5 micrograms, and the total protein of the virus is as high as 21-35 micrograms, which may cause strong adverse reactions; If the content of viral protein is reduced, it may not be able to induce effective protective immune response, so it cannot play the role of immune protection. As an RNA virus, novel coronavirus is very changeable. If we use mRNA vaccine or adenovirus vector vaccine to develop "Pan vaccine", we will face the problem of coronavirus mutation. The new mutant strain will break through the protective immunity induced by the original vaccine. "Both vaccines obtain the genetic information of novel coronavirus - gene sequence, which is delivered by liposome (mRNA vaccine) or virus vector (adenovirus vector) Methods to enter human cells, simulate virus infection, express virus antigens related to the above genetic information in cells, and induce the body to produce cellular and humoral immunity against the above viral genetic information, so as to inhibit virus replication and eliminate infection. " Wang Tao explained that when the novel coronavirus was replaced with a "vest", the immune system could not recognize it, and the immune memory cells could not be activated in time, so a breakthrough infection would occur. Find new R & D paths to make protection effective and lasting At present, scientific research institutions and some biological enterprises are also trying some new technical paths to make the vaccine play a "pan" role against coronavirus. For example, the vaccine of gbp511 uses mosaic method to design the vaccine, so as to present more antigens and deal with highly variable viruses. It showed 60 copies of spike protein receptor binding domain (RBD) in the form of trimer to induce effective immune response. On this basis, Duke University further developed the mosaic method and adopted the self-assembled nanoparticle technology, which is to mix a variety of coronavirus spike proteins with nanoparticles, and then through self-assembly, the viral proteins can be presented on the surface of nanoparticles. In this way, the surface of nanoparticles may contain a variety of coronavirus spike proteins, thus playing the role of Pan coronavirus vaccine. Against viruses, cellular immunity is often more important. Therefore, some technology companies deliver spike proteins and T-cell epitopes (antigen epitopes recognized by T-cell receptors) through self amplified mRNA vaccines, and generate humoral and cellular immunity at the same time, with stronger protection and longer duration. "The vector vaccine can also induce cellular immunity. At present, Casper is working closely with immunity bio to develop a double antigen vaccine containing novel coronavirus spike protein and Nucleocapsid (n) protein." Wang Tao explained that the existing novel coronavirus adenovirus vector vaccine only delivers spike protein, while nucleocapsid protein is an internal RNA binding protein, which has long been regarded as an important target for T cell response. Delivering spike protein and nucleocapsid protein through adenovirus vector can induce humoral and cellular immunity through spike protein on the one hand, and cell immunity through nucleocapsid protein on the other hand, so as to provide more extensive protection. Both self amplified mRNA vaccine and vector vaccine delivery of spike protein and nucleocapsid protein can simultaneously induce humoral and cellular immunity, making the protective effect efficient and lasting. There is still a long way to go before coronavirus vaccine becomes "universal" At present, the research and development of Pan coronavirus vaccine are basically in the pre clinical and clinical stages. Wang Tao believes that, just as no universal influenza vaccine has been developed so far, there are many difficulties in the research and development of the pan coronavirus vaccine, and there is still a long way to go before it goes public. "For novel coronavirus, due to the constantly changing spike protein, the original immune protection will be ineffective for the mutated new antigen." Wang Tao said, therefore, it is necessary to find a stable antigen, but the stable antigen is either not a protective antigen, or the immunogenicity (the ability to cause immune response) is weak, so it can not induce a protective immune response sufficient to prevent the virus from infecting the human body. In addition, how to activate effective and sustained cellular immunity and make cellular immunity play a role is also a difficult point. "Antibody is a passive immune agent, which can be considered as a form of vaccine. Screening to obtain human or animal derived nano antibodies against novel coronavirus, using antibody affinity maturation technology in combination with computational biology, and artificially modifying antibodies to obtain the ability to bind and neutralize a variety of coronaviruses are also the hot spots of current research." Wang Tao said. "In addition, following the example of influenza vaccine, the WTO predicts and recommends the influenza virus vaccine strains to be used in the next influenza season every year by analyzing global data." Wang Tao said that with the existing vaccine technology path, taking the vector vaccine as an example, in theory, it is only necessary to load the mRNA fragment of the epidemic variant virus into the vector every year to play an immune preventive role. However, based on our current understanding of coronavirus and technical means, we can not accurately predict the mutation site and mutation direction of coronavirus. Chinese scientists have also actively explored the research and development strategy of Pan coronavirus vaccine. In 2020, the cooperative team of academician Gaofu and researcher yanjinghua of Institute of Microbiology of Chinese Academy of Sciences published papers in cell in advance, and proposed a general vaccine design strategy for mers-cov, sars-cov-1 and sars-cov-2. This research pioneered the construction of dimeric RBD antigen of mers CoV, successfully induced high concentration neutralizing antibody in mouse model, protected mice from mers cov infection, and further extended this vaccine design strategy to the development of sars-cov-1 and sars-cov-2 vaccines, providing a new idea for the development of coronavirus vaccines. On June 1, 2022, Chenggong Laboratory of Medical College of Tsinghua University and its collaborators published the latest research online in the Journal of signal transduction and targeted therapy - a new "assembled" nano particle vaccine against the epidemic strain of novel coronavirus Omicron mutation. The vaccine organically integrates the two strategies of "nanoparticles" and "FC RBD dimer" to enhance immunogenicity, achieving the effect of "1+1gt; 2" in immunogenicity enhancement. This nano vaccine has the characteristics of free "assembly", and can freely match the key antigens of the corresponding vaccine, especially in dealing with the rapidly mutated novel coronavirus. This strategy also provides a new technical platform for the development of a more broad-spectrum multi linked multivalent new coronal vaccine. (outlook new era)