Could a pan-coronavirus vaccine be the coronavirus terminator while development is underway?

  At present, the research and development of pan-coronavirus vaccines are basically in the preclinical and clinical stages.

Just as no universal flu vaccine has been developed so far, the research and development of a pan-coronavirus vaccine is fraught with difficulties, and there is still a long way to go before it is launched.

  ◎Our reporter Chen Xi

  Since the outbreak of the new crown pneumonia, the new coronavirus (SARS-CoV-2) has coexisted with humans for more than three years.

During this period, the new crown vaccine has become a powerful weapon for human beings to protect their own health.

The new crown vaccines currently on the market include inactivated vaccines, mRNA vaccines, adenovirus vector vaccines and recombinant subunit vaccines.

  However, the cunning new coronavirus is also in an "arms race" with us, evading vaccines and natural immunity induced by natural infection by constantly mutating.

Recently, "Nature Review Drug Development" published an article stating that public health researchers are exploring ways to deal with the long-term threat of the new coronavirus, and using the influenza vaccine as a model, trying to develop a universal vaccine for coronavirus - a pan-coronavirus vaccine, which will eventually achieve annual A single injection can deal with future variants of the new coronavirus, providing lasting protection for humans and helping to end the new crown epidemic.

  It is difficult for the existing research and development path to achieve "broad protection" for vaccines

  Although the term "pan-coronavirus vaccine" appears frequently in various reports on vaccines under development, its specific meaning is unclear.

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 against various mutant strains of the new coronavirus.

Such vaccines should perhaps be called pan-SARS-CoV-2 variant vaccines.

Second, a pan-coronavirus vaccine should simultaneously eliminate or attenuate the threats to humans from SARS-CoV-1, Middle East respiratory syndrome coronavirus (MERS-CoV), and novel coronavirus (SARS-CoV-2).

Third, for vaccines that are inherently designed to be more inclusive, a pan-coronavirus vaccine should have the ability to protect susceptible populations threatened by the four seasonal coronaviruses that cause the common cold.

  The project leader of the Coalition for Epidemic Preparedness Innovations (CEPI) also defined the vaccine.

He said the vague definition of human protection against cross-branched coronaviruses sparked many "painful discussions" and they settled on "broad protection" to describe any vaccine against multiple coronaviruses, as well as "variant targeting" to describe the next generation of SARS-CoV-2 vaccines.

  There are currently four main routes of new crown vaccines: inactivated vaccines, mRNA vaccines, adenovirus vector vaccines and recombinant protein subunit vaccines.

However, there are difficulties in developing pan-coronavirus vaccines with broad protection through these routes.

  "Inactivated vaccine is to kill the complete new coronavirus, and then inject it into the body to trigger an immune response in the body." Wang Tao said that according to the current standard, inactivated vaccine requires 3-5 micrograms of total virus protein per dose.

If the inactivated vaccine is used as the "pan-vaccine" line, 7 kinds of coronaviruses need to be inactivated and injected into the body at the same time, each virus is 3-5 micrograms, and the total virus protein is as high as 21-35 micrograms, which may cause strong Adverse reactions; if the viral protein content is reduced, an effective protective immune response may not be induced, thus failing to play a role in immune protection.

  As an RNA virus, the new coronavirus is very changeable. If a "pan-vaccine" is developed with an mRNA vaccine or an adenovirus vector vaccine, it 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 the new coronavirus -- the gene sequence, and the genetic information enters human cells by means of liposome delivery (mRNA vaccine) or viral vector delivery (adenovirus vector), simulating viral infection, within the cell. Expression of the viral antigens related to the above genetic information induces the body to produce cellular and humoral immunity against the genetic information of the above viruses, thereby inhibiting virus replication and clearing the infection." Wang Tao explained that when the new coronavirus changes its "vest", the immune system cannot recognize it. Immune memory cells cannot be activated in time, and a breakthrough infection occurs.

  Finding new R&D avenues to make protection efficient and long-lasting

  At present, scientific research institutions and some biological enterprises are also trying some new technical paths to make vaccines have a "pan" effect against coronavirus.

  For example, the vaccine of GBP511 adopts the mosaic method, and uses the mosaic method for vaccine design to present more antigens and deal with viruses with high variability.

It displays 60 copies of the spike protein receptor binding domain (RBD) in trimeric form to induce potent immune responses.

  On this basis, Duke University has further developed the mosaic method, using self-assembled nanoparticle technology, which is to mix a variety of coronavirus spike proteins with nanoparticles, and then self-assemble, so that viral proteins can be presented on nanometers. The surface of the particle, so that the surface of the nanoparticle may contain the spike proteins of various coronaviruses, thus acting as a 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-amplifying mRNA vaccines, generating both humoral and cellular immunity, with stronger and longer-lasting protection .

  "Vector vaccines can also induce cellular immunity. Currently, Casper is working closely with Immunity Bio to develop a dual-antigen vaccine containing the new coronavirus spike protein and nucleocapsid (N) protein." Wang Tao explained that the existing new coronavirus adenovirus Vector vaccines deliver only the spike protein, while the nucleocapsid protein, an internal RNA-binding protein, has long been regarded as an important target of T-cell responses.

The delivery of spike protein and nucleocapsid protein by adenoviral vector can induce humoral and cellular immunity through the spike protein on the one hand, and cellular immunity can be induced by the nucleocapsid protein on the other hand, thus providing broader protection.

  Both self-amplifying mRNA vaccines and vector vaccines deliver spike protein and nucleocapsid protein, both of which can induce humoral and cellular immunity in the human body at the same time, making the protective effect efficient and durable.

  There is still a long way to go before the coronavirus vaccine becomes "pan"

  At present, the research and development of pan-coronavirus vaccines are basically in the preclinical and clinical stages.

Wang Tao believes that just like no universal influenza vaccine has been developed so far, the development of a pan-coronavirus vaccine is difficult and there is still a long way to go before it is launched.

  "For the new coronavirus, due to the constant change of the spike protein, the original immune protection will be ineffective for the mutated neoantigen." Wang Tao said, therefore, a stable antigen must be found, but the stable antigen may not be a protective antigen, Or the immunogenicity (the ability to elicit an immune response) is weak enough to induce a protective immune response sufficient to prevent the virus from infecting the human body.

  In addition, how to activate effective and persistent cellular immunity so that cellular immunity can play a role is also a difficulty.

  "Antibody is a passive immune preparation, which can be considered as a form of vaccine. Screening to obtain human-derived antibodies or animal-derived nanobodies against the new coronavirus, using antibody affinity maturation technology combined with computational biology, artificially transforming antibodies to obtain antibodies against a variety of coronaviruses The ability of virus binding and neutralization is also a hot spot of current research." Wang Tao said.

  "In addition, following the example of influenza vaccines, the WTO analyzes global data every year to predict and recommend influenza virus vaccine strains to be used in the next season of influenza." Wang Tao said, using the existing vaccine technology path, taking vector vaccines as an example, the theory Every year, only the mRNA fragments of the popular mutant strains are loaded into the vector to play the role of immune prevention.

However, with our current understanding of coronaviruses and technical means, it is still impossible to accurately predict the mutation sites and mutation directions of coronaviruses.

  Chinese scientists have also actively explored the research and development strategy of pan-coronavirus vaccines.

  In 2020, the cooperative team of Academician Gao Fu of the Institute of Microbiology of the Chinese Academy of Sciences and Researcher Yan Jinghua published a paper in Cell in the form of advance disclosure, proposing a new method for MERS-CoV, SARS-CoV-1 and SARS-CoV-2. Generic vaccine design strategy.

  This study pioneered the construction of the dimerized RBD antigen of MERS-CoV, successfully induced high concentrations of neutralizing antibodies in a mouse model, protected mice from MERS-CoV infection, and further developed this vaccine design strategy. It is extended to the vaccine research and development of SARS-CoV-1 and SARS-CoV-2, which provides new ideas for the research and development of coronavirus vaccines.

  On June 1, 2022, Cheng Gong's laboratory of Tsinghua University School of Medicine and collaborators published the latest research online in the journal "Signal Transduction and Targeted Therapy" - an "assembly" targeting the novel coronavirus Omicron mutant epidemic strain. Formula" Novel Nanoparticle Vaccines.

The vaccine organically integrates two strategies to enhance immunogenicity, "nanoparticles" and "Fc-RBD dimer", and achieves the effect of "1+1>2" in terms of 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 mutating new coronavirus.

This strategy also provides a new technical platform for the development of a broader-spectrum, multivalent, multivalent vaccine against COVID-19.