21st Century Business Herald reporter Wei Xiao Shenzhen reported that on March 8, according to Wang Zhigang, minister of science and technology, the mainland is actively developing a broad-spectrum drug to deal with the coronavirus or the new crown virus; through nasal spray, inhalation vaccination, this work is also in the study, and now there is good progress.
In fact, since the beginning of the outbreak of the new crown epidemic, Professor Jiang Shibo, academician of the American Academy of Microbiology and director of the Institute of Pathogenic Microbiology of Fudan University, has repeatedly emphasized that the new crown virus will definitely mutate in the future, so he proposed that the strategy of "responding to changes with no change" should be adopted to develop an efficient and broad-spectrum anti-human coronavirus universal vaccine and drug as soon as possible.
On March 9, Professor Jiang Shibo pointed out in an interview with the 21st Century Business Herald reporter that nasal spray-type vaccines mainly induce T cell immunity and are less susceptible to viral receptor binding domain (RBD) variations containing major neutralizing antibody epitopes. Therefore, it may be broader than injecting vaccines (which mainly induce antibody reactions). In addition, nasal spray vaccines can mimic the virus's natural route of infection, acting directly on key sites of virus invasion and infection.
The same is true of the advantages of nasal inhaled COVID-19 drugs. It is worth noting that Jiang Shibo pointed out that nasal spray inhalation of new crown drugs can be used as a nebulization inhalation for lung treatment, and can also be used for nasal spray to play a preventive effect. "The new crown virus mainly infects people's upper respiratory tract, and people can not wear masks when eating, etc., they can use peptide drugs in the respiratory tract by nasal injection to achieve the purpose of prevention; but if they are used for treatment, it is best to use nebulized inhalation to deliver drugs to the lungs."
What are the advantages of nasal spray vaccines and drugs?
It is reported that the mucosal immune system is an important part of the human immune system, including the respiratory tract, reproductive tract, digestive tract, and communication with the outside world, therefore, the mucosal surface will continue to be in direct contact with external microorganisms.
It is worth noting that the nasal inhalation new crown vaccine uses nebulizers to atomize the vaccine into tiny particles, which can enter the respiratory tract and lungs through respiratory inhalation, thereby stimulating mucosal immunity and producing corresponding antibodies.
What are the advantages of injecting vaccines into the nasal cavity compared to injecting vaccines? Professor Jiang Shibo pointed out in an interview with the 21st Century Business Herald reporter that first of all, compared with the injection of vaccines, nasal spraying vaccines can simulate the natural infection route of the virus and directly act on key parts. "The coronavirus is mainly transmitted through the upper respiratory tract (nose, pharynx, larynx) and lower respiratory tract (trachea, bronchi, and lungs), which then causes an inflammatory response in the lungs. Nasal spraying of the vaccine induces an immune response directly in the upper and lower respiratory tracts against the virus. The antibodies produced by intramuscular vaccines will reach the various organs of the body through blood circulation, and only a small number of antibodies can reach the upper and lower respiratory tracts. ”
Xu Jianqing, distinguished professor of Fudan University, researcher of the Institute of Biomedical Research, and doctoral supervisor, also pointed out to the media that in the early stage of infection with the new crown, the virus will replicate in the upper respiratory tract and have a strong ability to spread. For the new crown vaccine, if you really want to prevent infection, you must establish immune protection in the upper respiratory tract, and the upper respiratory tract to establish immune protection can only be done by nasal spray vaccines, and muscle vaccination cannot be done. "Muscle vaccination does not establish immune protection in the upper respiratory tract, and T cells can only pass when the virus is infected, but this requires a reaction time of 48 hours."
Jiang Shibo said that because the immune response induced by nasal injection of vaccine can directly fight the invading virus in the upper and lower respiratory tracts, it requires less vaccine dosage than intramuscular injection, and may be more effective.
Secondly, Jiang Shibo pointed out: "The current vaccine is mainly through the neutralizing antibody site on RBD to induce neutralizing antibody response, and its antibodies are mostly protective by binding to RBD." Therefore, once the RBD is mutated, the protective effect of the vaccine will become poor or completely ineffective, which is one of the main reasons why the effectiveness of many vaccines on the Aumecreon variant is reduced. Nasal injection vaccines mainly induce protective T cell immune responses, so they are less susceptible to RBD changes, so it is speculated that nasal injection vaccines are more broadly protective than injected vaccines. ”
In addition, Jiang Shibo pointed out that injecting vaccines will cause pain and inflammation in the local area of injection, and nasal spraying vaccines does not have this drawback.
It is worth noting that the nebulized inhalation vaccine also has a supplementary strengthening effect on traditional vaccines, through nebulization inhalation, the triple protection of mucosal immunity, cellular immunity and humoral immunity can be obtained at the same time, and the use of nebulized inhalation vaccine 28 days after intramuscular injection can strengthen the immune effect, produce a high level of neutralizing antibodies, and resist the mutation of the new crown virus.
Xia Ningshao, dean of the School of Public Health of Xiamen University, also previously said that in the animal attack and protection test, the nasal spray vaccine has a unique antiviral protection effect on the new crown virus infection in terms of rapid onset of action, broad-spectrum anti-mutation, long-term effectiveness, and post-exposure emergency protection.
But not all technical routes of COVID-19 vaccines can be used in the form of nasal inhalation. Jiang Shibo pointed out that the current nasal cavity and injection method are mainly suitable for adenovirus or influenza virus vector vaccines, but they are not suitable for DNA or mRNA vaccines.
Xu Jianqing also pointed out that the main reason why many carriers are not suitable for nasal spray vaccines is the lack of effective adjuvants. For example, under normal circumstances, proteins do not work in the mucosal area, so it is difficult to find an effective mucosal adjuvant.
Nasal injection vaccines also have their limitations. Jiang Shibo said that intramuscular injection can accurately control the dosage, but nasal injection vaccines are relatively difficult to control, because everyone's nasal cavity size is different, whether ventilation is smooth, and whether there is inflammation of the respiratory mucosa may affect the inhalation vaccine dosage. In addition, because the nasal injection vaccine needs to be inhaled voluntarily, it is difficult for children to use if they do not cooperate, so it may not be suitable for children.
The same is true of the advantages of nasal spray inhalation of COVID-19 drugs. Jiang Shibo pointed out that nasal spray inhalation of new crown drugs can directly act on the upper and lower respiratory tract areas where the virus invades and replicates, and the effect may be better; while oral or injectable drugs will circulate to all organs and tissues throughout the body, and only a small amount of drugs can reach the surface of the upper and lower respiratory tract (including the lungs). As a result, the therapeutic effect may be relatively poor.
In addition, nasal spray inhalation drugs are safer. "Unlike small molecule or antibody drugs, nasal inhalers generally do not get a lot of blood or into key organs of the body (such as the liver, kidneys, etc.). Therefore, there should be no potential threat to these body organs. Jiang Shibo said.
Which drugs can be inhaled as aerosol? Jiang Shibo believes that the most suitable is a peptide drug. "Because peptide drugs have moderate molecular weight, they can enter the upper and lower respiratory tract (including the lungs) through nebulization inhalation, and the new crown virus mainly invades and replicates in these areas." Therefore, the atomization inhalation method can push the drug to the most critical part at once. Small molecule drugs persist on the surface of the mucosa of the upper and lower respiratory tracts for a short time because they either quickly enter the bloodstream and circulate to other organs, or are excreted with secretions on the surface of the respiratory tract. Antibody (IgG or IgM) drugs, on the other hand, have too much molecular weight and are less easily inhaled into the lungs through nebulization. Of course, nano-antibodies with relatively small molecular weight can also enter the lungs by nebulizing inhalation. ”
Jiang Shibo also pointed out that nasal spray inhalation of new crown drugs can be inhaled into the lungs for treatment, and can also be used for nasal spraying to the upper respiratory tract to play a preventive effect. "The coronavirus, especially the Aomi Kerong variant, mainly invades the human body through the human upper respiratory tract. People cannot wear masks in occasions such as eating, so peptide drugs can be used through nasal spraying to achieve the purpose of prevention. ”
The research and development of domestic new vaccines ushered in breakthroughs
Jiang Shibo pointed out that the current nasal injection method is mainly suitable for adenovirus or influenza virus vector vaccines, that is, viral vector vaccines, at present, at least two pharmaceutical companies in the mainland have carried out or completed clinical trials, in addition, there are a number of pharmaceutical companies in the pre-clinical development stage.
In terms of adenoviral vector vaccine, on March 7, Zhu Tao, chief scientific officer of CanSino Biologics Co., Ltd., revealed that CanSino Biologics' inhaled new crown vaccine completed phase I and PHASE II clinical trials last year, and launched clinical trials of about 10,000 people to do large-scale safety and immunogenic bridging, according to the current mainland management methods, these data can be applied for emergency use of vaccines.
It is reported that the vaccine was developed by the team of academician Chen Wei of the Military Medical Research Institute in cooperation with CanSino Biological Co., Ltd. According to Academician Chen Wei, there is an S protein on the surface of the fat membrane wrapped in the new coronavirus particles, and after the virus enters the human body, it is through this protein that it binds to the angiotensin-converting enzyme 2 (ACE2) on the cell surface, thereby invading human cells. After injecting the adenovirus vector vaccine containing the S protein into the body, the immune system can recognize the viral antigen and produce an antiviral immune response. In the future, if the human body is infected by the new crown virus, the immune system with memory will immediately recognize it and produce antibodies that can bind to the antigen of the virus, thus preventing the virus from invading the body's cells.
It is worth noting that The world's first inhaled COVID-19 vaccine of CanSino Bio uses the same vaccine as intramuscular injection, and its formulation has not changed, only using different modes of administration. Zhu Tao also told the media that not all vaccines can be inhaled, and the new crown vaccine of CanSino Biologics has no adjuvant, and it is completely a form of liquid before it can be inhaled as a nebulization.
In terms of influenza virus vectors, the new crown nasal spray vaccine jointly developed by Xiamen University, the University of Hong Kong and Wantai Biology is a new coronavirus gene fragment inserted into the influenza virus vector to make a live virus vector vaccine to stimulate the human body to produce an immune response to the new crown virus.
According to Xiamen University, the vaccine developed by Xiamen University and others is a temperature-sensitive replicated live viral vector vaccine prepared by introducing the RBD fragment of the new coronavirus S gene on the basis of the double attenuated influenza virus vector (CA4-dNS1), which is inoculated by nasal spray to form a first-line protective immune response against the new coronavirus in the respiratory tract, with the characteristics of rapid onset, long-lasting protection, broad-spectrum anti-mutation, convenient vaccination, and good safety.
On November 12, 2021, Wantai Biotech announced that its nasal spray influenza virus vector COVID-19 vaccine developed in cooperation with Xiamen University and the University of Hong Kong has been approved by the South African Food and Drug Administration for Phase III clinical trials, approving the protection efficacy and safety of nasal spray new crown vaccine in adult subjects aged 18 years and above in the protection and safety of international multicenter, randomized, double-blind, placebo-controlled Phase III clinical trials.
Jiang Shibo's team published an article in Science Advance a year before the outbreak (2019) showing that they have developed a peptide drug candidate (EK1) that can fight coronavirus in everyone. Recently, in Cell Research, it was proved that EK1 series peptides can also be very effective in inhibiting infection of the Omiljung variant strain, which is highly resistant to antibody drugs.
Jiang Shibo's team found that the highly efficient and broad-spectrum EK1 series of peptides is expected to be used to prevent and treat the infection of the new coronavirus and its variants and MERS-CoV that are now circulating with nasal sprays and nebulized inhalation dosage forms, and can also prevent and treat new and reproduced SARS-like infections in the future. The EK1 series of peptides developed by Jiang Shibo's team is currently the most efficient and broad-spectrum human coronavirus fusion/entry inhibitor.
At present, its team is working with Shanxi Jinbo Biologics and has obtained the "Drug Clinical Trial Approval Notice" for EK1 atomizer, which means that in the near future, a highly efficient and broad-spectrum anti-coronavirus drug based on universal coronavirus fusion/entry inhibitor independently developed by the mainland is expected to be listed.
On November 15, 2021, Hanyu Pharmaceutical and the Institute of Microbiology of the Chinese Academy of Sciences officially signed the new crown nasal spray polypeptide drug cooperation project, according to the agreement, Hanyu Pharmaceutical will obtain the patented technology of "a polypeptide anti-novel coronavirus and its application" by the Institute of Microbiology of the Chinese Academy of Sciences in the form of "global exclusive license".
Recently, Hanyu Pharmaceutical said that the project is progressing smoothly as planned, and the project has conducted live toxicity research on the two main epidemic strains of Omicron and Delta; in vivo pharmacodynamic studies and non-clinical pharmacological and toxicological studies in animals; pharmaceutical research APIs have completed small trials and large-scale scale production; for the current research progress and research programs, they have communicated with the National Drug Review Center and received targeted replies.
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