Source 丨21 Healthnews21 original work
Author 丨 Wei laughs
Editor 丨Xu Xu
Picture 丨 Figure worm
The domestic new crown Aomi Kerong strain vaccine has been approved for clinical trials. Recently, two inactivated novel coronavirus vaccines (Aomi Kerong variant, hereinafter referred to as "O strain") developed by Sinopharm Group's China Biological Beijing Institute of Biological Products and Wuhan Institute of Biological Products were officially approved to carry out sequential immunological clinical research on the new crown vaccine in the Hong Kong Special Administrative Region.
It is worth noting that on April 14, the inactivated vaccine of the new crown virus developed by Kexing Bio based on the Aomi Kerong variant also received clinical approval in the Hong Kong Special Administrative Region.
In the face of the constantly mutating new crown virus, many vaccine developers at home and abroad have adopted a strategy of "variable strain" (redesigning vaccine antigens according to the amino acid sequence of the mutant strain S protein); but there are also many experts who believe that the development of efficient broad-spectrum vaccines is key.
Professor Jiang Shibo, an academician of the American Academy of Microbiology and director of the Institute of Pathogenic Microbiology of Fudan University, pointed out to the 21st Century Business Herald reporter: "Every time a new virus variant appears and a new vaccine is developed, this is always in a passive beating situation." ”
Since the beginning of the outbreak of the new crown epidemic, Professor Jiang Shibo proposed that the strategy of "responding to changes with no change" should be adopted to develop an efficient broad-spectrum anti-coronavirus vaccine, which can prevent and control the infection of the epidemic strain at that time, prevent the spread of future mutant strains, and even prevent new and reproduced SARS-like infectious diseases in the future. His team used the strategy of "changing with the same" (using the RBD-Fc dimer of the original strain of the new coronavirus without modification as a vaccine antigen plus a highly effective adjuvant) to develop the first highly efficient broad-spectrum β coronavirus B spectrum (β-CoV-B, or "medium-wide spectrum") generic vaccine candidate.
The domestic new poison strain vaccine has been approved for clinical trials
Since the outbreak of the Aomi Kerong variant, China Biologics immediately organized a scientific research team to start the research and development of a vaccine for the Aomi Kerong strain. The Beijing Institute of Biological Products and the Wuhan Institute of Biological Products have gone all out to carry out scientific research and research, and have developed the BIBP-novel coronavirus inactivated vaccine (O strain) and the WIBP-new coronavirus inactivated vaccine (O strain) for the first time, and both vaccines are inoculated with Vero cells by Omicron (Omicron) strain, which are cultured, inactivated, purified, and adsorbed by aluminum hydroxide adjuvant.
After the successful development of the vaccine, China Biologics actively cooperated with the University of Hong Kong, submitted an ethical application and a clinical trial application to the Hong Kong Research Center at the first time, and successfully obtained ethical approval and clinical approval on April 12 and April 13, respectively.
In the next step, China Biologics will conduct sequential immunological clinical studies in people aged 18 years and above who have completed 2 or 3 doses of COVID-19 vaccination in the form of randomized, double-blind, cohort studies to evaluate the safety and immunogenicity of bibp-novel coronavirus inactivated vaccine (O strain) and WIBP-novel coronavirus inactivated vaccine (O strain).
Coching was equally swift. It is reported that when the Aomi Kerong variant appeared at the end of 2021, Kexing acted quickly, obtained a nasopharyngeal swab sample of the infected person with the Aomi Kejong variant on December 5, 2021, and cooperated with Professor Qin Chuan's team at the Institute of Medical Laboratory Animals of the Chinese Academy of Medical Sciences to carry out virus isolation and whole gene sequencing. On 9 December last year, samples of the Aumecreon variant isolated from the University of Hong Kong were introduced.
After obtaining the Aomi Kerong variant strain, Kexing Company actively promoted the research on the strain, cell matrix and process quality of the new crown vaccine of the Aomi Kerong strain, and has established a tertiary seed bank for vaccine production according to the requirements of GMP, and on the basis of the prototype vaccine, in accordance with the second generation of improved vaccine research and development ideas, the vaccine preparation process has been determined, and many batches of products have passed the self-inspection and review inspection of the Central Inspection Institute.
According to Coxing, the results of preclinical studies show that the inactivated vaccine of the Kohin Olmi kerong variant is safe and effective in animals. After completing the safety and efficacy evaluation and clinical trial design based on animal models, Kexing began to submit clinical applications to many countries and regions at the end of February. The clinical approval of the Hong Kong Special Administrative Region is the first clinical approval obtained by the Inactivated Vaccine of Kohin Olmikron Strain.
Recently, Albert Burla, CEO of Pfizer, said that the enhanced vaccine developed by Pfizer and its partner BioNTech against Aumecreon and other subtype variants may be launched this fall.
It is worth noting that German Health Minister Carl Lauterbach also recently told the German media that Germany is scheduled to start vaccinate against the new coronavirus variant Aomi Kerong in September. "It is increasingly difficult for us to deal with these variants due to the constant emergence of new strains of the new coronavirus, and it is very likely that the highly contagious Omilkeron variant with a fatality rate similar to the Delta variant may become an absolute killer variant."
According to a study on Sinopharm's COVID-19 vaccine booster published on the preprint website medrxiv in February this year, after receiving the fourth dose of inactivated vaccine BBIBP-CorV against the original strain of the new crown virus, although it can still have a boosting effect on the original strain of the new crown, the neutralizing antibody level produced against the Omilon strain has not changed significantly compared with the three doses of the vaccine.
The research team of the First Affiliated Hospital of Sun Yat-sen University said: "The development of an updated version of the vaccine with more different epitopes that can induce neutralizing antibodies against different variant strains will be the development direction of strengthening the vaccine in the future." At the same time, some recombinant protein vaccines or mRNA vaccines may be a good option for further strengthening immunity. ”
To be constant to respond to changes vs to change strain
In order to cope with the highly contagious Omikejong variant, many vaccine developers at home and abroad are developing enhanced vaccines for Omikejong and other subtype variants, using a strategy of "variable strain" (redesigning vaccine antigens according to the amino acid sequence of the S protein of the variant strain).
But the team of Jiang Shibo/Lu Lu/Liu Zezhong of Fudan University adopted the strategy of "responding to changes with invariance" (using the RBD-Fc dimer of the original strain without modification as a vaccine antigen plus a highly effective adjuvant).
At the beginning of 2020, Jiang Shibo began to develop an efficient and broad-spectrum β coronavirus B-spectrum generic vaccine (i.e., "medium-broad-spectrum vaccine") to prevent and control the infection of the new crown virus and its mutant strains. On January 14, 2022, Jiang Shibo et al. published a paper in Trends of Immunology calling for the development of a universal vaccine for β coronavirus (β-CoV) (i.e., a "broad-spectrum vaccine") as soon as possible, which can be used both to prevent current and future infections with new strains of the new coronavirus and as a strategic reserve vaccine to prevent possible future new variants of the β coronavirus - SARS-CoV-3 or MERS-CoV-2.
On February 24, 2022, the team of Jiang Shibo/Lu Lu/Liu Zezhong of Fudan University and the team of the University of Hong Kong and the Chinese Academy of Human Rights jointly published a paper at Cell Research (IF=25.617) to prove that the antibodies they developed from the β-CoV-B universal vaccine can effectively inhibit the infection of the new coronavirus variant strains that are resistant to most vaccines and antibody drugs, the euviruses and pseudoviruses of Omiljung.
Since the outbreak of COVID-19, more than a dozen COVID-19 vaccines around the world have been approved for marketing or emergency use in many countries. The first generation of COVID-19 vaccines can effectively reduce the infection rate of the original strain, reduce the severe illness rate and case fatality rate of infected people, but there are still breakthrough infections.
Breakthrough infection is closely related to lower levels of neutralizing antibodies induced by the first generation of COVID-19 vaccines. Jiang Shibo pointed out that the common disadvantage of more than a dozen COVID-19 vaccines that have been approved for marketing or emergency use is the hasty selection of vaccine antigens with low neutralization immunogenicity – spike (S) proteins or viral particles. The primary site of the induced neutralizing antibody is present in a fragment of the S protein S1 subunit -- the receptor-binding domain (RBD). Neutralizing antibody sites in RBD are not fully exposed in S protein vaccines, so high levels of neutralizing antibodies cannot be induced in humans. Moreover, the immune dominant region in the S protein S2 subunit can induce high levels of non-neutralizing antibodies, further inhibiting the ability of RBD to induce high levels of neutralizing antibodies.
"The first generation of COVID-19 vaccines generally induced neutralizing antibodies in humans with lower levels of cross-neutralizing antibodies against variants, and the rapid decay of neutralizing antibodies (more than 4 times every six months), resulting in inefficient, short-acting and narrow-spectrum results." Jiang Shibo said.
In 2003, when SARS-CoV spread around the world, Jiang Shibo, who was working at the New York Blood Center at the time, immediately organized research on anti-SARS-CoV drugs and vaccines. He put Liu Shuwen in charge of the development of peptide drugs, while He Yuxian was in charge of vaccine research. At that time, there were dozens of R&D teams in the world using different technology platforms (such as subunit vaccines, adenovirus vector vaccines, DNA vaccines, attenuated virus vaccines, inactivated virus vaccines, etc.), but only two vaccine antigens were used - S protein or virus particles. The neutralizing antibody titer induced by these vaccines in immune animals is only a few tens to a few hundred.
In order to design a more efficient vaccine, Jiang Shibo and He Yuxian used SARS-CoV's S1 subunit (containing RBD and NTD) and S2 subunit design vaccine, and Li Wenhui of Michael Farzan's laboratory at Harvard Medical School published a paper proving that the SARS-CoV receptor is inspired by ACE2, Jiang Shibo immediately contacted Michael Farzan and obtained an expression plasmid of RBD-Fc to make a subunit vaccine. Jiang Shibo's team found that the antibody titers of the neutralizing SARS-CoV pseudovirus and live virus induced by the RBD-Fc vaccine in immune animals are more than 10,000, which is more than ten to dozens of times higher than the neutralizing antibody titer induced by the S1 and S protein vaccines.
Jiang Shibo published an article in the BBRC, becoming the first published research paper on the RBD vaccine in the world. Since then, they have published more than a hundred papers proving that RBD is the best target for the development of coronavirus vaccines and antibodies, and that RBD-Fc spontaneously forms parallel dimers with the highest neutral immunogenicity: RBD-Fc dimer > RBD trimer > RBD monomer > S1 protein > S protein > viral particles.
It is worth noting that some people have questioned whether the RBD-Fc vaccine can induce high titers of neutralizing antibodies in monkeys, but not necessarily induce the same high titers of neutralizing antibodies in humans. Therefore, more preclinical and clinical trials need to be carried out, and the production process of the vaccine should be repeatedly optimized (to ensure that the RBD-Fc vaccine produced under the condition of mass production can maintain the optimal spatial configuration), the ratio of vaccine to adjuvant, the preservation and transportation conditions of the vaccine, the dosage of the vaccine, the immune pathway of the vaccine, etc., so as to obtain an optimal vaccine candidate that can induce high-titer cross-neutralizing antibodies in humans.
Many R&D teams now use RBD as the antigen for COVID-19 vaccines, and a number of RBD-based COVID-19 vaccines have been approved for use or entered clinical trials. For example, the recombinant protein vaccine of Zhifei Biologics that has been approved for emergency use is RBD tandem dimer as the vaccine antigen; the recombinant protein RBD new crown vaccine produced by insect cells developed by The team of academician Wei Yuquan has entered the third phase of the clinic and is applying for emergency use; and the mRNA vaccine of Aibo Biologics (in clinical phase III) is an RBD monomer expressed by mRNA as the vaccine antigen. In addition, the "Recombinant Novel Coronavirus Fusion Protein Vaccine (V-01)", developed by Livzon Pharmaceuticals and has been conducted in phase III clinical trials in several countries, also uses RBD-Fc dimer as the antigen of the vaccine.
After the outbreak of the new crown epidemic, the team of Jiang Shibo/Lu Lu/Liu Zezhong adopted the strategy of "changing with constant response" to develop the first highly efficient and broad-spectrum β-CoV-B generic vaccine candidate, which can not only neutralize the infection of SARS-CoV, bat SARS-related coronavirus (SARSr-CoV), new coronavirus (SARS-CoV-2) and its variants in immune monkeys. It also effectively neutralizes pseudoviruses of the Semikron variant (cross-neutralizing antibody titers above 35,000) and true viruses (cross-neutralizing antibody titers above 9,000) that are resistant to most vaccines and antibody drugs.
It is reported that the team is currently working with Bowo Bio and Furgent in the United States, hoping to push this highly efficient and broad-spectrum β coronavirus B universal vaccine into the clinic as soon as possible.
Wu Ke, founder of Bowo Biologics, pointed out, "Based on the existing results of Fudan University and Furgent, we hope to develop a broad-spectrum vaccine for the B spectrum of the β coronavirus, so that the epidemic situation is more controllable, and the vaccine is long-acting and efficient." Use its own industrial development capabilities to promote vaccines to clinical application as soon as possible and benefit global public health. ”
Currently, the team is developing a universal vaccine β-CoV ("medium-broad spectrum"),which will be used to prevent various strains of the new coronavirus and MERS-CoV currently circulating in the Middle East and new highly pathogenic β-CoV variants in the future—SARS-CoV-3 or MERS-CoV-2.