Source: Beijing Daily
How the COVID-19 vaccine is "upgraded"
Zhang Tiankan
The devil is one foot tall, and the road is one foot high. The coronavirus has been mutating since its inception, creating many new challenges. In response to the new crown virus variant, various studies on the upgrading of the new crown vaccine have also been in full swing.
On May 1, the sequential immunomic research of the inactivated vaccine of the New Coronavirus variant of the Omikerong variant developed by Sinopharm Group's Beijing Institute of Biological Products was officially launched in Hangzhou, Zhejiang Province. After relevant testing, informed consent, basic physical examination, blood sampling and other links, the volunteers received the inactivated vaccine of Ao zhu in Shulan (Hangzhou) Hospital. This is the world's first inactivated covid-19 vaccine to enter clinical trials against the Omiljung variant.
1 The virus mutates, and the vaccine can also change
No matter how many technical routes there are in the development of vaccines, it is necessary to use the new crown virus as an antigen, some use inactivated new crown virus as an antigen, and some use a part of the new crown virus, such as a part of the shell, a part of the envelope, or a part of a special part, such as dozens of receptor binding domains on the new crown virus spike protein as antigens.
Spike protein is an important structure of the new crown virus and human (host) cells binding, spike protein gene mutation will not only change the infectivity, pathogenicity and toxicity of the virus, but also lead to changes in the body's immune response, such as neutralizing antibodies produced more and less.
Now, the mutation of the new crown virus is mainly due to multiple changes in the receptor binding domain on the spike protein. Currently, the main pathogen triggering the COVID-19 outbreak around the world is BA.2, a branch of the Omiljung variant, which has more than 50 amino acid mutations, of which 29 are present on spike proteins.
Vaccine research is based on the virus and part of the virus (such as some mutations on the spike protein) as an antigen, if the virus has changed, it is necessary to use the changed virus as the original, so that after vaccination, can stimulate the body's immune system to recognize the mutated virus, and produce a sufficient amount of neutralizing antibodies to prevent the virus from invading human cells.
When the virus mutates, only the inactivated whole virus as the antigen, or the amino acids mutated on the spike protein as the antigen to develop a vaccine, will be targeted. This situation is a bit like the annual flu vaccine, because the main antigen hemagglutinin and neuraminidase on the influenza virus envelope have changes, and there are dozens of combinations of these two antigens, so the vaccine is re-developed every year according to the changes in the influenza virus. In the future, the changeable new crown virus will also prompt people to frequently develop different vaccines to deal with the outbreak caused by the mutated virus.
2 The technical route of the mainland to develop an Austrian vaccine
The old vaccine is a vaccine developed with the original strain of the new crown virus as an antigen. Therefore, the old vaccine can be collectively referred to as version 1.0, and the new vaccine is developed with a mutated virus as an antigen, which can be collectively referred to as version 2.0.
There are more new coronavirus variant virus strains, and now the main cause of infection and incidence is the Aomi Kerong variant strain, so the vaccine developed with the Omi kerong variant as an antigen, that is, the Ao strain vaccine, has become a representative of the new vaccine.
The 5 technical routes of vaccines can produce different vaccines, there are 5 types of vaccines in version 1.0, and there will be 5 types of vaccines in the upcoming 2.0 version. They are: inactivated vaccines, adenovirus vector vaccines, recombinant protein vaccines, attenuated influenza virus vector vaccines and nucleic acid vaccines.
In the past, the mainland used the original strain of the new coronavirus as an antigen to develop vaccines, and the most produced were inactivated vaccines, including the inactivated vaccine developed by the China Biological Institute of China Biological Products of Sinopharm Group and the inactivated vaccine of Beijing Kexing Zhongwei Biotechnology Co., Ltd., which were referred to as Sinopharm Vaccine and Kexing Vaccine respectively. At present, the 2.0 new vaccine Austrian strain vaccine developed by the mainland is also based on inactivated vaccines, that is, the inactivated Aomikron whole virus as an antigen.
On April 26, the State Drug Administration of China officially approved the inactivated covid-19 vaccine developed by Kexing Holdings Biologics and Sinopharm China Biologics based on the Aomi Kerong variant into clinical research to evaluate the safety and immunogenicity of the new coronavirus variant vaccine in various populations. This is the world's first inactivated vaccine approved for clinical use of the Omikejong strain.
After animal testing, a vaccine must also undergo human phase 1-3 clinical trials before it can be officially approved for disease prevention and control. Previous results from animal tests have shown that the Inactivated Vaccine for the Kohin Olmikron variant is safe and effective. At the same time, Sinopharm China Bio-utilization of the newly built P3 high-grade biosafety laboratory has completed the screening, passage and amplification of Theoso strains, established a tertiary poison seed bank, and completed process verification, preparation of multiple batches of large-scale products, quality standard research, in vivo safety evaluation and immunogenicity studies in animals. The results showed that the inactivated covid-19 vaccine of Sinopharm Ao strain can produce high-titer neutralizing antibodies against the Olympian strain and a variety of variant strains.
Upon approval, both China Biologics and Kexing will conduct immunological clinical studies in people aged 18 years and older 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 the Inactivated COVID-19 vaccine for the Aumecreon variant.
At the same time, there is also a recombinant protein vaccine route in the research and development of the new vaccine 2.0 vaccine in mainland China. Recombinant protein new crown vaccine is to analyze and calculate the natural structural characteristics of the aumi kerong mutant strain spike protein receptor binding domain biological analysis and calculation, using genetic engineering technology to recombinant the antigen protein of the virus, as an antigen to produce vaccine, after inoculation can induce the body to produce neutralizing antibodies against the Omicron mutant strain, blocking the virus from binding to human cells. The 2.0 recombinant protein vaccine developed in China is based on the first generation of recombinant COVID-19 vaccines, and the second-generation broad-spectrum COVID-19 vaccine is designed and developed by computational analysis of the evolution law and immune escape ability of the embolus site of the Ami kerong epidemic strain.
On April 26, the State Drug Administration of China also approved the recombinant COVID-19 vaccine developed by Sinopharm Zhongsheng Biotechnology Research Institute/National Engineering Research Center for Novel Vaccines to enter clinical trials. Therefore, there are three kinds of Chinese version 2.0 Austrian vaccines, including two inactivated vaccines and one recombinant vaccine.
3 New vaccines for different variants are being developed
The variant of the new crown virus is not only one of the Omiqueron, but also a variety of vaccines for different variants in the future version 2.0.
The World Health Organization's Technical Advisory Group on the Evolution of COVID-19 divides mutated viruses into three categories: concern variants, concern variants, and severe consequence variants. At present, the World Health Organization believes that the serious consequence variant has not yet emerged, and the focus of monitoring is the concern variant, there are 5, namely: the Alpha variant found in the UK in December 2020, the Beta variant found in South Africa in December 2020, the gamma variant found in Brazil in January 2021, the Delta variant found in India at the end of 2020, and the Omiljung variant found in southern Africa at the end of 2021.
As early as the epidemic of Delta strains in 2021, in September of that year, the Chinese Center for Disease Control and Prevention successfully isolated multiple Delta strains from clinical samples imported from Guangdong, Shanghai, Beijing and other clinical samples with more epidemics. Through three consecutive generations of cloning and purification, the selection and identification of vaccine strains and the establishment of tertiary seed banks have been preliminarily completed, and preparations have been made before entering the production workshop from the laboratory to large-scale production.
Only later, the epidemic suddenly changed, and Omicron became the main variant of faster transmission and wider coverage, triggering the global epidemic, so the focus of research and development of the 2.0 vaccine shifted to the Austrian vaccine, and the Delta vaccine pressed the pause button. However, this does not mean that new vaccines with other variants are no longer being studied. Various vaccine research and development units in China have also carried out research on broad-spectrum or multivalent recombinant protein vaccines for different variants of the new coronavirus, and have also carried out research and development of adenovirus vector vaccines and nucleic acid vaccines for beta strains and Delta strains, and some scientific research units have completed animal efficacy and safety experiments.
These efforts are actually preparing for the future, once the new coronavirus variant is transferred from Omilon to other variants, or new variants are produced, they can also be prepared, quickly start research on new vaccines for different variants, and carry out large-scale production.
4 Other countries are also developing new vaccines
Other countries in the world are also developing a new 2.0 vaccine against the new coronavirus variant, of which the 2.0 new crown vaccine developed by the University of Washington School of Medicine in the United States has been clinically tested in Phase 3.
The vaccine, called GPB510, is a protein molecular vaccine that is made with partial antigens, such as the protein, polysaccharide or peptide of a pathogen, and can actually be classified as a recombinant protein vaccine.
From the perspective of mechanism of action and research and development route, GPB510 is composed of protein nanoparticles, which is a tiny protein ball in shape, which is covered with 60 spike protein receptor binding domains of the new crown virus. This protein nanomolecular vaccine entered the research and development state at the end of 2020, and tests on animals found that nanoparticle vaccines can produce high levels of virus neutralizing antibodies at low doses, which can produce immunostimulatory effects and antibodies against multiple different sites of coronavirus spike proteins, thus having an anti-anti-viral effect on new coronavirus variants.
The principle that the GPB510 vaccine stimulates the body's immune system to produce antibodies to the new crown variant is that this vaccine uses multiple antigen components of the new crown virus, that is, dozens of receptor-binding domains on the spike protein. These new coronavirus spike protein receptor binding domain protein molecules can stimulate the body's immune cells to produce neutralizing antibodies and remember these variant molecules at the same time. Therefore, when vaccinated, the body's immune system can recognize the new coronavirus variant and produce antibodies.
On April 25 of this year, through a multi-country Phase 3 clinical trial of 4,037 adults over the age of 18 and comparing the effects of the Oxford/AstraZeneca vaccine Vaxzevria (adenovirus vector vaccine) (studied with GPB510 in one group and Vaxzevria in two doses of 4 weeks apart), it was found that GPB510 was higher than the protective antibody levels produced by Vaxzevria.
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Does the new vaccine still work in the development of the old vaccine?
New research shows that despite the mutation of the new crown virus, the old vaccine still works. On January 4, 2022, Israel launched a fourth COVID-19 vaccination program for high-risk groups, including the elderly over the age of 60 and immunodeficiency, and the vaccine is Pfizer BN162b2 vaccine.
On April 13, Israeli researchers published a study of the fourth dose of the vaccine in the New England Journal of Medicine (NEJM), showing that during the Omilon epidemic, people who received the fourth dose of the new crown vaccine (the old vaccine) were significantly more resistant to the virus than their peers who had only received three doses of the vaccine.
The data for the study, from 258994 vaccinators from January 3 to February 18, 2022, compared two groups of people who had received four injections versus only three, and the average age of the participants in both groups was 72 years old.
Older people who receive a fourth dose of the vaccine have some of the following benefits compared to people who receive only three doses. In the 7-day to 30-day cycle after vaccination: the COVID-19-positive rate decreased by 45 percent; the proportion of symptomatic infections decreased by 55 percent; the COVID-related hospitalization rate decreased by 68 percent; the severe illness rate decreased by 62 percent; and the COVID-related mortality rate decreased by 74 percent.
In the 14- to 30-day cycle after vaccination: the proportion of COVID-19 positives decreased by 52%; the proportion of symptomatic infections decreased by 61%; the probability of COVID-19-related hospitalizations decreased by 72%; the rate of severe illness decreased by 64%; and the proportion of COVID-19-related deaths decreased by 76%.
However, studies have also shown that the fourth version of the old vaccine in version 1.0 does not have much preventive effect against infections and onset of the Ami kerong variant. On March 17, a study by the Israeli Sheba Medical Center showed that 270 of the 600 volunteers received the fourth dose of the Pfizer/Modena vaccine, but the effect was not obvious, and the levels of antibodies and neutralizing antibodies in the people received the fourth dose were not higher than the levels they measured a month after the third dose, but were basically flat.
In the face of this situation, What China needs to do is to get a third injection. China's vaccination coverage rate is more than 90%, and the full vaccination rate is more than 87%, but the vaccination rate of the third booster immunization should be further improved. Therefore, while waiting for the 2.0 version of the new crown vaccine, it is best to continue to receive a third dose of the old vaccine, which has a protective effect on people and at least reduces morbidity, severe illness and case fatality.