Original title: How the new crown vaccine is "upgraded"

  The new coronavirus has been mutating since its emergence, bringing many new challenges to people.

For the new coronavirus variant, various researches on the upgrade of the new crown vaccine have also been in full swing.

  On May 1, the sequential immunization clinical study of the inactivated vaccine against the new coronavirus of the Omicron variant developed by Sinopharm China Bio-Beijing Institute of Biological Products was officially launched in Hangzhou, Zhejiang.

After the volunteers went through relevant testing, informed consent, basic physical examination, blood sampling and other links, they were vaccinated with the Austrian strain of new crown inactivated vaccine at Shulan (Hangzhou) Hospital.

This is the world's first inactivated vaccine against the new coronavirus that has entered clinical trials against the Omicron variant.

Viruses mutate, so can vaccines

  No matter how many technical routes there are in the development of vaccines, they all use the new coronavirus as an antigen, some use an inactivated new coronavirus as an antigen, and some use a certain part of the new coronavirus, such as a part of the shell, envelope, or part of a special part , such as dozens of receptor-binding domains on the new coronavirus spike protein as antigens.

  The spike protein is an important structure for the combination of the new coronavirus and human (host) cells. The gene mutation of the spike protein 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 neutralization. More and less antibodies are produced.

  Now, the mutation of the new coronavirus is mainly a variety of changes in the receptor binding domain on the spike protein.

At present, the main pathogen causing the new crown epidemic in the world is the branch BA.2 of the Omicron variant, which has more than 50 amino acid mutations, 29 of which are present on the spike protein.

  Vaccine research uses the virus and some components of the virus (such as some mutations on the spike protein) as the antigen. If the virus has changed, the changed virus must be used as the original. After such vaccination, the human immune system can be stimulated Identify mutated viruses and produce sufficient amounts of neutralizing antibodies to prevent the virus from invading human cells.

  When the virus mutates, the vaccine can only be developed using the inactivated whole virus as the antigen or the mutated amino acid on the spike protein as the antigen.

This situation is a bit like the annual flu vaccine, because the main antigens on the envelope of the influenza virus, hemagglutinin and neuraminidase, change, and there are dozens of combinations of these two antigens. Reinvent the vaccine.

In the future, the changeable new coronavirus will also prompt people to frequently develop different vaccines to deal with the epidemic caused by the mutated virus.

The technical route of research and development of Austrian strain vaccine in my country

  The old vaccine is a vaccine developed with the original strain of the new coronavirus as the antigen.

Therefore, the old vaccines can be collectively referred to as version 1.0, and the new vaccines are developed using mutated viruses as antigens, which can be collectively referred to as version 2.0.

  There are many mutated strains of the new coronavirus, and now the infection and disease are mainly caused by the Omicron variant. Therefore, the vaccine developed with the Omicron variant as the antigen, that is, the Omicron vaccine, has become the representative of the new vaccine.

  The five technical routes of vaccines can produce different vaccines. There are these five types of vaccines in version 1.0, and the upcoming version 2.0 will also have these five types of vaccines.

They are: inactivated vaccine, adenovirus vector vaccine, recombinant protein vaccine, attenuated influenza virus vector vaccine and nucleic acid vaccine.

  In the past, my country used the original strain of the new coronavirus as the antigen to develop vaccines, and the most produced inactivated vaccines, including the inactivated vaccines developed by Sinopharm China Bio-Beijing Biological Products Research Institute and the inactivated vaccines of Beijing Kexing Zhongwei Biotechnology Co., Ltd. Vaccines are referred to as Sinopharm Vaccines and Kexing Vaccines for short.

At present, the 2.0 new vaccine Austrian strain vaccine developed in my country is also mainly inactivated vaccine, that is, the inactivated Omicron whole virus is used as the antigen.

  On April 26, the State Drug Administration of China officially approved the inactivated vaccine of the new coronavirus developed by Sinovac and Sinopharm Group based on the Omicron variant to enter clinical research to evaluate the effectiveness of the new coronavirus variant vaccine in various countries. Safety and immunogenicity in human populations.

This is the world's first inactivated Omicron strain vaccine approved for clinical use.

  After a vaccine has been tested on animals, it must also undergo Phase 1-3 clinical trials in humans before it can be officially approved for disease prevention and treatment.

Previous results of animal tests have shown that the inactivated vaccine of Kexing Omicron variant is safe and effective.

At the same time, Sinopharm Group China Bio used the newly built P3 high-level biosafety laboratory to complete the screening, passage, and expansion of Austrian strains, established a three-level virus library, and completed process validation and multiple batches of large-scale production. Product preparation, quality standard research, animal in vivo safety evaluation and immunogenicity research.

The results show that Sinopharm's Austro-strain new crown inactivated vaccine can produce high-titer neutralizing antibodies against Austro-strain and various variant strains.

  After approval, both Sinobiology and Sinovac will use a randomized, double-blind, cohort study to conduct immunization clinical studies in people aged 18 and over who have completed 2 or 3 doses of the new crown vaccine to evaluate the Austrian Safety and immunogenicity of inactivated vaccines against 2019-nCoV with Mikron variant strains.

  At the same time, there is also a recombinant protein vaccine route in the research and development of my country's 2.0 new vaccine Austrian strain vaccine.

The recombinant protein new crown vaccine is to biologically analyze and calculate the natural structural characteristics of the receptor binding domain of the spike protein of the Omicron variant, and use genetic engineering technology to recombine the antigen protein of the virus as an antigen to produce the vaccine. It can induce the body to produce neutralizing antibodies against the Omicron variant, blocking the combination of the virus with human cells.

The 2.0 recombinant protein vaccine currently developed in China is based on the first-generation recombinant new crown vaccine, through the computational analysis of the evolution law and immune escape ability of the mutation site of the Omicron epidemic strain, designed and developed the second-generation broad-spectrum vaccine Corona vaccine.

  On April 26, the China National Medical Products Administration also approved the Austrian strain recombinant new crown vaccine developed by Sinopharm Biotechnology Research Institute/National Engineering Research Center for New Vaccines to enter clinical trials.

Therefore, there are three types of Austrian strain vaccines of version 2.0 in China, including two inactivated vaccines and one recombinant vaccine.

New vaccines for different variants are in development

  The mutant strain of the new coronavirus is not only one of Omicron, but the future version 2.0 new vaccine will also have multiple vaccines for different mutant strains.

  The World Health Organization's New Coronavirus Evolution Technical Advisory Group classifies mutant viruses into three categories: concern variants, concern variants, and severe consequences variants.

At present, the World Health Organization believes that the serious consequence variant has not yet appeared, and it is necessary to focus on monitoring the variant of concern. There are 5 variants, namely: the alpha variant discovered in the United Kingdom in December 2020; the beta discovered in South Africa in December 2020. Variant; Gamma variant discovered in Brazil in January 2021; Delta variant discovered in India at the end of 2020; Omicron variant discovered in southern Africa at the end of 2021.

  As early as 2021, when the delta variant was prevalent, 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, and Beijing with a high number of epidemics.

Through three consecutive generations of cloning and purification, the selection and identification of vaccine strains and the establishment of a tertiary seed bank have been preliminarily completed, and preparations have been made for large-scale production from the laboratory to the production workshop.

  It was only later that the epidemic mutated, and Omicron became the main variant that spread faster and more widely, and caused the global epidemic. Therefore, the focus of the research and development of the 2.0 vaccine shifted to the Ostrain vaccine, and the Delta vaccine pressed the pause button.

However, this does not mean that new vaccines for other mutant strains 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 against different variants of the new coronavirus, and have also carried out research and development of adenovirus vector vaccines and nucleic acid vaccines for beta and delta strains , some scientific research units have completed animal efficacy and safety experiments.

  These works are actually preparing for the future. Once the new coronavirus variant is transferred from Omicron to other variant strains, or new variant strains are generated, we can be prepared and quickly start the research on new vaccines for different variant strains, and carry out mass production.

Other countries are also developing new vaccines

  Other countries in the world are also developing 2.0 new vaccines against the new crown variant. Among them, the 2.0 new crown vaccine developed by the University of Washington School of Medicine in the United States has undergone clinical phase 3 trials.

  This vaccine, called GPB510, is a protein molecular vaccine, which is made of partial antigens, such as proteins, polysaccharides or peptides of pathogens, and can actually be classified as recombinant protein vaccines.

  In terms of mechanism of action and R&D route, GPB510 is composed of protein nanoparticles, which is a tiny protein sphere in appearance, and is covered with 60 new coronavirus spike protein receptor binding domains.

This protein-nanomolecule vaccine entered research and development at the end of 2020. Tests on animals found that the nanoparticle vaccine can produce high levels of virus-neutralizing antibodies at low doses, which can target multiple different sites of the coronavirus spike protein. It produces immunostimulatory effects and produces antibodies, and thus has a resistance to the new coronavirus variant.

  The principle that the GPB510 vaccine can stimulate the body's immune system to produce antibodies to the new coronavirus variant is that this vaccine uses a variety of antigenic components of the new coronavirus, that is, dozens of receptor binding domains on the spike protein.

These protein molecules in the receptor binding domain of the new coronavirus spike protein can stimulate immune cells in the body to produce neutralizing antibodies and remember these mutant 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 this year, a multi-country Phase 3 clinical trial was conducted on 4037 adults over 18 years old and compared the effect of the Oxford/AstraZeneca vaccine Vaxzevria (adenovirus vector vaccine) (the research method was that one group was given GPB510, and the control group was given GPB510. The group was given Vaxzevria twice, 4 weeks apart), and it was found that GPB510 produced higher levels of protective antibodies than Vaxzevria.

Does the new vaccine still work in the development of the old vaccine?

  New research shows that old vaccines work despite the mutated new coronavirus.

On January 4, 2022, Israel launched the fourth Covid-19 vaccination program for high-risk groups, including the elderly over the age of 60 and immunocompromised people. The injected vaccine is the Pfizer BN162b2 vaccine.

  On April 13, Israeli researchers published a study on the fourth dose of the vaccine in the New England Journal of Medicine (NEJM), showing that the fourth dose of the new crown vaccine (the old vaccine) was administered during the Omicron epidemic period. ), the ability to resist the virus is significantly stronger than that of peers who have only been vaccinated with three shots.

  The data for this study came from 258,994 vaccinated people from January 3 to February 18, 2022. The researchers compared two groups of people who received four doses and only three doses. The two groups participated in the test. The average age of the personnel is 72 years old.

  Older adults who received a fourth dose of the vaccine had some of the following benefits compared to those who received only three doses.

In the 7- to 30-day period after vaccination: 45% reduction in Covid-19 positivity; 55% reduction in symptomatic infections; 68% reduction in Covid-19-related hospitalizations; 62% reduction in severe cases; Covid-19-related deaths rate fell by 74%.

  In the 14- to 30-day period after vaccination: 52% reduction in Covid-19 positivity; 61% reduction in symptomatic infection; 72% reduction in Covid-related hospitalizations; 64% reduction in severe illness rates; Covid-19-related deaths rate fell by 76%.

  However, some studies have also shown that the fourth version of the old vaccine version 1.0 does not have much preventive effect on infection and disease caused by the mutant strain of Omicron.

On March 17, the results of a study at the Sheba Medical Center in Israel showed that 270 of the 600 volunteers received the fourth dose of the Pfizer/Modena vaccine, but the effect was not obvious. Those who received the fourth dose The levels of antibodies and neutralizing antibodies in the body were not higher than those measured one month after the third injection, but were basically the same.

  Faced with this situation, what China needs to do is to get the third shot.

The vaccination coverage rate in China exceeds 90%, and the whole-course vaccination rate exceeds 87%, but the vaccination rate of the third booster immunization should be further increased.

Therefore, in the process of waiting for the 2.0 version of the new crown vaccine, it is best to continue to receive the third dose of the old vaccine, which has a protective effect on people and can at least reduce the morbidity, severe and fatality rates.

(Zhang Tiankan)

Keywords: