The new crown vaccine is one of the "key hands" in the fight against the epidemic, and it has been proved that the new crown vaccine that has been listed has a very prominent role in preventing severe disease and death, but there are still deficiencies in curbing breakthrough infection.
According to a recent press release issued by the HKSAR Government, about 88.3% of the 5,435 deaths in the fifth wave of the epidemic have not received two doses of COVID-19 vaccine. The mortality rate for patients who had received at least two doses of COVID-19 vaccine was 0.09%, compared with 0.7% and 2.58% for those who had received one dose or no dose, respectively, showing that vaccination definitely helped to reduce mortality. First Finance also previously reported that according to the latest research data from Hong Kong, the effectiveness of the three needles Kexing or Fubitai in preventing severe diseases and preventing death is more than 97%.
At present, various vaccines are not omnipotent in dealing with the new crown virus, but if there is no vaccine, it is still impossible.
The new crown virus has mutated to the Omikejung strain, can the vaccine finally completely interrupt the transmission? If the answer is yes, how far is it to develop a vaccine that can completely block the new crown virus?
Vaccines hold the most important line of defense
The highly contagious Aomi Kerong variant has spread to 28 provinces across the country since it first appeared in Tianjin in January this year. Since March, the cumulative number of local infected people has exceeded 70,000, and there are more than 600 medium and high-risk areas. But unlike before, this wave of outbreaks is more asymptomatic or mild.
At a recent press conference held by the joint prevention and control mechanism of the State Council, Wu Zunyou, chief expert of epidemiology at the Chinese Center for Disease Control and Prevention, said that a year ago, everyone was not immune to the new crown virus, and now ninety percent of people have obtained certain immunity through vaccination.
As of March 24, more than 1.24 billion people have been vaccinated against COVID-19, accounting for nearly 90% of the total population. At present, in the areas affected by the Ami kerong variant, asymptomatic and mild diseases are the majority. According to Jiao Yahui, director of the Medical Administration Bureau of the National Health and Health Commission, from the perspective of the condition of the infected people in this round of epidemic, mild and asymptomatic accounted for more than 95%, and some of them were more serious due to advanced age, underlying diseases or no vaccination, and the proportion of severe diseases including severe and critical diseases was less than 0.1%. Existing studies have shown that the Omikejong variant does not completely escape existing vaccines. That said, existing vaccines are still effective against the Opmi kerong variant.
Jiang Shibo, director of the Institute of Pathogenic Microbiology of Fudan University, told the first financial reporter that the working principle of the vaccine is that by injecting antigens with viral labels into the human body, the body's immune system can recognize the virus antigen and establish a specific immune response to the virus. Even if the virus is not completely eliminated, severe illness or death due to excessive inflammatory response is reduced.
On October 5, 2021, workers packed the locally filled COVID-19 vaccine produced by China Kexing at the Fa Ma Company bottling plant on the outskirts of Kuala Lumpur, Malaysia. Xinhua
Zhang Lunan, executive director and vice chairman of the board of directors of Aidi Weixin Biology, told the first financial reporter that vaccines can play three levels of protection, the first level represents the highest level of protection, can play a role in blocking the spread of the virus, or no longer detoxification after infection; the second level can play a preventive effect, such as no fever and cough and other symptoms, that is, the so-called "asymptomatic infection"; the third level can prevent severe illness and death, but there is no clear boundary between these three levels. As for what kind of disease, which vaccine level corresponds to, it also varies.
From the current point of view, among the vaccines that have been listed, whether it is mRNA vaccines, inactivated vaccines, recombinant protein vaccines, adenovirus vector vaccines, etc., at the highest level, that is, in the prevention of infection, they have "failed". What is the reason why vaccines with 50% infection prevention ability in the original clinical use data are "weak" in the face of the Ami Kerong mutant strain?
Jiang Shibo believes that the average time to successfully develop an antiviral vaccine in the past is 30 years, but the development of more than a dozen new coronavirus vaccines on the market this time has only taken more than a year, because the coronavirus has a fatal vaccine target - the receptor binding domain (RBD), which contains the main neutralizing antibody site. Any antigen containing coronavirus RBD (e.g., viral particles, S proteins, S1 subunits, RBD fragments) can induce a certain level of neutralizing antibody response and a protection rate greater than 50% against infection of the original strain in humans and animals. The disadvantage of the first generation of new crown vaccines is that the neutralizing antibody titer they induce in humans is generally low (tens to hundreds), the cross-neutralizing antibody titer contained in it against the variant strain is lower (a few to dozens), and the decay rate of the new coronavirus neutralizing antibody is very fast, which can be reduced to less than 1/4 of the original every six months.
"Most of the first generation of COVID-19 vaccines chose S protein or virus particles as vaccine antigens, but the neutralizing antibody sites of RBD cannot be fully exposed in these vaccine antigens, and they cannot induce highly effective neutralizing antibodies and cross-neutralizing antibodies in humans, which is a common disadvantage of the first generation of COVID-19 vaccines." Jiang Shibo said.
The attenuation of antibodies to the new crown vaccine has been scientifically confirmed. At the state council joint prevention and control press conference on October 24, 2021, Wang Huaqing, chief expert of the immunization program of the Chinese Center for Disease Control and Prevention, said that according to the current research results at home and abroad, with the passage of vaccination time, some people's neutralizing antibody levels are declining, and the protective effect is weakening. In this case, boosting immunity can raise antibody levels.
However, Jiang Shibo said that how high the titer of neutralizing antibodies should be to prevent the infection of the new crown virus, there is no clear conclusion. "Some published papers have proved that the load of the new crown virus in the upper and lower respiratory tract is inversely proportional to the titer of neutralizing antibodies in the blood of infected people, and the higher the titer of neutralizing antibodies, the lower the viral load. When the titer of neutralizing antibodies in the blood is around 300, the load of the new crown virus in the upper and lower respiratory tract drops by 90%. Therefore, I personally believe that when the antibody production peaks after the vaccine injection, the titer of the neutralizing antibody should be above 1000, so that after half a year, even if it is reduced to 1/4 of the original, the titer of the neutralizing antibody can remain at about 250. ”
"The weakening of the vaccine's role in preventing infection is related not only to the amount of neutralizing antibodies, but also to viral variation. In the protective effect of vaccines, neutralizing antibodies are present in body fluids, when the virus enters the human body, the first to clear the virus is the neutralizing antibody, which is also a vaccine protection indicator that is relatively easy to quantify. However, the neutralizing antibodies of all vaccines will decay over time, but the half-life of the new crown vaccine is shorter, such as the half-life of the measles vaccine antibody can reach more than 3,000 years, the hepatitis A inactivated vaccine antibody can last for more than 30 years, and the new crown vaccine begins to decline at 6 months, which is one of the reasons for the weakening of the role of infection prevention. A virology professional said that the second is that the vaccine also has to face a constantly mutating virus, and the vaccine that has been listed is based on the original strain, and the preventive effect is weakened in anticipation. But thankfully, the vaccines currently on the market still have a strong anti-severe and fatal effect.
Zhang Lunan also believes that the frequent mutation of the new crown virus poses a challenge to the protective efficacy of vaccines. Every time the new coronavirus mutates, it may cause immune escape problems, because the morphological structure of the virus will change, making it difficult to effectively capture the immune response induced by the original vaccine target.
On February 8, in Rome, Italy, medical staff helped an elderly man to get a COVID-19 vaccine. On the same day, some regions of Italy began to vaccinate the elderly aged 80 and above with the new crown vaccine. Xinhua
A second-generation vaccine in full swing
The first generation of COVID-19 vaccines has completed the task of reducing severe illness and death, how to further explore the role of vaccines in preventing infection in the future?
Since the Emergence of the Omikejong variant in South Africa in November 2021, the global prevention and control alarm has sounded, and many scientific research teams have been involved in the research and development of a second-generation COVID-19 vaccine.
Recently, Zheng Zhongwei, head of the vaccine research and development special class of the scientific research group and director of the Science and Technology Development Center of the National Health Commission, said that from the beginning of the Emergence of the Aomi Kerong variant, the mainland's vaccine research and development team has taken action.
According to Zheng Zhongwei, so far, the progress is relatively fast, and the research and development of vaccines for the unit valent and multivalent of the Opichron variant strain has made positive progress, and the rapid progress has completed the preclinical research, and the declaration materials for clinical trials are being submitted to the national drug regulatory department on a rolling basis. In terms of inactivated vaccines, the research and development of the unit price, as well as the Delta + Omicron bivalent, as well as the prototype strain + Delta + Omicron trivalent vaccine, has basically completed the preclinical research and has been manufactured. In terms of recombinant protein vaccines, there are also research and development of alpha + beta + delta + Omicron quadrivalent vaccines, and are applying for overseas clinical trials. In addition, adenovirus vector vaccines have also been optimized for vaccine strain preparation, and preclinical studies are being carried out. The mRNA vaccine is also actively promoting some preclinical research work. In addition, some of the previous vaccines, in the process of the phase III clinical sequential research currently promoted overseas, have also obtained some protective data for the Omiljung variant.
In February this year, Healthyuan (600380.SH) announced that the "recombinant novel coronavirus fusion protein vaccine" (i.e. "V-01") developed by its indirect holding subsidiary Livzumab has completed the interim master data analysis of the sequential enhancement phase III clinical trial, and obtained key data, and has submitted a listing application for V-01 as a sequential reinforcement needle for the new crown vaccine to the Chinese review department, and the listing declaration to other countries is also in progress.
At that time, Jin Fang, chief scientist of Jiankangyuan Pharmaceutical Group, told the first financial reporter that the V-01 sequential strengthening phase III clinical trial protocol was the world's first randomized, double-blind Phase III clinical trial to strengthen the protection of the Omicron research sequence. This clinical trial adopts a relatively protective and effective standard, and unlike the traditional blank placebo regimen control, the clinical trial obtained 61.35% of the absolute protective power data, which is based on the protective efficacy of inactivated vaccines and the data generated under the Aomi Kerong epidemic, which also meets the WHO standard.
Liu Peicheng, spokesman of Kexing Holding Biotechnology Co., Ltd., told the first financial reporter, "Regarding the research on the new crown unit-valent bivalent and trivalent vaccines, we are advancing, and more research data are yet to be released, and the new crown multivalent inactivated vaccine plan will begin to submit declaration materials on a rolling basis in the near future." ”
"In order to cope with the virus mutation, everyone is developing a new generation of vaccines, the overall is divided into two ways, one is to specifically develop a vaccine against the Omikejung variant; the other is to develop a broad-spectrum vaccine for the new crown virus that is not easy to mutate, and when the virus mutates again next time, the effectiveness of the vaccine can be maintained, and we are more inclined to develop a broad-spectrum vaccine." Zhang Lunan said.
Block the direction of vaccine development for infection
The new COVID-19 vaccine battle has been launched, which route and which technology platform will give birth to a vaccine that can block transmission? What are the future vaccine blockers?
The most popular at the moment are specific strain vaccines, polyvalent vaccines and broad-spectrum vaccines.
First of all, broad-spectrum vaccines have become an important direction of current scientists' research, and it is also a vaccine research and development direction proposed by the WHO.
On August 18, 2021, Linfa Wang, an emerging disease specialist at the Duke-Nugget University of Singapore School of Medicine, singapore, published a paper in the New England Journal of Medicine, "Pan-Sarbecovirus Neutralizing Antibodies in BNT162b2-Immunized SARS-CoV-1 Survivors", reporting the findings of a new study in patients who have been infected with SARS, After vaccination against COVID-19, antibodies can be produced against all variants of the new coronavirus that currently exist. The report argues that this finding demonstrates the viability of a pan-coronavirus vaccine strategy.
In Jiang Shibo's view, broad-spectrum vaccines can be divided into small broad spectrum, medium broad spectrum, large broad spectrum and ultra-broad spectrum. Among them, small broad-spectrum vaccines are mainly vaccines developed against the new crown virus and its variants.
Medium-wide spectrum vaccine, aimed at the vaccine developed by the β coronavirus B-lineage virus (i.e., sarbecovirus), can neutralize the infection of SARS-CoV, bat SARS-associated coronavirus (SARSr-CoV), new coronavirus (SARS-CoV-2) and its variant strains, which is also a vaccine that needs to be urgently developed and can be used to prevent and control current and future new and reproduced SARS-like infectious diseases.
The Broad-Spectrum Vaccine, developed for all β coronaviruses, can both prevent infection with the currently circulating strain of the new coronavirus (Omi kerong) and MERS-CoV infection circulating in the Middle East, as well as possible future new variants of the β coronavirus , SARS-CoV-3 or MERS-CoV-2.
Ultra-broad-spectrum vaccines, vaccines for all 7 human coronavirus types. Jiang Shibo said that the development of ultra-broad-spectrum vaccines is extremely difficult because they use different receptors, and the amino acid sequences and structures of the receptor-binding domain (RBD) of their spike (S) proteins are also very different.
Jiang Shibo said that the development routes of the new crown vaccine of different technology platforms have different strategies for developing a broad spectrum. The technical route of recombinant subunit vaccines is best suited for the development of broad-spectrum vaccines, as it is easier to change the design of vaccine antigens and the selection of highly effective immune adjuvants. If the inactivated virus technology route is used, it is not easy to directly modify the viral antigen, and if it is to become broad-spectrum, it may be possible to choose different variants of inactivated viruses to be used in combination to develop a multivalent vaccine. The technical route of mRNA vaccines and adenovirus vector vaccines can also improve immune response and broad spectrum by moderately changing vaccine antigens or adding intramolecular immune adjuvants. In addition, viral antigens from different variants or different variants can be made into multivalent vaccines to improve their broad spectrum.
But what is the protective effect of broad-spectrum vaccines of different lines, and what are the reasons for the emergence of covid-19 vaccines that affect the transmission of transmission?
"The high efficacy of the COVID-19 vaccine determines its long-term efficacy and broad spectrum. Because the neutralizing antibody level is high enough, the cross-neutralizing antibody titer contained in it against the mutant strain will also increase accordingly, and even if the neutralizing antibody drops several times after half a year, it still maintains a certain height, so as to achieve long-term and broad-spectrum purposes, which plays the role of 'constant response to change'. Jiang Shibo said that in order to make the vaccine antigen induce a higher level of neutralizing antibodies, choosing a highly effective vaccine adjuvant is also key, but the development of a new adjuvant that can be used in the human body is very challenging, because the requirements for its safety are very high.
Zhang Lunan believes that absolute standards have not yet been established for the relationship between antibody levels, cellular immunity levels and the preventive efficacy of the new crown vaccine. "If there are absolute indicators, the road to vaccine development will be smoother." It is precisely because of the lack of relevant standards that the current development of the new crown vaccine requires large-scale phase III clinical trials, which must be judged by effectiveness indicators, which not only greatly increases the difficulty of vaccine development, but also increases the cost of development. ”
However, people still expect that a vaccine that can interrupt transmission will emerge, and only then will it be possible for humans to end the virus, otherwise humans will need to consider coexisting with it.