The new crown war "epidemic" has entered its third year, the global epidemic is still spreading, and many countries in the world are facing severe challenges in epidemic prevention and control.
As of now, the cumulative number of confirmed cases of COVID-19 in the world has exceeded 500 million, which is only three months after the 300 million cases in early January. In addition, from March 1 to April 18, 31 provinces (autonomous regions and municipalities directly under the Central Government) and the Xinjiang Production and Construction Corps reported a cumulative total of 497214 cases of indigenous infection, affecting all provinces except the Tibet Autonomous Region.
Under the continuous mutation and continuous ravages of the new crown virus, the global pandemic has not yet ushered in an "inflection point". In this situation, vaccines, as the first line of defense against the new crown virus, are still the most effective means for human beings to cope with the crisis.
According to data from the National Health Commission, as of April 23, 2022, 31 provinces (autonomous regions and municipalities directly under the Central Government) and the Xinjiang Production and Construction Corps have reported a cumulative total of 3,329.766 million doses of covid-19 vaccine. According to the statistics of Oxford University Our World in Data, as of 16:00 London time on April 21 (23:00 Beijing time on April 21), the global cumulative number of vaccinations against the new crown virus has been reported 11.49 billion doses, and 65% of the world's population has received at least one dose of the new crown vaccine.
However, the completion of the full vaccination is no longer enough to build a solid immune barrier, and vaccination has become one of the most effective and feasible ways to effectively reduce the severe and mortality of the new crown in the world at this stage. On April 21, at the 2022 annual meeting of the Boao Forum for Asia, Zheng Zhongwei, head of the vaccine research and development working group of the joint prevention and control mechanism of the State Council, also pointed out that with the evolution of the epidemic, more than two years of practice have proved that two injections are not enough to achieve the best protective effect, and a third injection is imperative.
As early as last October, the mainland launched the new crown vaccine booster vaccination (homologous enhanced immunization), and then in February this year, the National Health Commission began to deploy a sequential booster of immunization (commonly known as "mixed beating").
On February 19, the joint prevention and control mechanism of the State Council announced at a press conference that the target population over the age of 18 who have been vaccinated with the inactivated vaccine of Sinopharm Zhongsheng Beijing Company, Wuhan Company and Beijing Kexing Company, and the adenovirus vector vaccine of Tianjin CanSino Company for 6 months can be upgraded with a dose of homologous enhancement, that is, strengthened with the original vaccine. After the implementation of the sequential enhanced immunization strategy, the target population who has completed the full vaccination of the above three inactivated vaccines can also choose the recombinant protein vaccine of Zhifeilong Koma or the adenovirus vector vaccine of Cansino for sequential enhanced immunization.
According to the National Health Commission, as of April 18, the country has reported a total of 3.317463 million doses of covid-19 vaccines, the total number of vaccinated people is 1.282.12 million, and 1.246769 million people have been vaccinated, covering 90.94% and 88.43% of the total population of the country, respectively. 732.659 million people were immunized intensively, of which 25.426 million were continuously immunized. The vaccination of the elderly over the age of 60 has reached 225.521 million, and the whole process of vaccination has reached 213.938 million, and the number of people covered and the number of people vaccinated throughout the whole process account for 85.41% and 81.03% of the elderly population, respectively. Immunization enhancements have been completed for 154.874 million people.
It can be seen from the data that the overall COVID-19 vaccination rate of the elderly in the mainland is currently low. This has also brought development opportunities for subsequent domestic vaccine companies, especially those approved to strengthen vaccines in an orderly manner. However, with the gradual end of the competition for the first half of the new crown vaccine, despite the huge demand for domestic vaccination, due to the late entry of the "latecomers", most of their new crown vaccines are still in the clinical trial stage, and the situation of the sequential strengthening of the second half is still unknown.
Produced | 21st Century New Health Research Institute
Written by| Zhu Ping, senior researcher of the 21st Century New Health Research Institute, intern Hu Bingyue, Ouyang Xinyue, Li Wenhan
Editor| Xu Xu
Designed | Xu Hui
Part I: The epidemic situation at home and abroad is severe and complex
At present, the global epidemic situation is still grim, a new round of epidemic has struck many countries, and new confirmed cases in various countries continue to occur.
According to Worldometer real-time statistics, as of about 6:30 Beijing time on April 22, 2022, the cumulative number of confirmed covid-19 cases in the United States 82532355, and the cumulative number of deaths 1017449; compared with the data at about 6:30 a.m. the previous day, there were 91,023 new confirmed cases and 1,108 new deaths in the United States.
In addition, according to public reports, since April, some US government officials and members of Congress have been diagnosed one after another. On April 11, local time, Us. Rep. Rashida Tlaib of Michigan announced that he tested positive for new crown pneumonia and is currently in home isolation after being confirmed. On April 10, the New York City government issued a statement saying that New York Mayor Adams tested positive for the new crown virus on the same day, has no other symptoms, has been quarantined and will cancel public activities. On April 9, U.S. Secretary of Agriculture Tom Vilsack said he tested positive for COVID-19, becoming another U.S. minister diagnosed with COVID-19. On April 7, U.S. House speaker Pelosi tested positive for COVID-19. On April 6, U.S. Commerce Secretary Raimondo and Attorney General Garland were confirmed to be infected with the new crown virus.
Xinhua News Agency analyzed in the report on April 11 that recently, the new crown epidemic in the United States seems to be in the platform period, but epidemiologists said that factors such as incomplete epidemic statistics may seriously underestimate indicators such as the number of confirmed cases in the United States, so that the upward trend of the epidemic is "covered up". With the advent of holidays such as Easter and Spring Break in the United States, gatherings have increased, the spread of the virus may accelerate, and the epidemic in the United States may rise again.
On April 21, local time, the latest statistics released by the Italian Ministry of Health show that in the past 24 hours, there were 75,020 new confirmed cases of new coronary pneumonia in the country, with a cumulative 15934437 confirmed cases; 166 new deaths, 162264 cumulative deaths; 59,916 new cured cases, 14549360 cumulative cured cases; 1222813 existing confirmed cases.
Xinhua news agency reported that on March 31, Italy ended the emergency caused by the new crown epidemic and relaxed epidemic prevention measures from April 1. People no longer need to show a COVID-19 "green pass" when entering places such as banks, shops, post offices, outdoor areas of restaurants, or taking public transportation in the city.
According to the data released by the French public health department on April 21, local time, as of the afternoon of the same day, the cumulative number of confirmed cases of new coronary pneumonia in France reached 28076047, and 104007 new cases were added in 24 hours. The cumulative number of deaths reached 144799, and 167 new cases were added in 24 hours. French Health Minister Olivier Veyland said in an interview with the media on April 7 that France has crossed the peak of the rebound of the epidemic. But france's public health agency then called for caution, saying the coronavirus was still spreading and that the peak of the rebound could not be said to have passed.
In addition, according to the South Korean Central Epidemic Prevention Countermeasures Headquarters, as of 0:00 on April 21, South Korea had 90,867 new confirmed cases of infection with the new coronavirus at 0:00 on the previous day, a decrease of 20,452 cases of confirmed cases in a single day, and 147 new deaths; the cumulative number of confirmed 16674045 cases, the cumulative number of deaths was 21,667, and the average fatality rate was 0.13%.
According to South Korean media reports, the South Korean Department of Disease Control said on April 19 that south Korea found two cases of infection with the new coronavirus recombinant strain XE for the first time, and one case of XM infection. The South Korean DEPARTMENT of Disease Control and Prevention said that the WHO classified both XE and XM as Ami kerong strains, and the characteristics were not much different from the original Omi kerong strain BA.1. In view of the fact that there is no information on its spread and severe illness rate, the epidemic prevention department will strengthen the monitoring of the mutant strain.
South Korea's CDC said on April 12 that the first confirmed case of infection with the new coronavirus recombinant strain XL was found in China, and epidemiological investigation is underway. According to the report, the XL strain is one of the 17 recombinant strains (XA~XS) discovered so far, which are recombinant from the original strain BA.1 and subtype BA.2 of the "Omiljung". However, there is no information on the characteristics of XL strain transmission, which has only been found in the UK.
According to overseas network news, South Korean Prime Minister Kim Fu-kyun announced on April 15 that from April 18, the restriction on maintaining social distancing will be lifted completely, and the epidemic prevention measures of compulsory wearing masks indoors will remain. It is understood that the country's social distancing epidemic prevention measures have been implemented since March 2020, and it has been two years and another month. In addition, since April 18, in South Korea, private gatherings and large-scale event gatherings are no longer limited by the number of people, high-risk business sites can be opened 24 hours a day, and religious facilities are no longer restricted. This means that South Korea has chosen to "lie flat" in the context of the severe epidemic prevention and control situation.
According to the latest statistics released by the Robert Koch Institute of the German Federal Agency for Disease Control and Prevention, as of 00:00 local time on April 21, the cumulative number of confirmed cases of new coronary pneumonia in Germany reached 23844536, an increase of 186325 cases over the previous day; the cumulative number of deaths 133632, an increase of 324 cases over the previous day.
According to CCTV news, Agence France-Presse reported on April 21 that a German Finance Ministry official said that German Finance Minister Christian Lindner, who was attending the spring meetings of the International Monetary Fund and the World Bank in Washington, D.C., tested positive for the new crown virus. Lindner confirmed the news on social media that day.
On April 8, local time, German Health Minister Lauterbach said that after lawmakers vetoed the proposed fourth dose of vaccine task, Germany may need to re-implement the requirement to wear masks in public this fall. Lauterbach noted that the previous proposal to end mandatory quarantine was aimed at reducing the burden on health authorities and sent the wrong signal for that. But the pandemic hasn't passed, and "we still have more than 300 deaths every day," Lauterbach stressed at a news conference.
At present, The country is also suffering from the impact of a new round of epidemics, and sporadic local epidemics continue to appear across the country, and the number of single-day new crown infection cases is still at a high level.
At the press conference of the joint prevention and control mechanism of the State Council on April 19, according to Wu Liangyou, deputy director of the Disease Control Bureau of the National Health and Health Commission, from March 1 to April 18, 31 provinces (autonomous regions and municipalities directly under the central government) and the Xinjiang Production and Construction Corps reported a cumulative 497214 cases of local infection, affecting all provinces except the Tibet Autonomous Region. Recently, the national epidemic situation has gradually stabilized, but the impact of cross-input between regions is obvious, and the task of dynamically clearing zero in various places is very arduous. The epidemic situation in Hebei, Jiangsu, Zhejiang, Anhui, Guangdong, Fujian, Liaoning and other provinces generally tends to be stable. The epidemic situation in Jilin City, Jilin Province, has continued to improve and is in a downward trend, while the epidemic situation in Changchun City has shown a downward trend. The epidemic situation in Shanghai is still at a high level in recent days, the risk of community transmission is still high, the situation of prevention and control is still grim, and the task of prevention and control is still very arduous and urgent.
Since then, from April 19 to 22, the number of new local confirmed cases in China has exceeded 2,000 per day. From 0 to 24:00 on April 24, 31 provinces (autonomous regions and municipalities directly under the Central Government) and the Xinjiang Production and Construction Corps reported 2,680 new confirmed cases. Among them, there were 2666 local cases (2472 cases in Shanghai, 79 cases in Jilin, 26 cases in Heilongjiang, 14 cases in Beijing, 14 cases in Jiangxi, 13 cases in Zhejiang, 12 cases in Hunan, 9 cases in Inner Mongolia, 5 cases in Henan, 5 cases in Qinghai, 4 cases in Jiangsu, 3 cases in Liaoning, 3 cases in Guangdong, 2 cases in Shanxi, 2 cases in Shandong, 1 case in Tianjin, 1 case in Fujian, and 1 case in Sichuan), including 899 cases converted from asymptomatic infected people to confirmed cases (846 cases in Shanghai, 39 cases in Jilin, 12 cases in Zhejiang, 1 case in Fujian, and 1 case in Qinghai). There were 51 new deaths, all of which were local cases, in Shanghai; there were no new suspected cases.
The current round of the epidemic is fierce, and the first time that the number of new cases of new coronary pneumonia in Shanghai exceeded 10,000 in a single day was on April 4. On the same day, there were 13,354 new cases of local new coronary pneumonia infection in Shanghai, of which 268 new cases were confirmed and 13,086 new asymptomatic infected people were added.
Subsequently, the epidemic situation in Shanghai continued to operate at a high level. As of April 20, the cumulative number of infected people in this round of the epidemic in Shanghai exceeded 400,000. At the same time, as of 24:00 on April 23, Shanghai has reported a cumulative total of 87 deaths, with 160 cases of severe illness and 19 cases of critical illness. Subsequently, at 0-24:00 on April 24, there were 51 new local deaths in Shanghai. At present, the cumulative number of deaths in Shanghai in this round of the epidemic has exceeded 100.
In addition to Shanghai, Jilin, Heilongjiang and other places are also facing the challenge of epidemic prevention and control. At the beginning of March, a new round of epidemic broke out in Jilin Province after the beginning of 2022, and the new local confirmed cases in a single day went from single digits to breaking 100 to breaking 1,000. After nearly a month of hard work, the epidemic prevention and control work in Jilin Province has achieved phased results, and the production and living order of residents is gradually recovering.
According to the Jilin Health Commission, at 0-24:00 on April 21, there were 63 new locally confirmed cases in the province, including 53 cases in Changchun City, 5 cases in Jilin City, 4 cases in Yanbian Prefecture, and 1 case in Baicheng City; 244 new cases of local asymptomatic infection, including 211 cases in Changchun City, 14 cases in Yanbian Prefecture, 12 cases in Jilin City, 6 cases in Baicheng City, and 1 case in Songyuan City. On April 21, 873 new cured and discharged confirmed cases were added in the province, and 1,141 new asymptomatic infected people were released from isolation for medical observation.
At the press conference on the prevention and control of the epidemic in Jilin Province held on the morning of April 21, Geng Jianren, a member of the party group of the Jilin Provincial Health Commission, briefed on the overall work of epidemic prevention and control in the province: At present, the prevention and control of the new crown pneumonia epidemic in the province has achieved phased results, but the epidemic prevention and control situation is still grim, and it is still necessary to continue to adhere to the external prevention and rebound, adhere to the "dynamic clearance" without hesitation and wavering, pay close attention to various measures for epidemic prevention and control, and strictly abide by the bottom line of not rebounding on a large scale of the epidemic.
According to the official website of the Heilongjiang Provincial Health Commission, at 0-24:00 on April 21, there were 34 new local confirmed cases of new coronary pneumonia in the province (all in Harbin City), and 56 new cases of local asymptomatic infection (all in Harbin City). As of 24:00 on April 21, there were 304 locally confirmed cases and 224 locally asymptomatic infected people in the province; there were 1 confirmed case imported from abroad and 5 cases of asymptomatic infected people imported from abroad.
In the face of the recent situation of many local cluster epidemic points, wide coverage and frequent occurrences in the country, the mainland epidemic prevention and control adheres to the general policy of "dynamic zero clearance" without wavering.
On April 22, Liang Wannian, head of the expert group of the National Health Commission's Leading Group for Epidemic Response and Handling and executive vice dean of the Vanke School of Public Health and Health of Tsinghua University, stressed in an interview with the media that the costs and benefits of adhering to "dynamic zeroing" should be calculated as a big account, an overall account, and a dynamic account. Now the cost of "dynamic clearance", including new crown vaccines, nucleic acid testing, cabin construction, human resources and other inputs, is like buying an insurance to deal with risks. In the face of the risks posed by Omi kerong, this insurance on the mainland has benefited 1.4 billion Chinese, controlled the spread of the epidemic, and in fact bought insurance for 1.4 billion people, which is worth the investment.
Liang Wannian pointed out that the new crown epidemic far exceeds the flu in terms of transmission, pathogenicity, and case fatality. Citing real-world data from Hong Kong as an example, the average case fatality rate of the Omiljung strain in the Hong Kong population is about 0.75%, which is seven to eight times that of influenza. From the perspective of the elderly population, especially the elderly over 80 years old, its case fatality rate will be nearly a hundred times that of the common flu.
Another key factor is the COVID-19 vaccination rate for the elderly on the mainland. According to the data released by the National Health Commission, as of April 18, the number of people over 60 years old in the mainland was vaccinated, covering 225.521 million people, completing the whole process of vaccination 213.938 million, the number of coverage and the number of people vaccinated throughout the whole process accounted for 85.41% and 81.03% of the elderly population, respectively, and the enhanced immunization has completed 154.874 million people.
"The number of elderly people in the mainland is huge, and the current vaccination rate of the elderly population is relatively not high enough." Liang Wannian said that once the epidemic control is relaxed, its outcome can be seen very clearly, it must be widely spread by the virus, and the number of severe illness and death of the elderly population is huge. It was a huge disaster for a country. The emergence of a large number of severe diseases, in turn, runs the medical system, and as medical workers are infected, they will inevitably cause the needs of normal medical services to be not effectively met, which will form a vicious circle.
Part II: Sequential strengthening of immunization
"Recently, with the approval of the joint prevention and control mechanism of the State Council, the National Health Commission has begun to deploy a sequential strengthening of immunization." At a press conference on the joint prevention and control mechanism of the State Council held on February 19, Wu Liangyou, deputy director of the Disease Control Bureau of the National Health Commission, said.
For the concept of "sequential immunization", Wang Huaqing, chief expert of the immunization program of the Chinese Center for Disease Control and Prevention, explained that sequential immunization refers to a strategy for vaccination using vaccines with different technical routes, in order to improve the preventive effect or further reduce the risk of serious adverse reactions according to a certain time interval and a certain dose.
At the above-mentioned press conference, Wu Liangyou specifically introduced the two current domestic sequential immunization enhancement programs:
One is homologous booster immunization. Previously, the target population over the age of 18 who had been vaccinated with the inactivated vaccine of Sinopharm Zhongsheng Beijing Company, Wuhan Company, Beijing Kexing Company, and the adenovirus vector vaccine of Tianjin CanSino Company for 6 months could be activated with a dose of homologous enhanced immunity, that is, strengthened with the original vaccine. In addition, the joint prevention and control mechanism of the State Council also approved the homologous enhanced immunization of the new coronavirus inactivated vaccine of Shenzhen Kangtai Company and the Institute of Biology of the Medical Academy.
The second is heterologous enhanced immunization. After the implementation of the sequential enhanced immunization strategy, the target population who has completed the full vaccination of the above three inactivated vaccines can also choose the recombinant protein vaccine of Zhifeilong Koma or the adenovirus vector vaccine of Cansino for sequential enhanced immunization.
Wu Liangyou also pointed out that whether it is homologous strengthening or sequential strengthening, it is implemented in people over 18 years old who have completed the full vaccination for 6 months. For your target demographic, choose one of them. Research data show that homologous booster immunization and sequential booster immunity can further improve the immune effect.
In fact, this is not the first time that the mainland has carried out sequential immunization. Wang Huaqing pointed out at the press conference that the previous sequential immunization was mainly used in live attenuated polio vaccine (that is, "polio sugar pills"), and 4 doses were required throughout the process, the first two doses were inactivated trivalent polio vaccine, and the last two doses were given bivalent live attenuated vaccine.
"For viruses that are highly variable and difficult to deal with, sequential immunization is often used." For why it is necessary to promote the sequential strengthening of immunization at this time, Shao Yiming, a member of the expert group of the vaccine research and development special class of the scientific research group of the joint prevention and control mechanism of the State Council, explained that one is that different vaccines can complement each other's advantages, and the other is that different human physiques are different, which may produce more side effects on a certain type of vaccine, and the use of different technical routes for vaccination can avoid side effects.
Since the announcement of the sequential immunization deployment, there has been a lot of concern about which populations can undergo sequential enhanced immunization. Wang Huaqing said that the following conditions need to be met to strengthen immunization sequentially:
First, the target of vaccination is a person over 18 years old;
Second, the vaccinated population should complete 2 doses of inactivated vaccination, and these 2 doses are the inactivated vaccine of the new crown virus of Sinopharm Zhongsheng Beijing Company, Beijing Kexing Company and Sinopharm Zhongsheng Wuhan Company;
Third, the vaccination subject should complete 2 doses of vaccination throughout the whole process, and the interval between sequential enhancement immunization should not be less than 6 months;
Fourth, the vaccinated subjects had not undergone booster immunization prior to the sequential booster immunization, i.e., had not received a third dose.
In addition, Wang Huaqing also reminded that when vaccinating, it is necessary to do a good job of personal protection, truthfully reflect their health status to the vaccination doctor, and the vaccination doctor will judge whether there are contraindications and whether they need to be delayed; after vaccination, they should stay for 30 minutes, and when there is a suspicion of adverse reactions related to vaccination, such as a long duration and serious symptoms, one should report to the vaccination unit, and the other should seek medical treatment in time.
Since the introduction of the sequential immunization policy, Fujian, Shandong, Hunan, Henan, Chongqing, Chengdu, Xi'an and other places have launched the new crown vaccine sequentially to strengthen immunization. Prior to this time, there were similar deployments and implementations abroad. Wang Huaqing, chief expert of the immunization program of the Chinese Center for Disease Control and Prevention, pointed out that in some countries in the Americas, Europe and Southeast Asia, they have begun to implement a sequential strengthening of immunization.
It is reported that on October 20, 2021, the US Food and Drug Administration revised the emergency use authorization for the new crown vaccine, allowing vaccinators to choose a vaccine booster injection that is different from the previously vaccinated brand. Canada's National Advisory Committee on Immunization announced new rules in June 2021 that allow mixed COVID-19 vaccinations to further accelerate the vaccination process. South Korea, the United Kingdom and other countries have launched clinical trials on the sequential vaccination of the new crown vaccine in the first half of 2021.
Shortly after the implementation of sequential vaccination in many countries, WHO issued provisional guidelines for "mixed- vaccination" of COVID-19 vaccines (hereinafter referred to as the "Guidelines") on 16 December 2021, based on available research data. Guidelines recommend that if the first dose is given against a viral vector, the messenger ribonucleic acid (mRNA) vaccine can be given in the second dose or a booster, and vice versa. If the inactivated vaccine is given initially, follow-up vaccinations with viral vector vaccines or mRNA vaccines may be given.
Who says that based on the safety, immunity and efficacy of vaccines, the standard practice is to use vaccines produced by the same manufacturer throughout the vaccination process. However, considering the accessibility of vaccines, vaccines produced by different manufacturers can be flexibly combined. However, WHO also stresses that "mixed play" can only be carried out if the availability of vaccines and the potential advantages and risks of specific vaccine products are carefully considered.
Part III: Who is the next sequential booster vaccine?
According to the statistics of the 21st Century Business Herald reporter, as of now, a total of 7 new crown vaccines in the mainland have been approved for marketing or emergency use, namely Sinopharm Beijing and Sinopharm Wuhan, Kexing Zhongwei, Kangtai Biological (300601. SZ), inactivated vaccines from the Institute of Biology of the Chinese Academy of Medical Sciences, 688185. SH) adenovirus vector vaccine, as well as Zhifei Bio (300122. SZ) recombinant protein vaccine. At present, the mainstream domestic new crown vaccine is an inactivated dosage form, and the manufacturers mainly include Sinopharm Beijing, Sinopharm Wuhan, Kexing Zhongwei, Kangtai Biology, and The Institute of Biology of the Chinese Academy of Medical Sciences. With the approval of the sequential strengthening of the application, the recombinant protein vaccine manufacturer Zhifei Bio (300122. SZ), adenoviral vector vaccine manufacturer CanSino (688185. SH) will benefit. At the same time, Watson's mRNA vaccine and Livzon Group's recombinant protein vaccine are still in the clinical phase III trial stage.
3.1 Prospects for vaccination of approved sequential vaccines
On February 19, according to the press conference of the joint prevention and control mechanism of the State Council, after the implementation of the sequential strengthening immunization strategy, the target population that completed the full vaccination of three inactivated vaccines (Sinopharm Beijing, Sinopharm Wuhan and Kexing Zhongwei inactivated vaccine) could also choose the recombinant protein vaccine of Zhifeilong Koma or the adenovirus vector vaccine of CanSino for sequential enhanced immunization. As a result, Cansino Biologics' adenoviral vector vaccine Kwesa ® and Zhifeilong Koma's recombinant new crown protein vaccine (CHO cells) ZF2001 was officially approved to enter the ranks of sequential strengthening needles.
3.1.1 CanSino Bio Kwesa ® Vaccine
In 2021, the recombinant novel coronavirus vaccine (type 5 adenovirus vector) developed by the team of CanSino and Chen Wei, an academician of the Chinese Academy of Engineering and a researcher of the Academy of Military Sciences, obtained conditional ® listing approval from the State Food and Drug Administration and emergency use authorization from many overseas countries.
According to the official website of CanSino, Kwesa ® uses a 1-dose vaccination program, which can greatly shorten the vaccination cycle, and the vaccine can be stored and transported for a long time between 2 °C and 8 °C, which can greatly reduce the cost of vaccination management. According to the 21st Century Business Herald reporter, the current bottleneck of CanSino's production capacity has been alleviated, and it is expected to increase the scale of shipments. Previously, CanSino only had a production capacity of 200 million doses per year in Tianjin, and on January 28 this year, CanSino was put into operation at its Baoshan plant in Shanghai, increasing its production capacity by 200 million doses per year.
In December 2021, the international authoritative medical journal The Lancet published the results of Keweisha's ® global multicenter Phase III clinical trial. The data shows that it is safe and effective after vaccinating 1 dose of Kwesa ® in healthy people aged 18 years and older. After 14 days, the critical illness protection rate was 96.0%, the overall protection rate was 63.7%, meeting the standard of protection rate recommended by the World Health Organization for the new crown vaccine, and no serious adverse reactions related to the vaccine occurred.
Adenovirus vector vaccine since Cansino has officially become one of the options for sequential booster immunization. Guojin Securities analysis believes that the Keweisha ® injection form will carry out homologous and cross-sequential vaccination, both of which will increase sales in the domestic market.
According to a paper published in BioRxiv in January 2022, Kwesa's ® neutralizing antibody levels against Omi Kerong were 6 times higher than those of inactivated vaccine homology enhancement and 3 times the sequential strengthening of recombinant protein vaccines. According to the previous clinical trial data conducted by the Jiangsu Provincial Center for Disease Control and Prevention, the inhaled dosage form of Keweisha ® is used for cross-strengthening vaccination of the new crown, and the safety and immunogenicity are excellent. At 14 and 28 days after inhalation dosage form enhancement, the neutralizing antibody levels of the subjects were 6.7-10.7 times higher than those in the inactivated homologous enhancement group, respectively.
It is reported that Kwesha ® has accepted the verification submitted by the World Health Organization (WHO) after its application for inclusion in the Emergency Use List (EUL). Combined with the current epidemic situation, if it is included in the EUL, CanSino's overseas orders for COVID-19 vaccines are expected to increase significantly.
3.1.2 Zhifei Bio-Recombinant Protein COVID-19 Vaccine "ZF2001"
Among the approved sequential enhanced vaccines, the recombinant protein vaccine (CHO cell) ZF2001 (hereinafter referred to as "ZF2001"), developed by Zhifei Longkema, a wholly-owned subsidiary of Zhifei Biologics, in cooperation with the Institute of Microbiology of the Chinese Academy of Sciences, adopts the recombinant protein technology route, making it the first approved domestic recombinant new coronavirus protein vaccine.
As one of the five major technical routes of the new crown vaccine, the vaccine products of the recombinant protein route have low biosecurity requirements on the production workshop, and have the advantages of high purity, better safety, high yield and low cost.
In March 2021, ZF2001 was approved for emergency use by the State Drug Administration, becoming the fourth new coronavirus vaccine approved for emergency use in China; in the same month, the vaccine was registered and listed in Uzbekistan, becoming the first recombinant subunit new coronavirus vaccine registered and marketed in the world; and in February this year, the vaccine was approved as a sequential (heterologous) reinforcement needle for the new crown inactivated vaccine. On March 2, Zhifei Bio issued an announcement that the company learned from the official website of the State Food and Drug Administration that the recombinant new coronavirus vaccine (CHO cells) was approved for conditional listing and is suitable for the prevention of diseases caused by new coronavirus infection.
Whether approved for marketing or emergency use, it is based on the safety and efficacy of the vaccine. On August 27, 2021, Zhifei Bio officially released the data of the international multicentre Phase III clinical trial of the recombinant novel coronavirus vaccine (CHO cells). The data showed a total of 221 primary endpoint cases monitored to the full range of vaccinations, and the protective efficacy against COVID-19 of any severity was 81.76%, meeting the WHO-required COVID-19 vaccine efficacy standards. Among them, the protective effect for severe cases and above of COVID-19 and deaths is 100%. According to the preliminary analysis results after genotyping, the protective efficacy of the vaccine against the Alpha variant was 92.93% and the protective efficacy against the Delta variant was 77.54%. From the perspective of safety, the incidence of overall adverse events/reactions, there was no significant difference between the vaccine group and the placebo group, and the safety was good.
3.2 The road to a potential COVID-19 vaccine
3.2.1 Livzon Group Recombinant Protein Vaccines
V-01 is an innovative RECOM protein vaccine developed by Zhuhai LizhuZumab Biotechnology Co., Ltd. ("Livuzumab"), a subsidiary of Livzon Group, in cooperation with the Institute of Biophysics of the Chinese Academy of Sciences, which is a two-dose vaccination, and its antigen structure is fused with human interferon as a biological adjuvant, which can significantly enhance the level of virus neutralizing antibodies and produce an effective cellular response.
V-01 was approved by the State Food and Drug Administration for clinical trials in early 2021, and was subsequently approved to carry out sequential enhanced Phase III clinical trials in the Philippines, Pakistan, Russia, Malaysia and other countries. On February 17, Livzon Group (000513. SZ) announced that V-01 has completed the sequential enhancement of interim master data analysis of Phase III clinical trials and obtained key data.
According to the results of the current analysis of the trial, the annual human incidence rate of V-01 sequential strengthening group and two-dose inactivated vaccine group was 6.73% and 12.80%, respectively, with significant differences, and the absolute protective power after V-01 sequential strengthening was 61.35%, which had significant effectiveness and met the WHO standard. All 60 valid specimens in this trial were Omicron in the first generation of the new coronavirus genotyping (the rest are still undergoing second-generation sequencing), indicating that the enhanced V-01 sequence can produce good protection against COVID-19 caused by Omicron infection. At the same time, no security issues of concern were found.
It is reported that at present, the production of V-01 has achieved localization of raw materials, the raw material supply chain is stable, and the reserves are sufficient. Based on advanced molecular design, V-01 adjuvant uses conventional aluminum adjuvants, which get rid of the dependence of protein vaccines on strong adjuvants with toxic side effects and patent monopolies, and help promote sustained and stable production capacity release. Formulation production capacity is expected to reach 1.5 billion doses this year.
For the future market of V-01, Livzon Group responded that although the domestic COVID-19 vaccination rate is already very high, and some provinces have successively launched enhanced vaccination, in the face of the challenge of the continuous spread of the global mutant strain virus epidemic, the national overall epidemic prevention policy is also actively supporting the accelerated research and development of more technical vaccines. If Livzon V-01 is listed in China, it is expected to provide more flexible and scientific options for continuous strengthening of immunization in the future, and contribute to the fight against the epidemic.
"For the company, the benefits are important, but if our vaccines can play a certain role in fighting the epidemic, the social benefits are more important than the corporate benefits, which is also our responsibility and responsibility as a pharmaceutical company." Faced with the balance between commercial interests and social benefits, Livzon Group said.
3.2.2 Clover recombinant protein vaccine
Another potential recombinant protein vaccine company is Clover (02197. HK), its core product is the recombinant protein COVID-19 vaccine SCB-2019 (CpG 1018/aluminum adjuvant) (hereinafter referred to as "SCB-2019"). SCB-2019 is a trimer recombinant protein COVID-19 vaccine candidate, using a two-dose vaccination regimen, intramuscular injection, and clinical trials have reached the primary and secondary endpoints of vaccine protective efficacy.
Recently, Clover bio issued an announcement that on January 21, The Lancet published the final protective effect data of SCB-2019. Studies have shown that two doses of SCB-2019 provide significant protective efficacy against COVID-19 of any severity caused by the recombinant new coronavirus (SAR-CoV-2) variant. The protection against severe and hospitalized Coronavirus Disease (COVID-19) caused by any strain is 100%, the protection against moderate to severe COVID-19 caused by any strain is 83.7%, and the protective efficacy against any severity of COVID-19 caused by any strain is 67.2%. In terms of viral variants, the vaccine efficacy against any severity of COVID-19 caused by the three main variants is 78.7% (Delta variant), 91.8% (gamma variant), and 58.6% (Miu variant), respectively. There were no safety issues during the follow-up period of the efficacy analysis, and the rate of adverse events occurred in the groups was comparable.
In the context of the deployment of sequential enhancement, the SCB-2019 heterologous enhancement test also obtained preliminary data. A Phase 2 clinical trial in Brazil initially showed that in individuals who had previously received two doses of the AstraZeneca vaccine, the neutralizing antibody levels of one dose of SCB-2019 booster were at least three times higher than those of one dose of AstraZeneca vaccine. In addition, cognate enhanced test data are also coming soon. According to the announcement issued by Clover, after the SPECTRA trial was revised in January 2022, scAB-2019 was started as a homologous reinforcer for evaluation trials. The Phase II clinical trial began in Brazil in November 2021 and preliminary results are expected to be released in the first half of 2022.
In terms of production capacity, Clover plans to produce 1 billion doses of COVID-19 vaccine per year. According to the announcement, Clover has signed a long-term vaccine supply agreement with the United Nations Children's Fund (UNICEF), agreeing to provide 414 million doses of SCB-2019 vaccine to COVAX's COVID-19 Vaccine Implementation Plan by 2022.
Clover said it expects to complete the registration application to the State Food and Drug Administration in mid-2022, and complete the registration application to the World Health Organization and the European Medicines Agency in the third quarter of 2022, and launch the SCB-2019 product market once it obtains conditional approval.
3.3 Acceleration of domestic mRNA new crown vaccine
As a novel vaccine technology, mRNA vaccines, unlike attenuated or inactivated vaccines, mRNA only expresses specific antigens and induces an immune response in a targeted manner. In addition, it promotes humoral and cellular immune responses and induces an innate immune system. MRNAs are safer and more effective than DNA vaccines because expression does not need to enter the nucleus, and the probability of random genome integration is almost zero. In addition, mRNA degrades in cells in a short period of time (2-3 days) and has a short development cycle and a broad spectrum. Moreover, engineered mRNA vaccines can greatly increase their stability and immune efficacy.
Therefore, at present, the mRNA new crown vaccine has a high degree of international recognition. Many research data also confirm that mRNA vaccines are more advantageous.
In the past year, the advantages of the mRNA vaccine technology route and its outstanding advantages in responding to the global COVID-19 epidemic have become the focus of research and development of COVID-19 vaccines by mainland pharmaceutical companies. Many companies have begun to develop mRNA new crown vaccines, from Abbott Bio and Emmy vaccines to CSPC Pharmaceutical Group and CanSino, which are now approved for clinical trials, the momentum of mRNA vaccine research and development in mainland China is rapid.
3.3.1 CSPC and CanSino mRNA vaccine approved for clinical trials
From April 3 to 4, 2022, two mRNA vaccines successively obtained clinical trial approval documents issued by the State Drug Administration, namely SYS6006 independently developed by CSPC Pharmaceutical Group and the new coronavirus mRNA vaccine jointly developed by CanSino and Canadian Precision NanoSystems.
The results of both mRNA vaccine preclinical studies show that the immune protection efficacy against current mainstream mutant strains can more effectively protect the body from infection with existing variants. This means that these two new mRNA vaccines can play an important role in the fight against Omicron's NEW crown pneumonia.
The mRNA covid-19 vaccine SYS6006 developed by CSPC Group is specially developed for the new coronavirus variant strain, and its preclinical studies have shown that the product has a good immunoprotective effect on the current mainstream mutant strains, including Omicron and Delta; it provides immune protection for the body through humoral immunity and cellular immunity, and can produce memory B cells to provide long-term protective efficacy.
In addition, CSPC also said that the preclinical safety evaluation data also fully proved the safety of the product. The product uses advanced production technology, the process is highly controllable, the consistency between batches is good, it is easy to achieve amplification and industrialization; and the stability is good, and it can be stored for a long time between 2 °C and 8 °C. The Group has achieved internalized production and localization substitution of key production raw materials and excipients for mRNA technology, which can meet the demand for large-scale capacity supply.
The vaccine developed by CanSino is also better protected against existing variants. Its preclinical findings show that the vaccine can induce high-titer neutralizing antibodies against a variety of important variants recognized by the World Health Organization (WHO), including the current epidemic strain, with a stronger broad spectrum, which can more effectively protect the body from infection with existing variants.
At the same time, CanSino Biologics said that in the future, it will fully rely on the core technology platform including viral vector technology and mRNA technology to continue to carry out research and development of targeted vaccines.
3.3.2 The Ellie vaccine mRNA vaccine has entered Phase II/III clinical trials
The novel coronavirus mRNA vaccine LVRNA009 is an independently developed Immy vaccine and approved by the State Food and Drug Administration to carry out clinical trials in March 2021, which is the third domestic mRNA vaccine approved for clinical trials after Aibo Bio and Si Microorganism. Currently, LVRNA009 has entered Phase II/III clinical trials and has submitted a sequential vaccination application.
On January 8, 2022, I-Mély Vaccine Phase I clinical trial data showed good safety and tolerability results. LVRNA009 all overall adverse events occurred at the level of 1-2, with no adverse events above level 3, and no SAE and special concern solicitation adverse events occurred. Throughout the trial, there were no cases of fever of grade 3 or higher.
Specifically, the results of the live virus neutralizing antibody test showed that the geometric average titer (GMT) of the live virus neutralizing antibody of the vaccine was more than 570 on the 56th day of the adult low-dose group, more than 1500 GMT on the 56th day of the adult medium-dose group, and more than 840 on the 56th day of the adult high-dose group." Compared with the results of phase I clinical trials of similar products, it shows very good safety and immunogenicity.
In addition to safety and immunogenicity, LVRNA009 is not "demanding" for storage temperatures. It is understood that the vaccine can be stored for 1 month under conditions of 2 ° C ~ 8 ° C, and 12 months under the condition of -20 ° C.
From the perspective of industrialization, it is reported that Emmy Vaccine is currently laying out modular production workshops for mRNA vaccines in many places, and plans to be able to carry out mass production of mRNA new crown vaccine projects in June 2022. In addition, in Shanghai, Beijing and other places, Aimei Vaccine intends to build a new factory, which is expected to be completed at the end of this year and put into operation next year, with an estimated annual production capacity of 400 million doses.
In addition, the Emmy vaccine also has a new coronavirus Delta variant mRNA vaccine in research, which is in the preclinical stage.
3.3.3 Watson Bio & Aibo Bio Phase 3 clinical trial is basically completed
The mRNA new crown vaccine ARCoV (hereinafter referred to as "ARCoV"), jointly developed by the Chinese Academy of Military Medical Sciences (AMMS), Aibo Biologics and Watson Biology, has completed Phase 1 and Phase 2 clinical studies, and Phase 3 clinical trials have basically ended, and have entered the relevant data cleaning stage.
In November 2021, Watson Bio was approved to carry out a clinical trial of "COVID-19 inactivated vaccine + NEW MRNA vaccine" for people over 18 years old in Guangxi and Yunnan. At present, the above clinical trials have completed enrollment. On January 24 this year, Lancet Microbe, an international authoritative medical journal, published the results of the phase I clinical trial of the ARCoV vaccine online. The results showed that ARCoV was safe and well tolerated at 5 different doses (5ag, 10ug, 15ug, 20ug, 25 ug), and was able to induce strong humoral and cellular immune responses, of which the 15ug test group induced the highest neutralizing antibody titer, which was about twice that of patients who recovered from COVID-19.
ARCoV is more stable and accessible, and can remain stable for a long time (at least 6 months) at normal refrigerator temperatures (2-8 °C). In contrast, Moderna's mRNA vaccine needs to be preserved and transported at -20 °C (stable at 2-8 °C for 30 days), while the Pfizer mRNA vaccine needs to be stored and transported at -70 °C (stable at 2-8 °C for 5 days).
However, it is also worth noting that the incidence of systemic side effects of ARCoV is 50%-100%, and the incidence of side effects in the 15μg dose group in the Phase 3 trial is also as high as 95%.
According to Watson Bio's disclosure on March 21, at present, the field work of the domestic phase III clinical trial of the new crown mRNA vaccine is basically over, data collation and continuous serum testing are underway, and the international multi-center phase III clinical trial has also made phased progress, and has been carrying out case collection work, and continues to maintain communication with the local drug regulatory department.
Part IV: Who is expected to win the second half?
Due to the early approval for listing, Sinopharm Zhongsheng and Kexing Zhongwei have become the beneficiaries of the "first half" of the new crown vaccine. Among them, sinopharm Beijing and Sinopharm Wuhan's inactivated covid-19 vaccines were conditionally listed in China on December 30, 2020 and February 25, 2021, respectively. In June 2020, the state approved the inclusion of Kexing's new crown vaccine for emergency use. On February 5, 2021, the State Food and Drug Administration approved the conditional listing of Kexing's new crown vaccine in China in accordance with the law.
According to the official WeChat public account of "China Biology", as of November 16, 2021, Sinopharm Zhongsheng has produced and supplied nearly 2.5 billion doses of COVID-19 vaccines at home and abroad, and the annual production capacity has exceeded 7 billion doses. Up to now, China's biological COVID-19 vaccine has been registered and listed in 10 countries around the world, and 112 countries, regions and international organizations have approved emergency use or market access.
In addition to Sinopharm, the first echelon of the new crown vaccine is also Kexing Zhongwei. According to the financial report, in the first half of 2021, Kexing Zhongwei's sales were 11 billion US dollars (about 70 billion yuan) and net profit was 8.6 billion US dollars (about 54 billion yuan). The main source of its performance surge is the self-developed inactivated new crown virus vaccine CoronaVac. In addition, according to the financial report disclosed by China Biopharmaceutical, its attributable profit attributable to the associated company reached 13.63 billion yuan in 2021, a sharp increase of 47 times year-on-year. The financial report specifically mentioned that the performance of the domestic new crown vaccine manufacturer Kexing Zhongwei in the associated company was "particularly prominent". As a result, many investors have calculated that the net profit of Kexing Zhongwei in 2021 may exceed 90 billion yuan according to the shareholding ratio of China Biopharmaceutical in Kexing Zhongwei.
According to Lian Xiaojuan, deputy general manager of Kexing Zhongwei, on November 18 last year, Kexing Zhongwei has supplied 2.2 billion doses of COVID-19 vaccines to the world, of which 1.3 billion doses are supplied to the domestic market and another 900 million doses are supplied to the international market. On June 1, 2021, China's Kexing COVID-19 vaccine was included in the WHO's emergency use list. As of January 29, 2022, Coshing has supplied 2.7 billion doses of COVID-19 vaccines to the world, accounting for 23% of the total global COVID-19 vaccine supply.
At present, the overall annual production capacity of Kexing's new crown vaccine exceeds 2 billion doses, and it has been authorized for emergency use or conditionally listed by 60 countries, regions and international organizations.
However, Chen Zhu, chief analyst of CITIC Securities Pharmaceutical, told the 21st Century Business Herald reporter that the competition for the new crown vaccine must enter the second half, and the biggest winner is likely to be (Sinopharm) Zhongsheng Group, because it has an inactivated vaccine, recombinant protein vaccine and mRA vaccine are also entering the market quickly, which is the "national team" with the most complete vaccine variety.
With the help of the dividend of the new crown vaccine, the performance of the other three A-share listed companies on sale has grown rapidly, and they have to face the competition of their peers. According to the newly released performance report, in 2021, Anhui Longkema's parent company Zhifei Bio (300122. SZ) achieved revenue of 30.637 billion yuan, an increase of 101.68% year-on-year; achieved a net profit attributable to the mother of 10.197 billion yuan, an increase of 208.88% year-on-year. According to the proportion of the performance contribution of the new crown vaccine in the first half of the year, the company's annual revenue and net profit of the new crown vaccine were about 11 billion yuan and 7 billion yuan, respectively. With the contribution of the new crown vaccine, CanSino Bio (688185. SH) also turned a profit in one fell swoop. According to the performance report, the revenue in 2021 was nearly 4.3 billion yuan, an increase of 171 times year-on-year, and the net profit was 1.91 billion yuan. According to the annual performance forecast, Kangtai Bio (300601. SZ) in 2021 attributable net profit scale of at least more than 1.2 billion yuan, is expected to increase by up to 106.13% year-on-year.
However, in the face of factors such as limited by their own production capacity, R&D and listing process, and fierce market competition, the market share of the three companies is still inferior to that of Sinopharm, Kexing and other "forerunners".
However, Chen Zhu pointed out that compared with the early stage of the outbreak, the demand and heat of vaccination must have declined, but like the flu, there may be a probability of repeated vaccination every year.
At present, it seems that the new crown vaccine market in the first half has been occupied by eight or nine. With the promotion of sequential strengthening of immunization, domestic latecomers of the new crown vaccine enterprises are accelerating their pace into the competitive track of sequential strengthening. However, due to the late "entry", most of them are still in the clinical trial stage, and the time when their vaccines were approved for marketing is still unknown. Coupled with the impact of factors such as product pipelines, their own production capacity, and peer competition, it is still worth looking forward to whether they can win the second half of the battle for the new crown vaccine.
(Source: 21st Century Business Herald)