Just now, according to the official website of the Drug Administration, the State Drug Administration approved conditionally the listing of 2 new domestic crown vaccines.
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The two vaccines are Ad5-nCoV, a recombinant new coronavirus vaccine (type 5 adenovirus vector) jointly developed by Kangxino Biologicals and Chen Wei’s academician team, and Vero cells, a new inactivated coronavirus vaccine from Wuhan Institute of Biological Products of China National Pharmaceutical Group.
Among them, Concierto Novel Coronavirus vaccine is the first adenovirus vector Novel Coronavirus vaccine approved for marketing in China, before that, Concierto Novel Coronavirus vaccine has been authorized for emergency use in Pakistan and Mexico.
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Source: Reference 3
According to the phase III clinical trial data disclosed on the website of Convivox, the overall protection efficacy of the vaccine against all symptoms was 65.28% after 28 days of single dose vaccination, and 68.83% after 14 days of single dose vaccination.
The efficacy of protection against severe disease was 90.07% after 28 days of single dose vaccination and 95.47% after 14 days of single dose vaccination, respectively.
Concinox: the world’s first new crown vaccine to enter the clinic
In March 2020, the Phase I clinical trial of KangXinuo New Crown vaccine was launched in Wuhan, becoming the world’s first New Crown vaccine candidate to enter the clinical study phase.
The Phase I trial did not have a control group and included a total of 108 people. The low-dose group, the mid-dose group and the high-dose group each enrolled 36 individuals.
In the low-dose group, 83% of volunteers experienced an adverse reaction within seven days of vaccination, compared to 83% in the medium-dose group and 75% in the high-dose group.
Fifty-four percent of volunteers reported injection site pain, which was the most common adverse reaction in the Phase I trial. Other common systemic adverse reactions included fever (46%), fatigue (44%), headache (39%), and muscle pain (17%). The incidence of adverse reactions between dose groups did not exhibit statistical differences.
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Figure source: Reference 1
One volunteer in the high-dose group had an abnormal reaction of high fever, fatigue, dyspnea, and muscle pain after vaccination, and the vaccine team, after research, concluded that this adverse reaction was related to viraemia caused by Ad5 vector, which had previously been associated with similar adverse reactions to the Ad5 vector Ebola vaccine.
Otherwise, most of the reactions were mild to moderate and occurred within 24 hours of vaccination and subsided within 48 hours. No volunteers experienced serious adverse reactions during the 28-day trial cycle.
In the ELISA antibody and neutralizing antibody assays on days 14 and 28, the geometric mean of antibody titers was positive in all dose groups. Moreover, antibodies in all three dose groups peaked on day 28. The antibody titers were higher and statistically significant in the high dose group compared to the medium and low dose groups, and the immune response of T cells peaked on day 14 after injection.
However, the results of the phase I trial suggested that volunteers aged 45 to 60 years had a lower rate of positive seronegative antibody transitions compared to younger volunteers.
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Source: Reference 1
In April 2020, the Phase II clinical trial of the vaccine was initiated in Wuhan.
Because the rate of Grade 3 adverse reactions was significantly higher in the high-dose group than in the medium and low-dose groups in the previous phase I trial, and one abnormal reaction was observed, only the low and medium doses were used in the phase II trial.
A total of 508 volunteers were enrolled in the phase II trial, including 253 in the medium-dose vaccine group, 129 in the low-dose group, and 126 in the control group.
After vaccination, 72% of the volunteers in the medium-dose group and 74% in the low-dose group experienced adverse reactions, with 24 (9%) in the medium-dose group and 1 (1%) in the low-dose group experiencing more intense reactions. In addition, 48% of volunteers in the placebo group also experienced adverse reactions. Similar to the Phase I trial, these reactions resolved on their own within 48 hours of occurrence.
As with the Phase I trial, there were no serious adverse reactions in the entire Phase II trial.
Data from the Phase II trial showed that 96% of volunteers in the mid-dose group and 91% of volunteers in the low-dose group were able to develop a humoral immune response to the new coronavirus 28 days after vaccination. Cellular immune responses were induced in approximately 90% of the volunteers.
The phase II trial also showed once again that age is a key factor in the vaccine’s effect: volunteers 55 years and older did not produce antibodies at the same level as younger volunteers after immunization. However, younger volunteers were more likely to develop a febrile response after vaccination.
Adenoviral vectors and pre-storage immunization
Among several neo-crown vaccine candidates at the forefront of development progress in China, Concierto’s Ad5-nCoV is the only neo-crown vaccine that uses a single-dose immunization procedure. Single-dose vaccination can achieve immune protection quickly and shorten the vaccination cycle. At the same Time, a single-immunization vaccine can reach up to twice as many people as a vaccine requiring two doses at the same vaccine capacity.
Because this vaccine uses the adenovirus vector technology route, it can be stored stably between 2°C and 8°C, like the recombinant Ebola virus disease vaccine (adenovirus vector) developed using the same technology route, making it easier to transport and store properly and providing greater vaccine accessibility.
Adenovirus is an envelope-free, double-stranded DNA virus that presents as a self-limiting disease in humans. Past studies have found that adenovirus vectors carrying protective antigen genes can stimulate strong antigen-specific humoral and cellular immune responses in humans.
The new Coronavirus vaccine is a replication-deficient human adenovirus type 5 (Ad5) vector, genetically engineered to express a novel coronavirus S antigen.
Previously, type 5 adenovirus vectors have been used in the development of Ebola vaccines, HIV vaccines, and influenza vaccines, all of which have made some progress. in October 2017, Ad5-EBOV, a type 5 adenovirus vector Ebola virus disease vaccine, also developed by Concino, was conditionally approved for marketing in China, and the product is currently being used as a national stockpile.
However, challenges remain in the practical application of adenoviral vector vaccines.
Ad5 is widespread in nature, and most people have been naturally infected and have pre-existing immunity to Ad5, a phenomenon known as preexisting immunity.
In China, for example, the seroprevalence of antibodies to Ad5 adenovirus is about 60% to 82%. In the Phase I trial of Convivox New Crown vaccine, there were volunteers with “pre-existing antibodies”.
These preexisting antibodies also affected to some extent the immunogenicity of the Ad5 vector vaccine, i.e., the ability of the vaccine to produce protective neo-coronavirus antibodies.
Other adenoviral vector-based neocrown vaccines
Among neo-crown vaccines that also use adenoviral vectors, clinical trial data have been published by Johnson & Johnson (Ad26.COV2.S), Oxford University/AstraZeneca (AZD1222) and the Gamaleya Research Center (Satellite V) in Russia.
On January 29, Johnson & Johnson Ad26 Adenoviral Vector New Crown Vaccine announced interim analysis data from its Phase III clinical trial. A total of 43,783 subjects were enrolled and 468 were infected with Neocon in the interim analysis.
After 28 days of single-dose vaccination, protection against moderate to severe neointimal pneumonia was 72% in the United States, 66% in Latin America and 57% in South Africa (95% of which were B.1.351 mutant strains). After 28 days of single-dose vaccination, the protection was 85% in severe cases.
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Source: Reference 5
On February 2, the Russian new crown vaccine Sputnik V (satellite V) was published in the Lancet as a phase III clinical trial, with 91.6% (95% CI: 85.6-95.2) protection for the satellite V vaccine.
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Source: Reference 6
On February 19, AZD1222, a new crown vaccine jointly developed by AstraZeneca and the University of Oxford, published the results of a phase III clinical trial in the Lancet.
The results showed that the vaccine protection was 54.9% (95% CI: 32.7 to 69.7) within 6 days after two standard doses. Between 22 and 90 days after the first vaccination, the vaccine protection was 76% (95% CI: 59-86) and antibody levels were stable in vaccine recipients. And 12 weeks after two standard doses, the vaccine protection was 82.4% (95% CI: 62.7 to 91.7).
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Source: Reference 7
How to overcome the problem of preexisting immunity has been the focus of attention for adenoviral vector vaccines. According to ClinicalTrials.gov, Oxford/AstraZeneca and Russian Satellite V have enrolled in a clinical trial to evaluate the safety and immunogenicity of a combination of the two vaccines as a way to circumvent the effect of preexisting antibodies to the Ad vector from the first dose on the effectiveness of the second dose.
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Source: ClinicalTrials.gov
Sinopharm Zhongsheng Wuhan: Another Inactivated Vaccine
In the New Crown vaccine development program, two units of Sinopharm China Biotech, the Wuhan Institute of Biological Products and the Beijing Institute of Biological Products, are working in parallel on the inactivated vaccine route.
The first neo-crown vaccine approved for marketing in China at the end of 2020 came from the Beijing Institute of Biological Products, and this time, the Wuhan Institute of Biological Products also brought Phase III clinical trial data.
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Source: Official website of Wuhan Institute of Biological Products of Sinopharm
According to the official website, Wuhan Institute of Biological Products of Sinopharm conducted a multicenter, randomized, double-blind, placebo-parallel-controlled phase III clinical trial of inactivated Neocrown vaccine in several countries, including the United Arab Emirates, from July 16, 2020.
The interim data analysis of the phase III clinical trial showed that after two doses of the immunization program, all vaccine recipients produced high titers of antibodies, with a positive neutralizing antibody conversion rate of 99.06%, and the vaccine’s protective efficacy against Neocrown pneumonia was 72.51%, meeting the requirements of the relevant standards of the State Drug Administration.
The conditional marketing application was submitted on the same day of February 21, 2021 as Kangxino, and was approved for marketing on the same day today. (Planning: gyouza)
Acknowledgements: This article was professionally reviewed by Dr. Immunology, Shanghai Pasteur Institute, Chinese Academy of Sciences @Last Time for Sugar, Dr. Microbiology, Chinese Academy of Sciences @Secondhand Scientist
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D. in Immunology, Shanghai Pasteur Institute, Chinese Academy of Sciences @Last Time for Sugar Reviewed by
Perhaps the biggest obstacle for this vaccine is the issue of Ad5 pre-existing immunity. Early clinical studies have shown that Ad5 pre-existing immunity slows the rapid immune response to SARS-CoV-2 while reducing the peak response, especially in humoral immunity, and has been demonstrated in animal studies with other vaccines; in addition, the high pre-existing immunity of Ad5 may also have an impact on vaccine-induced In addition, the high preexisting immunity of Ad5 may also have an impact on the persistence of the vaccine-induced immune response. With known high levels of Ad5 pre-existing immunity in Asia and Africa, and even high levels of Ad5 pre-existing immunity in more than 80% of the population in India, it can be expected that the Indian population may have a relatively poor response to this vaccine.
This is generally addressed by using either a heterologous or homologous combination with an Ad5 primary booster, which has been shown to significantly enhance immunogenicity, or by using a new generation of defective Ad5 vectors (E1/E2b/E3 deficient), which have shown preliminary evidence in mice to induce high titers of antibody in the presence of preexisting immunity.
In addition, published phase III data from the vaccine show higher protection rates at 28 days of vaccination compared to 14 days after vaccination, both for all symptoms and for severe disease, for reasons that are not yet known and may be related to the small number of cases and the poor randomization of onset times. COVID-19 weapon.
Image credit: Screenshot from Concierto’s website
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