On Feb. 25, the National Medical Products Administration of China (NMPA) conditionally approved the registration applications of two COVID-19 vaccines: Inactivated COVID-19 Vaccine (Vero Cell) of Sinopharm Wuhan Institute of Biological Products Co., Ltd., and Recombinant Novel Coronavirus Vaccine (Adenovirus Type 5 Vector) of CanSinoBIO, with the latter being the first Chinese-produced adenovirus vector-based COVID-19 vaccine approved.
The marketing registration applications of four Chinese-produced COVID-19 vaccines have so far received the NMPA’s conditional approval. In addition to the two mentioned above, the other two vaccines are the Inactivated COVID-19 Vaccine (Vero Cell) of Sinopharm Beijing Institute of Biological Products Co., Ltd. approved on Dec. 30, 2020, and the SARS-CoV-2 Vaccine (Vero Cell), Inactivated of Sinovac Life Sciences Co., Ltd. approved on Feb. 5, 2021. With real-world protection efficacy data reported in succession after vaccination, humanity is expected to usher in a new situation in the fight against the pandemic. These healthcare supply companies have made great contribution to the vaccination. COVID-19 vaccine R&D in China has also made new progress in succession. Let’s check it.
1. Sinopharm CNBG: The first inactivated COVID-19 vaccine approved for marketing in China
The inactivated COVID-19 vaccine from Sinopharm CNBG was conditionally approved by the NMPA at the end of Dec. 2020, making it the first inactivated COVID-19 vaccine approved for marketing in China. To put it simply, to make inactivated vaccines, the virus strains are first isolated, just like choosing good “seeds”; then they are cultured, for example, multiplying tens or hundreds of times; the live viruses are then killed so that they lose their infectivity and replication ability but retain part of their function of stimulating the human body to produce an immune response, and then they are finally turned into vaccines through purification and other processes. Inactivated vaccines are relatively faster to develop, but the required investment is huge.
The Lancet, an international academic medical journal, published the results of the Phase 1/2 clinical trial of the vaccine on Oct. 16, 2020. This randomized, double-blind, placebo-controlled, phase 1/2 trial divided 192 healthy adults into groups aged 18-59 and ≥60 to evaluate low, medium, and high doses of the vaccine. Participants in each group were randomly assigned 3:1 to separately receive the vaccine or the placebo. In phase 2, 448 healthy adults (aged 18-59) were assigned to four groups to receive the high-dose vaccine on day 0 or the medium-dose vaccine on days 0/14, 0/21, or 0/28 to mainly assess safety and tolerability, with the secondary outcome being immunogenicity, assessed as the neutralizing antibody responses against infectious SARS-CoV-2.
According to the results of the study on candidate vaccine-induced neutralizing antibodies and positive conversion rates, in phase 1 clinical trial, in the healthy adult group, seroconversion rates reached 100% at day 14 in both the low and medium dose populations and 96% at day 14 in the high dose population; in the elderly group, seroconversion rates reached 100% at day 28 for all populations; in all groups, neutralizing antibodies increased significantly from day 7 and peaked at day 42. Vaccine-induced neutralizing antibody titers in the high-dose group were significantly higher than those in the low-dose group, but not significantly different from those in the medium-dose group. Furthermore, the vaccine-induced neutralizing antibodies neutralized various viral strains, including the natural variant with spike mutant (D614G) in the current pandemic. According to phase 2 clinical results, neutralizing antibodies increased from day 14 to day 28 after the second vaccination in the D0/D14 and D0/D21 procedures; vaccine-induced neutralizing antibody titers in the D0/D21 procedure were significantly higher than vaccine-produced neutralizing antibody titers in the D0/D14 procedure.
The results showed that the vaccine was effective in inducing neutralizing antibodies in the age groups, and the neutralizing antibody levels were comparable to those reported in other vaccine studies, proving the good immunogenicity of the vaccine. Furthermore, the difference in the adverse reaction rate between the vaccine and placebo groups was not statistically significant, and the vaccine’s adverse reaction rate was lower than the levels reported in the currently published clinical studies of related vaccines, indicating a good safety profile of this inactivated vaccine in humans.
According to the results of the interim analysis of the vaccine’s phase 3 clinical trial, all vaccinees produced high titers of antibodies after two injections of the immunization procedure, the neutralizing antibody positive conversion rate was 99.52%, and the protective efficacy of the vaccine against COVID-19 was 79.34%. The data results met the relevant technical standards of the World Health Organization and the relevant standard requirements in the Guidelines for the Clinical Evaluation of Prophylactic Vaccines against COVID-19 (Trial) issued by the NMPA.
2. Sinovac: The second inactivated COVID-19 vaccine approved for marketing in China
On Feb. 5, 2021, the NMPA conditionally approved the registration application of the SARS-CoV-2 Vaccine (Vero Cell), Inactivated of Sinovac Life Sciences Co., Ltd., which is indicated for the prevention of the disease caused by SARS-CoV-2 infection (COVID-19).
It is learned that the vaccine, with a trade name CoronaVac, is indicated for the prophylactic vaccination of people aged 18 and above. It is the second inactivated COVID-19 vaccine approved for marketing in China.
CoronaVac® is made by inoculating African green monkey kidney cells (referred to as Vero cells) with SARS-CoV-2 (CZ02 strain) and then through culture, virus solution harvest, virus inactivation, concentration, purification, and aluminum hydroxide adsorption, and it contains no preservative.
On Apr. 16, 2020, the vaccine entered Phase 1/2 clinical studies and demonstrated good safety. In July of the same year, Phase 3 clinical studies were conducted successively in four geographically different and distinct countries: Brazil, Chile, Indonesia, and Turkey. These studies were conducted independently using the same vaccine batch (medium dose 600 SU), following the same immunization procedure (0,14) and according to the requirements of the Good Clinical Practice (GCP), with a total of 25,000 people enrolled.
Phase 3 clinical studies conducted in Brazil and Turkey separately evaluated the protective efficacy of CoronaVac® in the high-risk population (medical personnel treating COVID-19 patients) and the general population in a multicenter, randomized, double-blind, placebo-controlled design in both countries, with the primary endpoint being the incidence of COVID-19 14 days after two doses of the vaccine or the placebo.
By Dec. 16, 2020, the study of the vaccine in Brazil enrolled a total of 12,396 medical workers aged 18 or above and obtained 253 positive cases during the observation period. After 14 days following vaccination with two doses of vaccine following a 0, 14 day procedure, the efficacy rate against diseases caused by COVID-19, including mild symptoms not requiring medical attention, was 50.65% for all cases, 83.70% for cases with significant symptoms requiring medical treatment, and 100.00% for hospitalized, severe, and fatal cases.
The target populations of the phase 3 clinical trial of the vaccine in Turkey are medical workers at high risk (K-1) and the general population at normal risk (K-2), with all participants ranging from 18 to 59 years old. By Dec. 23, 2020, there were 918 subjects enrolled in K-1 and 6,453 subjects in K-2, with a total of 7,371. Among them, 1,322 subjects completed the two-dose vaccination and entered the 14-day observation period after receiving the second dose of the vaccination. Based on an analysis of 29 cases, the efficacy rate for COVID-19 prevention was 91.25% after 14 days following the two-dose vaccination, in adherence with the 0, 14 day procedure.
3. CanSinoBIO: Recombinant Novel Coronavirus Vaccine (Adenovirus Type 5 Vector)
The conditional marketing application of Recombinant Novel Coronavirus Vaccine (Adenovirus Type 5 Vector) (trade name: Convidecia™) co-developed by CanSino Biologics Inc. (CanSinoBIO) and Institute of Biotechnology, Academy of Military Medical Sciences, Academy of Military Sciences has been approved on Feb. 25, 2021, making it the first single-dose COVID-19 vaccine conditionally approved for marketing in China.
According to the announcement, the global multicenter phase 3 clinical study conducted by CanSinoBIO in Pakistan, Mexico, Russia, Chile, and Argentina has completed vaccination and interim data analysis of over 40,000 subjects.
According to the interim analysis results of the phase 3 clinical trial of CanSinoBIO’s Convidecia™, 28 days after single-dose vaccination of the vaccine, the overall protection against all symptoms was 65.28%; 14 days after single-dose vaccination of the vaccine, the overall protection against all symptoms was 68.83%. The vaccine’s efficacy of protection against severe symptoms was separately 90.07% 28 days after single-dose vaccination and 95.47% 14 days after single-dose vaccination. This means that a single dose of Convidecia™ can produce protection in only 14 days, and the product can achieve faster and more comprehensive protection for the populations.
Speed is key in the battle against COVID-19. The vaccine working in a dose can make the body develop immunity in the fastest possible time, thereby rapidly blocking the virus. Furthermore, the single-dose vaccine means that it can protect twice as many people as the two-dose vaccine under the same capacity condition. Plus, as the vaccine uses the same adenovirus vector-based technical route as the recombinant Ebola vaccine (adenovirus vector), it can be stably preserved between 2°C and 8°C, making it easier to transport and store normally and making it more accessible.
4. Wuhan Institute of Biological Products: Inactivated COVID-19 vaccine
Following the conditional marketing of the inactivated COVID-19 vaccine of Sinopharm Beijing Institute of Biological Products Co., Ltd., the conditional marketing of the inactivated COVID-19 vaccine of Wuhan Institute of Biological Products was approved by the NMPA on Feb. 25, 2021, making it CNBG’s second COVID-19 vaccine approved to be marketed conditionally.
Wuhan Institute of Biological Products started to conduct a phase 3 clinical trial of its inactivated COVID-19 vaccine in countries including the United Arab Emirates from July 16, 2020, which is an international multicenter, randomized, double-blind, placebo-controlled one. According to the interim analysis results of the phase 3 clinical trial, the inactivated COVID-19 vaccine of Wuhan Institute of Biological Products had good safety after vaccination; after the two-dose immunization procedure, all vaccinees produced high titers of antibodies, with a neutralizing antibody positive conversion rate of 99.06%, and the COVID-19 vaccine achieved 100% protection against the confirmed moderate to severe disease, with overall protection efficacy of 72.51%. The vaccine had good cross-neutralization against the SARS-CoV-2 strains, and the anti-SARS-CoV-2 antibodies produced by the vaccine had extensive cross-neutralization reactions against 10 prevalent or representative SARS-CoV-2 strains in China and abroad.
5. Fosun Pharma and BioNTech: mRNA COVID-19 vaccine
COMIRNATY (BNT162b2), the mRNA COVID-19 vaccine of Fosun Pharma and BioNTech, received Special Import Authorization in Macau, S.A.R., China, China on Jan. 25, 2021. Before this, this COVID-19 vaccine based on BioNTech’s mRNA technology received Authorization for Emergency Use in Hong Kong, S.A.R., China, China. BioNTech and Fosun Pharma announced entering into a strategic cooperation agreement in Mar. 2020, according to which, both parties would jointly develop and commercialize a COVID-19 vaccine in Greater China based on BioNTech’s proprietary mRNA technology platform.
mRNA is a natural molecule that can produce a target protein, or antigen, which activates the body’s immune response against various pathogens. Compared to traditional vaccines, an mRNA vaccine has advantages such as no viral component and no risk of infection; short development cycle, enabling rapid development of novel vaccine candidates to meet viral mutations; dual mechanism of humoral and T-cell immunity, with strong immunogenicity and not requiring adjuvants; and ease of mass production.
According to the earlier press release of Fosun Pharma, the global phase 3 clinical trial results showed that BioNTech’s mRNA-based COVID-19 vaccine met all primary efficacy endpoints, demonstrating effectiveness of 95% in preventing COVID-19 and 94% in adults over 65 years of age.
6. Clover Biopharmaceuticals: S-Trimer COVID-19 vaccine candidates
Utilizing Clover’s proprietary Trimer-Tag© technology, S-Trimer is a trimeric SARS-CoV-2 spike (S)-protein subunit vaccine candidate. Similar to other enveloped RNA viruses such as HIV, RSV, and influenza, SARS-CoV-2 is also an RNA virus that has a trimeric spike (S) protein on its viral envelope. The trimeric S protein of SARS-CoV-2 is responsible for binding to host cell surface receptor ACE2 and subsequent viral entry, making it the primary target antigen for vaccine development. S-Trimer resembles the native trimeric viral spike protein and is produced via a rapid mammalian cell culture-based expression system.
According to the pre-clinical study data and preliminary phase 1 clinical data, S-Trimer COVID-19 vaccine candidates demonstrated favorable tolerability and could induce high levels of neutralizing antibodies and strong Th1-biased cell-mediated immunity, thus they are worth continued assessments.
7. BioKangtai/AstraZeneca: Adenovirus vector-based COVID-19 vaccine, AZD1222
AstraZeneca announced a cooperation framework agreement on exclusive authorization in the Chinese mainland market with BioKangtai on Aug. 6, 2020, to actively advance the R&D, production, supply and commercialization of the adenoviral vector-based COVID-19 vaccine AZD1222, co-developed by AstraZeneca and the University of Oxford, in the Chinese mainland market through technology transfer. Both parties will continue to explore the possibility of cooperation in this vaccine in other regions and markets in the future.
On Nov. 23, 2020, AstraZeneca announced that the interim analysis of the Phase III trials of AZD1222 showed meeting the primary efficacy endpoint. According to data from 17,177 subjects accruing 332 symptomatic COVID-19 cases, protection efficacy reached 76% after a first dose, and with an inter-dose interval of 12 weeks or more, protection efficacy increased to 82%. Two doses of vaccination provided 100% protection against severe disease. The UK regulator had previously granted an emergency use authorization to the vaccine and recommended an interval of 4-12 weeks between vaccinations.
Clinical trials of the vaccine are currently underway in many countries around the world and are planned in more regions to validate the vaccine’s effectiveness in protecting people against SARS-CoV-2 infection and test the safety and immune responses in people at different ages receiving different doses. AstraZeneca has so far entered into collaboration agreements with many countries and organizations around the world.
This war with COVID-19 has finally ushered in the dawn after a long and dark year where human society paid the price of more than 60 million infections and 1.48 million deaths, and the advent of the vaccines has made this dawn increasingly bright.
References:
1. Safety and Immunogenicity of an Inactivated SARS-CoV-2 Vaccine, BBIBP-CorV: a Randomised,Double-blind,Placebo-controlled,Phase 1/2 Trial；
2. Tests confirm that Butantan vaccine is the safest in the final stage in Brazil. Retrieved October 20, 2020, from https://www.saopaulo.sp.gov.br/ultimas-noticias/governo-do-estado-atualiza-informacoes-sobre-o-combate-ao-coronavirus-3/；
3. China's Sinovac vaccine is safe, Brazil institute says. Retrieved October 20, 2020, from https://in.reuters.com/article/health-coronavirus-sinovac-brazil/update-1-brazils-butantan-says-tests-show-vaccine-by-chinas-sinovac-is-safe-idINL1N2HA14F；
4. Retrieved Feb. 10，2020, from http://www.cloverbiopharma.com/index.php?m=content&c=index&a=show&catid=11&id=41；
5. AstraZeneca COVID-19 vaccine authorised for emergency use by the World Health Organization.
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