CanSino COVID-19 vaccine

Extended version of the vaccine

CanSino COVID-19 vaccine

Authorization

World Health Organization Emergency Use Listing Procedure
Listed for emergency use on 19 May 2022 [WHO, 2022 ].
EUL/WHO Authorization: Authorized for emergency use in individuals from 18 to 59 years of age [WHO, 2022 ].
SAGE/WHO Recommendation: Authorized for emergency use in individuals 18 years of age and older [WHO, 2022 ].

European Commission (based upon the recommendation of the European Medicines Agency [EMA])
Not authorized.

China's National Medical Products Administration
Authorized on 15 February 2021 [National Medical Products Administration of China, 2020 ].
Conditional marketing authorization for individuals 18 years of age and older.

Regulatory Authorities of Regional Reference in the Americas

National Administration of Drugs, Foods and Medical Devices (ANMAT, Argentina)
Authorized for emergency use on 10 June 2021 [Ministerio de salud de Argentina, 2021 ].

Brazilian Health Regulatory Agency (ANVISA, Brazil)
Not authorized.

Health Canada
Not authorized.

Public Health Institute (ISP, Chile)
Authorized for emergency use on 7 April 2021 [ISP, 2021 ].
Authorized for individuals from 18 to 60 years of age.

National Institute of Food and Drug Monitoring (INVIMA, Colombia)
Not authorized.

Center for the State Control of Drug Quality (CECMED, Cuba)
Not authorized.

U.S. Food and Drug Administration
Not authorized.

Federal Commission for the Protection against Sanitary Risk (COFEPRIS, Mexico)
Authorized for emergency use on 22 March 2021 [COFREPRIS, 2021 ].

Authorization in jurisdictions in Latin America and the Caribbean
Ecuador
Paraguay

Authorization in other jurisdictions
Hungary
Indonesia
Malaysia
Moldova
Pakistan

The Emergency Use Authorization does not constitute marketing authorization in the country.

Manufacturing

Manufacturers
CanSino Biologics Inc., China [WHO, 2022 ].

Other manufacturers
Petrovax pharmaceutical company, Russia [The Moscow Times, 2020 ].

Drugmex, Mexico. Packaging of the vaccine is being produce in Queretaro state [Reuters Staff 1 MIN READ, 2021 ].

Solution Biologics, Malaysia. Produces final filling and packaging of the vaccine for distribution [Solution Biologics, 2021 ].

General characteristics

The recombinant coronavirus vaccine (adenovirus type 5 vector) is based on a mature non-recombinant human adenovirus type 5 vector platform, which efficiently expresses SARS-CoV-2 antigen (protein S) in infected cells. It induces a humoral and cellular immune response against the spike protein of SARS-CoV-2 after vaccination, providing protection to its recipients [Feng-Cai Zhu, 2020 ].

The full spike protein gene of SARS-CoV-2 based on the Wuhan-Hu-1 strain was codon-optimized with UpGene software, and the signal peptide was substituted with tPA for increased expression in mammalian cells. The gene was synthesized and cloned into the plasmid of the AdMax adenovirus system (Microbix Biosystem, Canada) by enzyme digestion and ligation. After sequencing, the plasmid with the target gene was transferred into HEK293 cells. The cells were lysed by three freeze-thaw cycles to release the recombinant viruses. The recombinant adenoviruses were monocloned by agarose plaque selection, amplified by serial passage on HEK293 cells, and purified by ion-exchange chromatography and size exclusion. The number of total viral particles was measured by ultraviolet spectrophotometer analysis [Wu S, 2020 ].

 

The vaccine contains the following ingredients
[WHO, 2022 ]:

Active ingredient
Non-replicating adenovirus Ad5-nCoV ≥4 x 1010 viral particles (PV)

Excipients 
25 mg mannitol
12.5mg sucrose
0.1 mg magnesium chloride
1.5 mg sodium chloride
0.30 mg of N-(2-Hydroxyethyl) piperazine-N´-(2-ethanesulfonic acid)
0.05 mg polysorbate 80
0.75 mg glycerol
459.8 mg of water for the manufacture of injectables

The vaccine does not contain adjuvants or preservatives.

Risk considerations

Clinical experience with the Ad5 platform is mixed. Two studies using an Ad5 vectored HIV-1 vaccine administered found an increased risk of HIV acquisition among vaccinated men. A consensus conference about Ad5 vectors held in 2013 warned that non-HIV vaccine trials that used similar vectors in areas of high HIV prevalence could lead to an increased risk of HIV-1 acquisition in the vaccinated population. The potential mechanism for this increased susceptibility is not completely clear but theories include dampening of HIV immunity, enhancing replication of the AIDS virus, or setting up more target cells for it [Buchbinder SP, 2020 ].

On the other hand, the same effect was not detected in a trial of a recombinant adenovirus type-5 vector-based Ebola vaccine tested in a population in Sierra Leone that had a relatively high HIV prevalence [Zhu FC ]. It is unknown what is the impact on this risk of the genetic engineering process that is applied to Ad5 by different vaccine producers.

Dosing and schedule

Dose-finding studies

CTII-nCoV is a randomized, double-blind, placebo-controlled, phase 2 trial sponsored by Institute of Biotechnology, Academy of Military Medical Sciences, PLA of China and conducted in China. It was registered with ClinicalTrials.gov, NCT04341389 [Insitute of Biotechnology, Academy of Military Medical Sciences, PLA of China, 2020 ].

The sample size was 603 volunteers. The inclusion criteria were healthy adults aged 18 years or over. The study evaluated two vaccination schedules, a single injection of 1×10¹¹ or 5×10¹⁰ viral particles per mL, or a placebo injection, which were randomized at a 2:1:1 ratio. Findings showed that seroconversion rates were 96% (95% CI 93–98) and 97% (92–99), respectively of both vaccine schedules, at day 28. Both doses of the vaccine induced significant neutralizing antibody responses to live SARS-CoV-2 [Zhu FC, 2020 ].

CTCOVID-19 is a non-randomized, dose-escalating phase I study sponsored by the Institute of Biotechnology, Academy of Military Medical Sciences, PLA of China and conducted in China. It was registered with ClinicalTrials.gov NCT04313127 [CanSino Biologics Inc., 2020 ].

The sample size was 108 healthy adults aged between 18 and 60 years, that were sequentially allocated to one of three dose groups (5×10¹⁰, 1×10¹¹, and 1.5×10¹¹ viral particles) to receive an intramuscular injection of vaccine. Safety was assessed over 28 days post-vaccination. Specific antibodies were measured with ELISA, and the neutralizing antibody responses induced by vaccination were detected with SARS-CoV-2 virus neutralization and pseudovirus neutralization tests. Results showed, ELISA antibodies and neutralizing antibodies increased significantly at day 14, and peaked 28 days post-vaccination. Specific T-cell response peaked at day 14 post-vaccination [Zhu FC, 2020 ].

Indications and contraindications

Indications

CanSino COVID-19 vaccine is indicated for individuals 18 years of age and over [WHO, 2022 ].

Contraindications

CanSino COVID-19 vaccine is contraindicated in individuals with a known history of a severe allergic reaction to any component of the vaccine [WHO, 2022 ]. (See the list of ingredients under 'General characteristics' in the extended version).

The second dose of the vaccine should NOT BE GIVEN to those who have experienced anaphylaxis to the first dose.

People who have had thrombosis with thrombocytopenia syndrome (TTS) following the first dose of the Cansino COVID-19 vaccine should not receive a second dose of the same vaccine [WHO, 2022 ].

Precautions
Allergic reactions [WHO, 2022 ].
Persons with a history of anaphylaxis to any other vaccine or injectable therapy should be observed for 30 minutes after vaccination in health care settings where anaphylaxis can be immediately treated.

In general, persons with an immediate non-anaphylactic allergic reaction to the first dose (such as urticaria, angioedema or respiratory symptoms, that occur within 4 hours of administration) should not receive additional doses, unless recommended after review by a health professional with specialist expertise.

Thrombosis with thrombocytopenia syndrome [WHO, 2022 ].
A very rare syndrome of blood clotting combined with low platelet counts, which is described as thrombosis with thrombocytopenia syndrome (TTS) has been reported around 3 to 30 days following vaccination with the Cansino vaccine. A causal relationship between the vaccine and TTS is considered plausible although the biological mechanism for this syndrome is still being investigated.

In countries with ongoing SARS-CoV-2 transmission, the benefit of vaccination in protecting against COVID-19 far outweighs the risks. However, benefit–risk assessments may differ from country to country. As data from additional studies become available, enabling a better understanding of the pathophysiology of TTS and its relationship to the vaccine, recommendations on vaccination will be updated.

Pregnancy [WHO, 2022 ].
Available data from clinical trials are still insufficient to assess vaccine safety or efficacy of the Cansino COVID-19 vaccine in pregnancy. Emerging post-introduction pharmacovigilance data have not identified any pregnancy-related safety concerns.

WHO recommends the use of Cansino COVID-19 vaccine in pregnant women when the benefits of vaccination to the pregnant woman outweigh the potential risks. To help pregnant women make this assessment, they should be provided with information about the risks of COVID-19 in pregnancy, the likely benefits of vaccination, and the current limitations of safety data.
WHO does not recommend pregnancy testing prior to vaccination. WHO does not recommend delaying pregnancy or terminating pregnancy because of vaccination.

Breastfeeding [WHO, 2022 ].
WHO recommends using the CanSino COVID-19 vaccine in breastfeeding as in non-breastfeeding women. This is based on the following considerations: (a) Vaccine effectiveness is expected to be similar in breastfeeding women as in other adults, and (b) CanSino COVID-19 vaccine is not a live virus vaccine, and it is biologically and clinically unlikely to pose a risk to the breastfeeding child.
WHO does not recommend discontinuing breastfeeding after vaccination.

Persons living with HIV [WHO, 2022 ].
Data on the administration of the CanSino COVID-19 vaccine are currently insufficient to allow the assessment of efficacy for persons living with HIV.
Given that the vaccine is nonreplicating, persons living with HIV who are well controlled may be vaccinated. Counseling should be provided to inform the individual benefit-risk assessment.

Persons with previous SARS-CoV-2 infection [WHO, 2022 ].
Vaccination may be offered regardless of a person’s history of symptomatic or asymptomatic SARS-CoV-2 infection.
The optimal time interval between a natural infection and vaccination is not yet known. An interval of 3 months could be considered.

Persons with current acute COVID-19 [WHO, 2022 ].
Persons with acute PCR-confirmed COVID-19 should not be vaccinated until after they have recovered from acute illness and the criteria for discontinuation of isolation have been met.

Other precautions

Vaccination should be postponed in individuals with an acute febrile illness (body temperature over 38.5ºC) until they are afebrile.

Co-administration with other vaccines [WHO, 2022 ].
For adults, COVID-19 vaccines may be administered concomitantly or at any time before or after other adult vaccines, including: live attenuated vaccines, inactivated, adjuvanted, or non-adjuvanted vaccines.
When administered concomitantly, the vaccines should be injected at separate sites, preferably different extremities.

Close observation for at least 30 minutes is recommended following vaccination.

Storage and logistics

Storage

CanSino COVID-19 vaccine is provided as a solution stored between 2°C to 8°C [35° to 46°F].
Vial can be stored refrigerated for up to 12 months between 2°C to 8°C (35° to 46°F) [WHO, 2022 ].
The vials should not be frozen.

Logistic at the time of administration [WHO, 2022 ]

The vaccine should be inspected visually for particulate matter and discoloration prior to administration.

The vial should be inspected visually for cracks or any abnormalities, such as evidence of tampering prior to administration. If any of these should exist, do not administer the vaccine.

Before administering a dose of vaccine, swirl the vaccine in an upright position. The vaccine should not be shaken.

Storage after first puncture [WHO, 2022 ]

After taking the first dose from the multidose vial, the vial should be used within a maximum of 6 hours or discarded at the end of the immunization session, whichever comes first. [WHO, 2022 ].
The single-dose vial should be used immediately after opening. The vial should not be shaken.
To improve traceability, the name and batch number of the administered product should be clearly recorded.

Administration

1. Using aseptic technique, clean the vial stopper with a single-use antiseptic swab.
2. Use a 3 ml reuse prevention syringe (RUP) or a 5 ml RUP syringe, and a 21G or narrower needle.
3. Gently invert the vial to mix, and withdraw the 0.5 ml dose. If the amount of vaccine remaining in the vial cannot provide a full 0.5 ml dose, discard the vial and the remaining volume.
4. Administer the vaccine intramuscularly, preferably into the deltoid muscle. Do not administer the vaccine intravascularly, subcutaneously, or intradermally.

Disposal

Due to the high risk that discarded vials of COVID-19 vaccines may be recovered, it is essential that they are guaranteed to be safely disposed of at the site of use; or study the possibility of applying reverse logistics, if the safe treatment and disposal of vaccine residues cannot be guaranteed, so that they are transferred to the place established for that purpose. Otherwise, consider the possibility that the discarded vaccine vials are shredded, if there is a safe way to do so [WHO, 2021 ].

Clinical studies - general characteristics

Randomized trials

CTII-nCoV was a randomized phase 2 trial (registered with the number NCT04341389 [Insitute of Biotechnology, Academy of Military Medical Sciences, PLA of China, 2020 ]), sponsored by the Institute of Biotechnology and the Academy of Military Medical Sciences, that it was conducted in China. The aim of the study was to evaluate two vaccination schedules. It was first registered in April 2020 and enrolled 603 participants, aged 18 years or older, that receive the vaccine or placebo vaccine in a 2:1:1 ratio. The study was completed in January 2021. Results showed 96% and 97% efficacy on the different vaccinations schemes in the trial [Zhu FC, 2020 ].

AMMS85-2004 was a randomized phase 1 trial sponsored by the Institute of Biotechnology, Academy of Military Medical Sciences, PLA of China, and conducted in China. It was registered in September 2020 with trial registry number NCT04552366 [Institute of Biotechnology, Academy of Military Medical Sciences, PLA of China, 2020 ]. The trial included healthy adults aged 18 years of age and older. The sample size was 230. The mean age of the participants was 36 years in the high dose group, 29 years in the low dose group and in the two-dose group, and 27 years in the aerosolized booster vaccine group and in the single-dose group. The proportion of females was 50%.

Participants were randomly assigned in a 1:1:1:1:1 ratio to one of the following groups:

-Initial high dose (HDmu group) of Ad5-nCoV vaccine on day 0, followed by a booster on day 28

-Low dose (LDmu group) of Ad5-nCoV vaccine on day 0, followed by a booster on day 28 - An initial intramuscular vaccine on day 0, followed by an aerosolized booster vaccine on day 28 (MIX group).

-One dose (1Dim group) of Ad5-nCoV on day 0.

-Two doses (2Dim group) of Ad5-nCoV on day 0 [Wu, Shipo, 2021 ].

CS-CTP-AD5NCOV-Ⅲ was a phase 3 randomized trial sponsored by CanSino Biologics Inc. and conducted in Argentina, Chile, Mexico, Pakistan, and Russia. It was registered in September 2020 with trial registry number NCT04526990 [CanSino Biologics Inc., 2020 ]. 
The trial included adults 18 years and older. 
The sample size was 36,982. The mean age of the participants was 37 years. The proportion of women was ranged from 28%-30% between intervention groups. 
Participants were randomly assigned in a 1:1 ratio to receive vaccine o placebo. The intervention was administered as a single intramuscular dose of 0.5 mL placebo or a 0.5 mL dose of Cansino COVID-19 vaccine [Halperin SA, 2021 ].

JSVCT116 was a phase 4 randomized trial sponsored by Jiangsu Province Centers for Disease Control and Prevention and conducted in China. It was registered in May 2021 with trial registry number NCT04892459 [Jiangsu Province Centers for Disease Control and Prevention, 2021 ]. The trial included healthy adults 18-59 years of age. The sample size was 300. The mean age of the participants was ranged from 42-45 years of age between groups. The proportion of women was ranged from 37%-47% between groups.

Participants were randomly assigned in a 1:1 ratio to one of the following groups:

- Two doses of Coronavac and a booster dose of Convidecia

- Two doses of Coronavac and a booster dose of CoronaVac 

- One dose of Coronavac and a booster dose of Convidecia

- One dose of Coronavac and a booster dose of CoronaVac [Jingxin Li, 2021 ].

Prometheus_Rus is a phase III clinical trial (registered with the number NCT04540419 [NPO Petrovax, 2020 ]) sponsored by NPO Petrovax that is being conducted in Russia. It was first registered on 11 September 2020 and enrolled 500 healthy adults aged 18 to 85 years old that received the Ad5-nCoV single-dose vaccine or placebo vaccine.

Halperin SA et al is an ongoing phase III trial (registered with the number ChiCTR2100044249 [Canadian Center for Vaccinology Dalhousie University/IWK Health Centre , 2021 ]) sponsored by Canadian Center for Vaccinology Dalhousie University/IWK Health Centre, that is being conducted in Pakistan, Argentina, Rusia, Chile and Mexico. It was first registered in March 2021 and plans to enroll 40000 adults of 18 years of age and more that will receive 0.5mL of intramuscular vaccine or placebo vaccine. It is expected to run until February 2022.

Ad5-nCoV-2020003 is an ongoing Phase 1/2 trial (registered with the number NCT04398147 [CanSino Biologics Inc., 2020 ]) sponsored by CanSino Biologics Inc., that is being conducted in Canada. It was first registered in August 2020 and plans to enroll 696 healthy adults from 18 to <55, and 65 to <85 years of age that will receive recombinant novel Coronavirus vaccine (Adenovirus Type 5 Vector) or placebo vaccine. It is expected to run until December 2021.

JSVCT118 is an ongoing single-center, randomized and double-blinded trial (registered with the number NCT04916886) sponsored by CanSino Biologics Inc. that is being conducted in China [CanSino Biologics Inc., 2021 ]. It was first registered in June 2021 and plans to enroll 2016 individuals 6-59 years of age that will receive Ad5-nCoV. It is expected to run until August 2022.

FH-58 is an ongoing double-blind, randomized, multi-center, placebo-controlled, clinical trial (registered with the number NCT05005156) sponsored by Fundación Huésped that is being conducted in Argentina [Fundación Huésped, 2021 ]. It was first registered in August 2021 and plans to enroll 876 participants 18 years of age and older, living with HIV that will receive Ad5-nCoV or placebo. It is expected to run until September 2022.

 

Other studies providing efficacy or safety data

CTCOVID-19 is a non-randomized study on 108 healthy adults aged between 18 and 60 years, that were sequentially allocated to one of three dose groups (5.0 × 1010, 1.0 × 1011, and 1.5 × 1011 viral particles) to receive an intramuscular injection of vaccine. The study was conducted in China from March 2020 to December 2020. The results were published in a scientific journal on May 22, 2020 [Zhu FC, 2020 ].

7 vaccines against COVID 19 is an ongoing prospective Cohort study (registered with the number NCT05228912 [Hospital Clinica Nova, 2021 ]) sponsored by Hospital Clinica Nova that is being conducted in Mexico. It was first registered in February 2022 and plans to enroll 1870 Children, Adult and Older Adult that will receive Pfizer-BioNTech, Moderna, Gamaleya, Cansino, Sinovac, Astrazeneca and Janssen COVID-19 vaccines. It is expected to run until October 2024.

Methods used to assess efficacy

In the CS-CTP-AD5NCOV-Ⅲ trial [Halperin SA, 2021 ], the primary efficacy objective was the prevention of symptomatic, PCR-confirmed COVID-19 infection at least 28 days after vaccination in all participants who were at least 28 days post-vaccination. Endpoints were judged by the independent endpoint review committee.

Confirmed cases of COVID-19 were categorized into primary endpoint cases and secondary endpoint cases according to the time of onset after vaccination:

  • Primary endpoint: the participant with the clinical symptom(s) occurred not less than 28 days post-vaccination and the PCR test is positive.
  • Secondary endpoint: the participant with the clinical symptom(s) occurred not less than 14 days post-vaccination and the PCR test is positive, or 4-fold or greater increase of anti-N IgG is detected after the occurrence of the clinical symptom(s).

Safety evaluation methods

In the CS-CTP-AD5NCOV-Ⅲ trial [Halperin SA, 2021 ], the primary safety objective is to evaluate the incidence of serious adverse events and medically attended adverse events within 52 weeks after vaccination in all participants.

The following secondary endpoints were included in safety assessments

  1. Incidence of solicited adverse reactions within 7 days after vaccination.
  2. Incidence of unsolicited adverse events within 28 days after vaccination.

Vaccine efficacy and effectiveness

Efficacy of preclinical studies on the vaccine

Results of geometric mean titers in mice showed that Ad5-nCoV had good immunogenicity and the value of antibody increased with the time of vaccination in a dose-dependent manner. Fourteen days after the injection, the levels of IFN-γ, TNF-α and IL-2 expressed by CD8+ T cells and CD4+ T cells in the vaccine groups were significantly higher than those in the control group (P < 0.001). It can be suggested that the recombinant novel coronavirus vaccine (adenovirus type 5 vector) can induce strong specific cellular immune responses in mice [Feng-Cai Zhu, 2020 ].

Studies in guinea pigs, showed that the anti-S protein IgG antibodies were detected 14 and 28 days after single vaccination. Results showed that the vaccine had good immunogenicity [Feng-Cai Zhu, 2020 ].

24 ferrets were randomly assigned to three groups: high dose vaccine group (2.0 × 1010 viral particles), low dose vaccine group (2.0 × 109 viral particles) and control group. Each ferret was injected intramuscularly once at day 0. The live SARS-CoV-2 virus was challenged at day 14 after vaccination. The results showed that the recombinant adenovirus vector vaccine could induce neutralizing antibodies within 2 weeks, and the replication level of upper respiratory tract virus in immunized animals was significantly lower than that in control animals. The results showed that the vaccine had good immunogenicity and could induce immune protection against upper respiratory tract SARS-CoV-2 infection [Feng-Cai Zhu, 2020 ].

12 rhesus monkeys were randomly assigned to three groups: high dose vaccine group (2.0 × 1011 viral particles), low dose vaccine group (5.0 × 1010 viral particles), and control group. Each rhesus monkey was injected intramuscularly once at day 0, and then the animal was challenged with the live SARS-CoV-2 virus at day 14 after vaccination. After challenge, there was no significant increase in body temperature in the vaccine groups, and a high level of viral load was detected in pharynx swab, anal swab, and lung tissue. Results suggest that high-dose and low-dose of vaccine has a certain protective effect [Feng-Cai Zhu, 2020 ].

Efficacy of the vaccine in clinical trials

Main immunogenicity outcomes

The primary endpoints for immunogenicity were the geometric mean titers (GMTs) of RBD-specific ELISA antibody responses and neutralizing antibody responses against live virus or pseudovirus at day 28 post-vaccination. A total of 508 participants were randomly assigned to vaccine or placebo, 253 participants were assigned to the 1 × 10^11 viral particles dose group, 129 to the 5 × 10^10 viral particles dose group, and 126 to the placebo group. The mean age of the participants was 39.7 years (range 18-83 years old).
RBD-specific ELISA antibody responses induced by the CanSino COVID-19 vaccine were detected from day 14 onwards, with GMTs of 94.5% (95% CI 80.5-110.8) and 85% (66-110) in the 1×10^11 and 5×10^10 viral particles dose groups, respectively. At day 28, the antibodies peaked at 657% (575.2-749.2) in the 1×10^11 viral particles dose group and 571% (467.6-697.3) in the 5×10^10 viral particles dose group. Seroconversion rates were 96% (95% CI 93-98), this means 244 of 253 participants in the 1×10^11 viral particles dose group and 97% (95% CI 92-99), this means 125 of 129 participants in the 5×10^10 viral particles dose group, at day 28 post-vaccination [Zhu FC, 2020 ] "

Both vaccine doses induced significant neutralizing antibody responses to live SARS-CoV-2, with GMTs of 19.5% (95% CI 16.8-22.7) and 18.3% (95% CI 14.4-23.3) in participants in the 1×10^11 and 5×10^10 viral particles dose groups, respectively, at day 28 post-vaccination. Seroconversion of the neutralizing antibody responses to live SARS-CoV-2 occurred in 59% (95% CI 52-65), this means 148 of 253 participants receiving the 1×10^11 viral particles dose, and in 47% (95% CI 39-56), this means 61 of 129 participants receiving the 5×10^10 viral particles dose 28 days post-vaccination. No significant differences were observed between the two-dose groups in the neutralizing antibody responses to live virus [Zhu FC, 2020 ].


Key messages

CanSino COVID-19 vaccine reduces the risk of contracting COVID-19

CanSino COVID-19 vaccine reduces the risk of contracting severe COVID-19

Main efficacy outcomes of CanSino COVID-19 vaccine

Contracting COVID-19 (measured at least 14 days after injection)

The relative risk of contracting COVID-19 in the group that received CanSino COVID-19 vaccine versus the group that received control vaccine was 0.7 (95% CI 0.19 to 2.58). This means CanSino COVID-19 vaccine reduced the risk of contracting COVID-19 by 30%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19. Comparison: CanSino COVID-19 vaccine versus control vaccine

In the trials identified in this review, 211 people not receiving CanSino COVID-19 vaccine out of 14586 presented this outcome (15 per 1000) versus 77 out of 14591 in the group that did receive it (10 per 1000). In other words, 5 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.5%, or that the intervention reduced the risk of contracting COVID-19 by 0.5 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNT is 200. Which means that 200 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Contracting severe COVID-19 (measured at least 14 days after injection)

The relative risk of contracting severe COVID-19 in the group that received CanSino COVID-19 vaccine versus the group that received control vaccine was 0.07 (95% CI 0.01 to 0.35). This means CanSino COVID-19 vaccine reduced the risk of contracting severe COVID-19 by 93%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting severe COVID-19. Comparison: CanSino COVID-19 vaccine versus control vaccine

In the trials identified in this review, 25 people not receiving CanSino COVID-19 vaccine out of 14586 presented this outcome (2 per 1000) versus 1 out of 14591 in the group that did receive it (0 per 1000). In other words, 2 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.2%, or that the intervention reduced the risk of contracting severe COVID-19 by 0.2 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNT is 500. Which means that 500 people need to receive the vaccine for one of them to not contract severe COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Mortality

The existing evidence does not allow to assess the impact of Pfizer-BioNTech COVID‑19 Vaccine on the risk of mortality. The information provided by randomized trials was not adequately powered to estimate a difference in this outcome. Deaths can occur in the intervention and control group for reasons unrelated to COVID-19 or the vaccine. Establishing that there is a reduction (or increase) in the risk of death attributable to COVID-19 would require trials with a higher statistical power.

Efficacy of the vaccine in subgroups


Contracting COVID-19 (>60y) (measured at least 14 days after injection)

The relative risk of contracting COVID-19 (>60y) at least 28 days after injection in the group that received CanSino COVID-19 vaccine versus the group that received control vaccine was 0.48 (95% CI 0.23 to 1.03). This means CanSino COVID-19 vaccine reduced the risk of contracting COVID-19 (>60y) at least 28 days after injection by 52%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (>60y) at least 28 days after injection. Comparison: CanSino COVID-19 vaccine versus control vaccine

In the trial identified in this review, 21 people not receiving CanSino COVID-19 vaccine out of 1347 presented this outcome (16 per 1000) versus 10 out of 1323 in the group that did receive it (8 per 1000). In other words, 8 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.8%, or that the intervention reduced the risk of contracting COVID-19 (>60y) at least 28 days after injection by 0.8 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNT is 125. Which means that 125 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The reason for downgrading the certainty of the evidence is imprecision because of the low number of events and wide confidence interval. No reasons for concern were detected in relation to risk of bias, inconsistency, indirect evidence or publication bias.

Contracting COVID-19 (Males subgroup) (measured at least 14 days after injection)

The relative risk of contracting COVID-19 (Males subgroup) at least 28 days after injection in the group that received CanSino COVID-19 vaccine versus the group that received control vaccine was 0.32 (95% CI 0.23 to 0.45). This means CanSino COVID-19 vaccine reduced the risk of contracting COVID-19 (Males subgroup) at least 28 days after injection by 68%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (Males subgroup) at least 28 days after injection. Comparison: CanSino COVID-19 vaccine versus control vaccine

In the trial identified in this review, 138 people not receiving CanSino COVID-19 vaccine out of 10009 presented this outcome (14 per 1000) versus 43 out of 9797 in the group that did receive it (4 per 1000). In other words, 10 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 1%, or that the intervention reduced the risk of contracting COVID-19 (Males subgroup) at least 28 days after injection by 1 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNT is 100. Which means that 100 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Contracting COVID-19 (Female subgroup) (measured at least 14 days after injection)

The relative risk of contracting COVID-19 (Female subgroup) at least 28 days after injection in the group that received CanSino COVID-19 vaccine versus the group that received control vaccine was 0.44 (95% CI 0.3 to 0.67). This means CanSino COVID-19 vaccine reduced the risk of contracting COVID-19 (Female subgroup) at least 28 days after injection by 56%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (Female subgroup) at least 28 days after injection. Comparison: CanSino COVID-19 vaccine versus control vaccine

In the trial identified in this review, 73 people not receiving CanSino COVID-19 vaccine out of 4577 presented this outcome (16 per 1000) versus 34 out of 4794 in the group that did receive it (7 per 1000). In other words, 9 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.9%, or that the intervention reduced the risk of contracting COVID-19 (Female subgroup) at least 28 days after injection by 0.9 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNT is 111. Which means that 111 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Summary of findings (iSoF) Table

Efficacy and effectiveness of the vaccine in subgroups

Sex

Randomized trials

The proportion of women in the CS-CTP-AD5NCOV-Ⅲ trial was 30.1% in vaccine group and 28.4% in placebo group (6,220 out of 21,250 participants) [Halperin SA, 2021 ]. The relative risk of contracting COVID-19 in women in the group that received the CanSino COVID-19 vaccine versus the group that received placebo vaccine was 0.58 (95% CI 0.33 to 1.02). This means the CanSino COVID-19 vaccine reduced the risk of contracting COVID-19 in women by 40%, compared with placebo vaccine. The relative risk of contracting COVID-19 in men in the group that received the CanSino COVID-19 vaccine versus the group that received placebo vaccine was 0.34 (95% CI 0.22 to 0.54). This means the CanSino COVID-19 vaccine reduced the risk of contracting COVID-19 in men by 66%, compared with placebo vaccine. 
The magnitude of the effect was similar between the subgroups, and there was no statistical evidence of a subgroup effect by sex

 

Age

Randomized trials

The proportion of participants ≥ 60 years years of age in the CS-CTP-AD5NCOV-Ⅲ trial was 7% (1,679 out of 21,250 participants) [Halperin SA, 2021 ].

In participants <60 years, vaccine efficacy was similar at 28 days and 14 days post-vaccination. In participants ≥60 years and older, vaccine efficacy after 14 days post-vaccination was lower than in the younger group (53.3%) and much lower 28 days post-vaccination than participants <60 years, with wide confidence intervals, being 17.5% (95% CI -127.6 to 70.1).

 

Children and adolescents

Randomized trials

Children were excluded from the CS-CTP-AD5NCOV-Ⅲ trial, therefore no data are available for this subgroup [Halperin SA, 2021 ].

The single-center, randomized and double-blinded trial JSVCT118 is currently evaluating the efficacy/safety/Immunogenicity of the vaccine in individuals 6-59 years of age [CanSino Biologics Inc., 2021 ].

Pregnancy

Randomized trials

Pregnant women were excluded from the CS-CTP-AD5NCOV-Ⅲ trial, therefore no data are available for this subgroup [Halperin SA, 2021 ].

 

Breastfeeding

Randomized trials

Breastfeeding women were excluded from the CS-CTP-AD5NCOV-Ⅲ trial, therefore no data are available for this subgroup [Halperin SA, 2021 ].

 

Immunocompromised persons

Randomized trials

Immunocompromised persons were excluded from the CS-CTP-AD5NCOV-Ⅲ trial, therefore no data are available for this subgroup [Halperin SA, 2021 ].

The double-blind, randomized, multi-center, placebo-controlled, clinical trial FH-58 is currently evaluating the Immunogenicity of the vaccine in participants 18 years of age and older, living with HIV [Fundación Huésped, 2021 ].

Contracting COVID-19

No studies reported or assessed this outcome.

Contracting severe COVID-19

No studies reported or assessed this outcome.

Transmission

No studies reported or assessed this outcome.

Immunogenicity outcomes

Omicron (B.1.1.529.1)

Zhe Zhang et al. recruited 904 participants with a previous CoronaVac two-dose vaccination scheme who recieved booster doses of the intramuscular CanSino (n=229), aerosolized CanSino vaccine (n=223), Anhui Zhifei vaccine (n=219), or CoronaVac (n=253) 6 months after their primary scheme. Neutralizing antibodies against the Omicron variant was increased after the booster dose, being superior in the CanSino booster groups (GMT of 261 [95% CI 178-382] for IM CanSino and 320 [95% CI 191-538] at day 14) compared to Anhui Zhifei and CoronaVac groups (GMT: 86 [95% CI 59-127], and 54 [95% CI 42-71], respectively) [Zhe Zhang, 2022 ].

Effectiveness outcomes

No studies reported or assessed this outcome.

No studies have reported immunogenicity, or effectiveness outcomes for booster schedules.

Immunogenicity outcomes

JSVCT116 was a phase 4 randomised trial sponsored by Jiangsu Province Centers for Disease Control and Prevention and conducted in China. The study included 101 participants: 51 with an heterologous two-dose schedule (Sinovac+CanSino), and 50 with a SinoVac two-dose homologous schedule. Results showed that the heterologous immunization with CanSino induced higher live viral neutralizing antibodies (GMT: 54.4 [CI 95% 37.9 to 78.0]) compared to the homologous immunization with Sinovac (GMT: 12.8 [CI 95% 9.3 to 17.5]) measured 14 days after the booster vaccination [Jingxin Li, 2021 ].

Li J et al. was a phase 4 randomised trial that included 300 participants: 200 with two doses of Sinovac + booster dose of Cansino and 100 with two doses of Sinovac + booster dose of Sinovac. The study showed superior post-vaccination GMTs of neutralizing antibodies against live wild-type SARS-CoV-2 virus in the heterologous group compared to the homologous group, with a Geometric mean fold increase (GMFI) of 78.3 evaluated 14 days after booster vaccination [Li J, 2022 ].

Immunogenicity outcomes

JSVCT116 was a phase 4 randomized trial sponsored by Jiangsu Province Centers for Disease Control and Prevention and conducted in China. The study included 101 participants: 51 with a heterologous two-dose schedule (Sinovac+CanSino), and 50 with a SinoVac two-dose homologous schedule. Results showed that the heterologous immunization with CanSino induced higher live viral neutralizing antibodies (GMT: 54.4 [CI 95% 37.9 to 78.0]) compared to the homologous immunization with Sinovac (GMT: 12.8 [CI 95% 9.3 to 17.5]) measured 14 days after the booster vaccination [Jingxin Li, 2021 ].

Li J et al. was a phase 4 randomized trial that included 300 participants: 200 with two doses of Sinovac + Cansino booster and 100 with two doses of Sinovac + Sinovac booster. The study showed superior post-vaccination GMTs of neutralizing antibodies against live wild-type SARS-CoV-2 virus in the heterologous group compared to the homologous group, with a Geometric mean fold increase (GMFI) of 78.3 evaluated 14 days after booster vaccination [Li J, 2022 ].

Pengfei J. et al was a phase 4 randomized trial that included 120 participants with previous CanSino vaccination receiving one or two booster doses of the Anhui Zhifei vaccine in two different schedules: (a) 0-28-5m (n=60), and (b) 0-56-6m (n=60). The study showed that a heterologous booster dose with the Anhui Zhifei vaccine induced a significantly higher neutralizing antibody response against wild-type SARS-CoV-2 in both schedules (GMT of neutralizing antibodies after the first booster dose of 58.4 [95% CI: 42.8 to 79.8] in the 28-day group, and 80.8 [95% CI: 53.1 to 122.9] in the 56-day group), compared to the initial immunization with CanSino. The T-cell response was robust after the heterologous booster dose and similar between the 28-day and 56-day groups.

Zhe Zhang et al. recruited 904 participants with a previous CoronaVac two-dose vaccination scheme, who received booster doses of the intramuscular CanSino (n=229), aerosolized CanSino vaccine (n=223), Anhui Zhifei vaccine (n=219), or CoronaVac (n=253) 6 months after their primary scheme. Heterologous boosting with CanSino via different routes elicited significantly higher binding antibody levels compared to the other groups with a median antibody fold increase of 284 (IQR: 115-507) for the IM CanSino booster and 361 (IQR: 149-841) for the aerosolized CanSino booster compared to 120 (IQR: 22-108) for CoronaVac and 120 (IQR: 42-360) for Anhui Zhifei. The heterologous booster schedules elicited a higher neutralizing response against the Omicron variant than the homologous schedule. Vaccination with a CanSino booster induced the highest levels of T-cell responses compared to baseline levels.

Safety of the vaccine

Safety of the vaccine in preclinical studies

Toxicity experiments performed in rats showed no changes in all animal indexes, including clinical observation, body weight and food intake. The recombinant novel coronavirus vaccine (adenovirus vector) was given to each rat by intramuscular injection at one dose, and no toxic reaction was observed. The maximum tolerated dose (MTD) of each rat was ≥ 0.5×1011 viral particles/dose [Feng-Cai Zhu, 2020 ].

Toxicity experiments of repeated intramuscular injection in cynomolgus monkeys were performed. During the experiment, no deaths were observed, and no abnormal reaction related to drug administration was found in clinical observation. Moreover, no allergic reaction symptoms were found in the clinical observation period after the two administration schedules. During the experiment, animals in the low and high dose groups (1 dose and 3 doses), showed normal clinical parameters regarding body weight and weight gain, body temperature, ECG waveform, and blood pressure parameters. In addition, clinicopathology, T lymphocyte subsets (CD3+, CD4+, CD8+, CD4+/CD8+), serum cytokines (IL-2, IL-4, IL-5, IL-6, TNF- α, IFN-γ), C-reactive protein and serum complement (C3, C4) did not change significantly or showed no abnormal changes in toxic physiology during the 4 weeks follow-up period [Feng-Cai Zhu, 2020 ].

Safety of the vaccine in clinical trials

Key messages

CanSino COVID-19 vaccine reduces the risk of any adverse event after the 1st dose

CanSino COVID-19 vaccine probably reduces the risk of serious adverse events

Main safety outcomes of CanSino COVID-19 vaccine

Any adverse event (within 7 days after injection)

The relative risk of any adverse event after the 1st dose in the group that received CanSino COVID-19 vaccine versus the group that received control vaccine was 1.29 (95% CI 0.87 to 1.9). This means CanSino COVID-19 vaccine increased the risk of any adverse event after the 1st dose by 29%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 1st dose. Comparison: CanSino COVID-19 vaccine versus control vaccine

In the trial identified in this review, 334 people not receiving CanSino COVID-19 vaccine out of 1698 presented this outcome (197 per 1000) versus 463 out of 1957 in the group that did receive it (253 per 1000). In other words, 56 more people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 5.6%, or that the intervention increased the risk of any adverse event after the 1st dose by 5.6 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNH is 18. Which means that 18 people need to receive the vaccine for one of them to present any adverse events.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Serious adverse events (within 7 days after injection)

The relative risk of serious adverse events in the group that received CanSino COVID-19 vaccine versus the group that received control vaccine was 0.36 (95% CI 0.02 to 7). This means CanSino COVID-19 vaccine reduced the risk of serious adverse events by 64%, compared with control vaccine.


In the trial identified in this review, 15 people not receiving CanSino COVID-19 vaccine out of 18478 presented this outcome (8 per 10000) versus 15 out of 18735 in the group that did receive it (3 per 10000). In other words, 5 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.05%, or that the intervention reduced the risk of serious adverse events by 0.05 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNT is 2000. Which means that 2000 people need to receive the vaccine for one of them to present serious adverse events.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate.


Summary of findings (iSoF)

Safety of the vaccine in subgroups

Sex

Randomized trials

The proportion of women in the CTII-nCoV was 50.3% (192 out of 382 participants) [Zhu FC, 2020 ].

The proportion of women that experienced adverse effects with CanSino COVID-19 vaccine versus the group that received placebo vaccine was not reported in detail.

The proportion of women in the CS-CTP-AD5NCOV-Ⅲ trial was 30.1% in the vaccine group and 28.4% in the placebo group (6,322 vaccine group and 6,154 placebo group) [Halperin SA, 2021 ]. The proportion of women that experienced serious adverse effects with the CanSino COVID-19 vaccine was 0.1%.

 

Age

Randomized trials

The proportion of participants 18-44 years of age in the CTII-nCoV was 60.7% (232 out of 382 participants) [Zhu FC, 2020 ].

The proportion of participants 45-54 years of age in the CTII-nCoV was 25.9% (99 out of 382 participants) [Zhu FC, 2020 ].

The proportion of participants >55 years of age in the CTII-nCoV was 13.4% (51 out of 382 participants) [Zhu FC, 2020 ].

Increasing age was statistically associated with a significantly lower occurrence of fever post-vaccination (p<0.001).

 

Children and adolescents

Randomized trials

Children were excluded from the CS-CTP-AD5NCOV-Ⅲ trial, therefore no data are available for this subgroup [Halperin SA, 2021 ].].

 

Pregnancy

Randomized trials

Pregnant women were excluded from the CS-CTP-AD5NCOV-Ⅲ trial, therefore no data are available for this subgroup [Halperin SA, 2021 ].

 

Breastfeeding

Randomized trials

Breastfeeding women were excluded from the CS-CTP-AD5NCOV-Ⅲ trial, therefore no data are available for this subgroup [Halperin SA, 2021 ].

 

Immunocompromised persons

Randomized trials

Immunocompromised persons were excluded from the CS-CTP-AD5NCOV-Ⅲ trial, therefore no data are available for this subgroup [Halperin SA, 2021 ].

Safety of the vaccine post-authorization

Post-authorization studies

Comparative studies

No comparative study reported or evaluated this outcome.

Non-comparative studies

None available.

Monitoring

WHO recommends the following research and post-authorization monitoring activities:

Safety surveillance and monitoring
- Serious adverse events, anaphylaxis and other serious allergic reactions, Bell’s palsy, cases of multisystem inflammatory syndrome following vaccination, cases of COVID-19 following vaccination that result in hospitalization or death.

Vaccine effectiveness
− Vaccine effectiveness over time and whether protection can be prolonged by booster doses.
− Studies to investigate whether this vaccine reduces SARS-CoV-2 transmission and viral shedding.
− Assessment and reporting of vaccination failures and virus sequence information.

Subgroups
− Prospective studies on the safety of COVID-19 vaccine in pregnant and lactating females.
− Randomized controlled trials on efficacy and safety of vaccination in children below the age of 18 years.
− Safety data on vaccination in immunocompromised people, including patients living with HIV and autoimmune disease.

Vaccination logistics
− Immunogenicity and safety studies of co-administration with other vaccines, including influenza and pneumococcal vaccines, to adults and older persons.
− Safety, immunogenicity, and impact of a delayed second dose, as currently implemented by certain countries.
− Stability of the vaccine under alternative cold-chain distribution and storage conditions.
− Effectiveness of the proposed strategies for the prevention and management of anaphylactic reactions.
− Interchangeability studies within and across COVID-19 vaccine platforms.

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