CanSino COVID-19 vaccine

Extended version of the vaccine

CanSino COVID-19 vaccine

Authorization

World Health Organization Emergency Use Listing Procedure
Not authorized
Dossier accepted for review [last checked at WHO EUL official website on September 30, 2021]

European Commission (based upon the recommendation of the European Medicines Agency)
Not authorized

China's National Medical Products Administration
Authorized [National Medical Products Administration of China, 2020 ]
February 15, 2021
Conditional marketing authorization in 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: 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: 7 April 2021 [ISP, 2021 ]
Authorize for individuals between 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: 22 March, 2021 [COFREPRIS, 2021 ]

Authorization in other jurisdictions in the Americas
Ecuador
Paraguay

Authorization in other jurisdictions
Hungary
Malaysia
Pakistan

Manufacturing

Manufacturers
CanSino Biologics Inc.; China: Manufacturer of recombinant novel Coronavirus vaccine (Adenovirus Type 5 Vector) conditionally approved in 2021. Production capacity of 500 million doses annually [Liu Wei, 2021 ]

Other manufacturers
Petrovax pharmaceutical company; Russia. Production of 10 million doses per month in 2021 [The Moscow Times, 2020 ]
Drugmex; Mexico. The company expects to produce 6.9 million doses between March and June, 2021, and then make 1.2 million shots available per week to fulfill its agreement for 35 million doses this year. 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 [The Malaysian in sight, 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 VP was measured by ultraviolet spectrophotometer analysis [Wu S, 2020 ].
Dosage form and ingredients
The pharmaceutical form is a solution for intramuscular injection that is provided in a monodose vial of 0.5 mL, or as a multidose vial of 10 doses of 0.5 mL each.

The vaccine contains the following ingredients:
Active ingredient:
Non-replicating adenovirus Ad5-nCoV ≥4x1010 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.

Dosification 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 older. 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 × 10^10, 1 × 10^11, and 1.5 × 10^11 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 ].

There is no data available on the interchangeability of the CanSino COVID-19 vaccine with other COVID-19 vaccines to complete the vaccination series.
There is no evidence yet about the effects of the coadministration of CanSino COVID-19 vaccine with other vaccines included in routine vaccination programs

Indications and contraindications

Indications
CanSino COVID-19 vaccine is indicated in adult individuals 18 years of age and older [Gobierno de México, 2021 ].

Contraindications
CanSino COVID-19 vaccine is contraindicated in individuals with a known history of a severe allergic reaction to any component of the vaccine [Gobierno de México, 2021 ].

Precautions
Severe allergic reaction (e.g., anaphylaxis) to a previous dose of any vaccine (not including CanSino COVID-19 vaccine).
Severe allergic reaction (e.g., anaphylaxis) to an injectable medication.
Vaccination should be postponed in individuals suffering from acute severe febrile illness, or acute infection [Gobierno de México, 2021 ].
Reactions related with stress or anxiety, such as syncope or hyperventilation may occur in association with vaccination as a psychogenic response to the needle injection. It is important that precautions are in place to avoid injury from fainting.
As with other intramuscular injections, the vaccine should be given with caution in individuals with bleeding disorders or other conditions that increase the risk of bleeding, such as anticoagulant therapy, thrombocytopenia, and hemophilia [Gobierno de México, 2021 ].
The available data of CanSino COVID-19 vaccine on pregnant females are insufficient to assess vaccine efficacy in pregnancy since no clinical trial evaluating vaccines to prevent COVID-19 has included pregnant females. The vaccine should only be given to pregnant females if risks outweigh the benefit [Gobierno de México, 2021 ].
The available data of CanSino COVID-19 vaccine on lactating females are insufficient to assess whether the vaccine is excreted in human milk or if there is any associated risk.
The available data on CanSino COVID-19 vaccine on children are insufficient to assess vaccine efficacy since no clinical trial evaluating vaccines to prevent COVID-19 has included children [Gobierno de México, 2021 ].
The interaction of concomitant administration of with other vaccines has not been studied. [Gobierno de México, 2021 ]
There should be a minimum interval of 14 days between the administration of this vaccine with any other vaccine in the immunization schedule, until data on co-administration with other vaccines are available.
Vaccination may be offered regardless of a person‘s history of symptomatic or asymptomatic SARS-CoV-2 infection.
Although there are currently no medical contraindications on the vaccinating of a person with COVID-19, it is recommended to defer all vaccinations until complete recovery [PAHO, 2020 ].
Although there are currently no contraindications on the vaccinating of a person who has had contact with a COVID-19 case, it is recommended to defer vaccination until the quarantine has been completed (14 days after the last exposure) [PAHO, 2020 ].

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 at 5°C /41°F (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) [Gobierno de México, 2021 ]
Do not freeze the vials

Logistic at the time of administration [Gobierno de México, 2021 ]
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. Do not shake.
Storage after first puncture
After taking the first dose from the multidose vial, use the vial as soon as possible, within a maximum of 6 hours. The single-dose vial should be used immediately after opening.
Do not shake the vial.
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 [Gobierno de México, 2021 ]
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 ongoing randomised, single-center, open-label, phase 1 trial sponsored by Institute of Biotechnology, Academy of Military Medical Sciences, PLA of China, and conducted China. It was registered in September 2020 with trial registry number NCT04552366.
The trial included healthy adults aged 18 years and older.
The sample size was 230. The mean age of the participants was 36 years in the HDmu group, 29 years in the LDmu and 2Dim groups, and 27 years MIX and 1Dim group. The proportion of females was 50%.
Participants were randomly assigned in a 1:1:1:1:1 ratio to one of 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 ]"
JSVCT116 was a phase 4, randomized, controlled, observer-blinded trial sponsored by Jiangsu Province Centers for Disease Control and Prevention and conducted China. It was registered in May 2021 with trial registry number NCT04892459.
The trial included healthy adults 18-59 years of age.
The sample size was 300. The mean age of the participants was ranged in age from 42-45 between groups years. 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:
1. Two doses Coronavac and a booster dose of Convidecia
2. Two doses Coronavac and a booster dose of CoronaVac
3. One dose Coronavac and a booster dose of Convidecia
4. One dose Coronavac and a booster dose of CoronaVac [Jingxin Li, 2021 ].

Ongoing randomized trials
Prometheus_Rus is an ongoing phase III">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 September 11, 2020 and plans to enroll 500 healthy adults aged 18 to 85 years old that will receive Ad5-nCoV single dose vaccine or placebo vaccine. It is expected to run until July 31, 2021.

Halperin SA et al is an ongoing phase III">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 for until August 2022.
FH-58 is an ongoing double-blind, randomized, multi-centre, 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 for until September 2022.

Other studies providing efficacy or safety data
CTCOVID-19 is a non-randomized, dose-escalating phase I study on 108 healthy adults aged between 18 and 60 years, that were sequentially allocated to one of three dose groups (5 × 10^10, 1 × 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 ].

Other ongoing registered studies

Methods used to assess efficacy and effectiveness

There are no phase 3 randomized trials that have yet reported outcome data.

Methods used to assess safety

There are no phase 3 randomized trials that have yet reported outcome data.

Efficacy and effectiveness of the vaccine

Efficacy of the vaccine in preclinical studies

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 (2×1010vp), low dose vaccine group (2×109vp) 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 (2×1011vp), low dose vaccine group (5×1010vp), 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 ].

Main efficacy outcomes of CanSino COVID-19 vaccine

Contracting COVID-19

The risk of contracting any COVID-19 infection has not yet been reported, so it was not possible to estimate the effect for this outcome.


Contracting severe COVID-19

The risk of contracting severe COVID-19 infection has not yet been reported, so it was not possible to estimate the effect for this outcome.


Efficacy and effectiveness of the vaccine on subgroups

Sex

Randomized trials
The proportion of female in the CTII-nCoV was 50.3% (192 out of 382 participants) [Zhu FC, 2020 ].
Male and female participants who received the vaccine showed similar RBD-specific ELISA antibody and neutralizing antibody responses post-vaccination.

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 ].
Age stratified analysis found that participants aged 55 years or older were associated with relatively low antibody responses in both dose groups post-vaccination, particularly in terms of neutralizing antibodies to live viruses. Increasing age was found to be a negative impact factor on the RBD-specific ELISA antibody (p=0·0018), and neutralizing antibody responses to live virus (p<0.001).
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 ].

Children and adolescents

Randomized trials
Children were excluded from the CTII-nCoV trial, so no data are available for this subgroup [Zhu FC, 2020 ].
Pregnancy

Randomized trials
Pregnant females were excluded from the CTII-nCoV trial, so no data are available for this subgroup [Zhu FC, 2020 ].
Breast-feeding

Randomized trials
Breastfeeding females were excluded from the CTII-nCoV trial, so no data are available for this subgroup [Zhu FC, 2020 ].
Immunocompromised persons

Randomized trials
Immunocompromised participants were excluded from the CTII-nCoV trial, so no data are available for this subgroup [Zhu FC, 2020 ].
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 ].

Other data from vaccine efficacy and effectiveness

Duration of protection

The exact duration of protection afforded by the vaccine is unknown as it is still being determined by ongoing clinical trials.
Comparative studies
None available
Non-comparative studies
None available

Limitations of vaccine effectiveness

Individuals may not be fully protected until 14 days after vaccination. As with all vaccines, vaccination with CanSino COVID-19 vaccine may not protect all vaccine recipients.
Comparative studies
None available
Non-comparative studies
None available

SARS-CoV-2 variants

Comparative studies
None available
Non-comparative studies
None available

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 ≥ 0.5×10^11vp/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 increases the risk of any adverse event

Main efficacy outcomes of CanSino COVID-19 vaccine

Any adverse event (mean follow up 28 days)

The relative risk of any adverse event in the group that received CanSino COVID-19 vaccine versus the group that received the control vaccine was 1.59 (95% CI 1.32 to 1.92). This means CanSino COVID-19 vaccine increased the risk of any adverse event in 59%, compared with the control vaccine.

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

In the trial identified in this review, 61 people not receiving CanSino COVID-19 vaccine out of 126 presented this outcome (484 per 1000) versus 294 out of 382 in the group that did receive it (770 per 1000). In other words, 286 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 28.6%, or that the intervention increased the risk of any adverse event by 28.6 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 3.

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

Serious adverse events

No serious adverse events were documented in the available trail within 28 days. Therefore, it is not possible to estimate the effect for this outcome [Zhu FC, 2020 ].

Summary of findings (iSoF)

Safety of the vaccine in subgroups

Sex

Randomized trials
The proportion of female in the CTII-nCoV was 50.3% (192 out of 382 participants) [Zhu FC, 2020 ].
The proportion of female that experienced adverse effects with CanSino COVID-19 vaccine versus the group that received placebo vaccine was not reported in detail.

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 significantly lower occurrence of fever post vaccination (p<0.001).
Children and adolescents

Randomized trials
Children were excluded from the CTII-nCoV trial, so no data are available for this subgroup [Zhu FC, 2020 ].
Pregnancy

Randomized trials
Pregnant females were excluded from the CTII-nCoV trial, so no data are available for this subgroup [Zhu FC, 2020 ].
Breast-feeding

Randomized trials
Breastfeeding females were excluded from the CTII-nCoV trial, so no data are available for this subgroup [Zhu FC, 2020 ].
Immunocompromised persons

Randomized trials
Immunocompromised participants were excluded from the CTII-nCoV trial, so no data are available for this subgroup [Zhu FC, 2020 ].

Safety of the vaccine post-authorization

Post-authorization studies

Comparative studies
None available
Non-comparative studies
None available

Spontaneous report data

Disclaimer: Reporting suspected adverse reactions after authorization of the medicinal product is important because it allows continuous monitoring of the benefit/risk balance of the vaccines. However, they do not indicate a causal association between the vaccine and the observed effects. Furthermore, this information should not be used to estimate the frequency of adverse events in people receiving the vaccine or to make comparisons between different vaccines. The information emerging about possible adverse effects needs to be carefully evaluated in order to first establish if the adverse effect might have been caused by the vaccine.
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 Moderna 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 persons, including persons living with HIV and persons with 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.

References

[National Medical Products Administration of China, 2020] National Medical Products Administration of China. China grants conditional approval for first COVID vaccine. 2020; National Medical Products Administration of China. China grants conditional approval for first COVID vaccine. 2020;
[Ministerio de salud de Argentina, 2021] Ministerio de salud de Argentina. Resolución 1671/2021. RESOL-2021-1671-APN-MS. Report. 2021; Ministerio de salud de Argentina. Resolución 1671/2021. RESOL-2021-1671-APN-MS. Report. 2021;
[ISP, 2021] ISP. ISP aprueba uso de emergencia e importación de la vacuna Cansino para combatir COVID-19. 2021; ISP. ISP aprueba uso de emergencia e importación de la vacuna Cansino para combatir COVID-19. 2021;
[COFREPRIS, 2021] COFREPRIS. COFEPRIS AUTORIZA EL USO DE EMERGENCIA PARA LOTES ENVASADOS EN MÉXICO DE LA VACUNA CANSINO. 2021; COFREPRIS. COFEPRIS AUTORIZA EL USO DE EMERGENCIA PARA LOTES ENVASADOS EN MÉXICO DE LA VACUNA CANSINO. 2021;
[Liu Wei, 2021] Liu Wei. Annual production of Chinese single-shot COVID-19 vaccine can reach 500m. 2021; Liu Wei. Annual production of Chinese single-shot COVID-19 vaccine can reach 500m. 2021;
[The Moscow Times, 2020] The Moscow Times. Russian Recruits Show ‘No Side Effects’ in Chinese Coronavirus Vaccine Trials. 2020. The Moscow Times. Russian Recruits Show ‘No Side Effects’ in Chinese Coronavirus Vaccine Trials. 2020.
[Reuters Staff 1 MIN READ, 2021] Reuters Staff 1 MIN READ. China's CanSino says first vaccines packaged in Mexico will be ready in March. 2021; Reuters Staff 1 MIN READ. China's CanSino says first vaccines packaged in Mexico will be ready in March. 2021;
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