CanSino COVID-19 vaccine

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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: Recommended for 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

The CanSino COVID-19 vaccine is administered as one dose of 0.5 mL [WHO, 2022 ].

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 3 doses of 0.5 mL each [WHO, 2022 ].
The preferred site of injection is the deltoid muscle of the upper arm.


Booster dose [WHO, 2022 ]
A booster dose is recommended for the highest and high priority-use groups (i.e. older adults, health workers, persons with comorbidities), administered 4–6 months after completion of the primary series.

Once high booster dose coverage has been achieved in the highest priority-use group, countries may also consider a booster for other lower priority-use groups.

If more than 6 months have elapsed since completion of the primary series, a booster dose should be given at the earliest opportunity.


Heterologous COVID-19 vaccine schedules [WHO, 2022 ]
CanSino COVID-19 vaccine may be used as a booster dose following a completed primary series using any other EUL COVID-19 vaccine.

Heterologous boosters should take into account current vaccine supply, vaccine supply projections, and other access considerations, alongside the potential benefits and risks of the specific products being used.


Vaccination schedule for immunocompromised persons [WHO, 2022 ]
WHO recommends an extended primary series, including an additional (second) dose for immunocompromised individuals. Available evidence from other COVID-19 vaccines suggests that an additional (second) dose should be given 1–3 months after the first dose in the standard primary series.

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 ].

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

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.


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.

Children and adolescents [WHO, 2022 ].
There are limited data on efficacy or safety for persons below the age of 18 years. Until such data are available, vaccination of individuals below 18 years of age is not routinely recommended.

Older persons [WHO, 2022 ].
Vaccination is recommended for older persons without an upper age limit

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 who previously received passive antibody therapy for COVID-19[WHO, 2022 ]
Although some reduction in vaccine-induced antibody titers has been observed in this group, the balance of benefits versus risks favors vaccination.

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.

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

The following randomized clinical trials have reported vaccine efficacy and/or safety data:

Phase 1:
The AMMS85-2004 trial, (NCT04552366 [Wu, Shipo, 2021 ]) conducted in China, initiated in August 2020, included 130 adults aged 18 years and older for the aerosol inhalation CanSino vaccine who were randomly assigned (1:1:1:1:1) to five groups. Participants in the two aerosol groups received an initial high dose (2 × 1010 viral particles; HDmu group) or low dose (1 × 1010 viral particles; LDmu group) of the CanSino vaccine on day 0, followed by a booster on day 0. day 28. The mixed vaccination group received an initial intramuscular vaccine (5×1010 viral particles) on day 0, followed by an aerosol booster (2×1010 viral particles) on day 28 (MIX group). The intramuscular groups received one dose (5×1010 viral particles; group 1Dim) or two doses (10×1010 viral particles; group 2Dim) of CanSino on day 0 [Wu, Shipo, 2021 ].

Phase 1/2:
The JSVCT127 trial (NCT05043259, [Jiangsu Province Centers for Disease Control and Prevention, 2021 ]) conducted in China, initiated in September 2020, included 420 adults over 18 years of age, who had previously received two doses of the inactivated SARS-CoV-2 vaccine Sinovac. Participants were randomly assigned (1:1:1) to receive aerosolized CanSino vaccine as a heterologous low-dose booster (10 × 1011 viral particles per mL; 0 1 mL; low-dose group), or a high dose (10 × 1011 virus particles per ml; 0.2 ml; high-dose group), or a homologous intramuscular vaccine with Sinovac (0.5 ml) [Li JX, 2022 ], [Jing-Xin Li, 2022 ].

Phase 2:
The CTII-nCoV trial (NCT04341389 [Insitute of Biotechnology, Academy of Military Medical Sciences, PLA of China, 2020 ]) conducted in China, initiated in April 2020, included 603 participants aged 18 years or older who were randomized in a 2:1:1 ratio to receive the vaccine at a dose of 1 × 1011 viral particles per mL or 5 × 1010 viral particles per mL, or placebo [Zhu FC, 2020 ].

Phase 3:
The CS-CTP-AD5NCOV-Ⅲ trial (NCT04526990 [CanSino Biologics Inc., 2020 ]), conducted in Argentina, Chile, Mexico, Pakistan, and Russia started in September 2020, enrolled 36,982 individuals over 18 years of age who were randomized in a 1:1 ratio to receive a single 0.5 mL intramuscular dose of placebo or a 0.5 mL dose of 5 × 1010 viral particles (VP)/mL Cansino vaccine [Halperin SA, 2021 ]

The Prometheus_Rus trial (NCT04540419, [NPO Petrovax, 2020 ]) conducted in Russia, initiated in September 2020, included 496 participants who received the Cansino vaccine or a placebo in a 3:1 ratio [Dzutseva, V., 2022 ].

Phase 4:
The JSVCT115 trial (NCT04833101 [Jiangsu Province Centers for Disease Control and Prevention, 2021 ]), conducted in China, initiated in April 2021, included 120 adults vaccinated with a single dose of CanSino 28 days prior, then randomly assigned to receive Anhui Zhifei (n=40) or a trivalent inactivated influenza vaccine (n=20) within 28 days, and 60 were randomly assigned to receive either Anhui Zhifei (n=40) or a trivalent inactivated influenza vaccine (n=20) within 56 days [Jin P, 2022 ], [Pengfei Jin, 2022 ].

The JSVCT116 trial (NCT04892459 [Jiangsu Province Centers for Disease Control and Prevention, 2021 ]) conducted in China, initiated in May 2021, included 300 healthy subjects between the ages of 18 and 59. Of these, 200 participants who were vaccinated with two doses of the inactivated SARS-CoV-2 vaccine were randomized in a 1:1 ratio to receive a booster dose of either the inactivated SARS-CoV-2 vaccine or CanSino at 3 - 6 months later. The other 100 participants randomized in a 1:1 ratio received a booster dose of inactivated SARS-CoV-2 vaccine or CanSino 1-3 months later [Li J, 2022 ].

The JSVCT117 trial (NCT04952727 [Jiangsu Province Centers for Disease Control and Prevention, 2021 ]) conducted in China, initiated in August 2021 included 299 participants aged 60 years or older, of whom 199 had two doses of CoronaVac in the last 3 to 6 months, and 100 had one dose of CoronaVac in the last 1 to 2 months. Participants were randomized 1:1 to receive one dose of CanSino or CoronaVac as a booster dose [Pengfei Jin, 2022 ].

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 ].

A phase 1 randomized trial evaluated the safety and immunogenicity of the CanSino vaccine against COVID-19 administered by aerosol inhalation in adults seronegative for SARS-CoV-2. Participants were enrolled and randomly assigned (1:1:1:1:1) into five groups to be vaccinated by intramuscular injection, aerosol inhalation, or both. Participants in the two aerosol groups received an initial high dose (2 × 1010 viral particles) or a low dose (1 × 1010 viral particles) of CanSino vaccine on day 0, followed by a booster dose on day 28. EL The mixed vaccination group received an initial intramuscular vaccine (5 × 1010 viral particles) on day 0, followed by an aerosol booster vaccine (2 × 1010 viral particles) on day 28. The intramuscular groups received one dose (5 × 1010 viral particles). viral particles) or two doses (10 × 1010 viral particles) of Ad5-nCoV on day 0. A total of 130 (56%) trial participants were enrolled and randomly assigned to one of five groups (26 participants per group) . On day 28 after the last vaccination, geometric mean titers of neutralizing antibodies against SARS-CoV-2 were measured; 107 (95% CI 47-245) in the high-dose aerosol group, 105 (47-232) in the low-dose aerosol group, 396 (207-758) in the mixed vaccination group, 95 (61- 147) in the one-dose intramuscular group, and 180 (113-288) in the second-dose intramuscular group [Zhu F, 2021 ].


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 ].

Vaccine effectiveness (other comparative studies)

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

Efficacy and effectiveness against SARS-CoV-2 variants

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 ].

Zhong J et al was a comparative study conducted in China. The study included 150 participants with two doses of CoronaVac vaccine: 50 received a low-dose aerosolized Ad5-nCoV booster, 50 received a high-dose aerosolized Ad5- nCoV booster, 50 received homologous booster and 14 received the ZF2001 booster. This study assessed whether heterologous immunization with aerosol inhalation induces robust antibody immune response. Neutralizing antibodies (NAbs) against Omicron for participants with low dose aerosolized Ad5-nCoV booster was 115.8 (95% CI, 48.63–73.86), for participants with high-dose aerosolized Ad5- nCoV booster was 115.8 (95% CI, 88.57–151.3) and 4.32 (95% CI, 4.00–4.84) for participants who received homologous booster. The conventional virus neutralizing assay confirmed that Ad5-nCoV booster induced higher titer of neutralizing antibodies than ZF2001 booster (116.80 (95% CI, 84.51–161.5) vs 4.40 (95% CI, 4.00–4.83)). [Zhong J, 2022 ]

Effectiveness outcomes
Delta (B.1.617.2)
Ma C et al. was a retrospective cohort study reporting the effectiveness of Ad5-nCov against symptomatic COVID-19 during a Delta variant outbreak in China. The study included 686 close contacts, 620 were vaccinated and 66 were unvaccinated. Adjusted vaccine effectiveness was 61.5% (95% CI 9.5 to 83.6) against symptomatic infection, and 100% (95%CI: 36.6 to 100) against severe COVID-19 [Ma C, 2022 ].

Vaccine efficacy and effectiveness for booster dose

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

Vaccine efficacy and effectiveness for heterologous schedule

Immunogenicity outcomes
JSVCT116 was a phase 4 randomized 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 ].

Vaccine efficacy and effectiveness for heterologous booster schedule

Immunogenicity outcomes
JSVCT116 was a phase 4 randomized 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 ].

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.

Pengfei Jin et al. was a phase 4 randomized trial that included 299 participants aged 60 years and older: 99 primed with two doses of CoronaVac and Cansino COVID-19 vaccine booster, 100 primed with two doses of Coronavac and homologous booster, 50 primed with one dose of CoronaVac and received a Cansino booster and 50 primed with one dose of CoronaVac and homologous booster. In the group primed with two doses of  CoronaVac and with a Cansino vaccine booster, GMTs of neutralizing antibodies against wild-type SARS-CoV-2 increased to 286.4 (95% CI: 244.6, 335.2) 14 days post boost vaccination. Among participants who were primed with one dose of CoronaVac, a heterologous second dose induced a GMT of neutralizing antibodies against wild-type SARS-CoV-2 of 70.9 (95% CI: 49.5, 101.7) [Pengfei Jin, 2022 ].

Li JX et al. was a phase 2 randomized trial that included 420 participants. This study assessed the immunogenicity of a heterologous immunization with an orally administered aerosolized adenovirus type 5-vectored vaccine (Convidecia) among participants previously vaccinated with an inactivated vaccine (CoronaVac). Participants were randomized to receive either high-dose or low-dose Ad5-nCoV, or a homologous CoronaVac booster. In the group primed with two doses of  CoronaVac and with a low dose Ad5-nCov vaccine booster GMTs of neutralizing antibodies against wild-type SARS-CoV-2 increased to 1937.3 (95% CI  1466.9 to 2558.4), in the high dose Ad5-nCov vaccine booster group neutralizing antibodies increased to 1350.8 (95% CI 952.6 to 1915.3), and in the CoronaVac boosted group to 73.5 (95% CI 52.3 to 103.3) 28 days post boost vaccination [Pengfei Jin, 2022 ].

Pengfei Jin et al. was a randomized trial conducted in China. This study included 120 participants with a Cansino primary schedule: 60  randomly assigned to receive ZF2001 or placebo at an interval of 28 days and 60 randomly assigned to receive ZF2001 or placebo at an interval of 56 days. The primary outcomes were the occurrence of solicited local or systemic adverse reactions within 7 days post-vaccination and the live virus neutralizing antibody titers against wild-type SARS-CoV-2 isolate at day 14 after each boost vaccination. Among participants receiving ZF001 as the second dose, the GMTs of neutralizing antibodies increased to 58.4 IU/ml (42.8 to 79.8) in the 28-day regimen, and to 80.8 IU/ml (53.1-122.9) in 56 days regimen at 14 days post first boost dose. The neutralizing antibodies of participants receiving placebo showed no increase. The GMTs of neutralizing antibodies increased to 334.9 IU/ml (95% CI 230 to 486.9) in C/Z/Z (D0-D28-M5) regimen and 441.2 IU/ml (260.8, 746.4) in C/Z/Z regimen at 14 days after the third dose [Jin P, 2022 ].

Zhong J et al was a comparative study conducted in China. The study included 150 participants with two doses of CoronaVac vaccine: 50 received a low-dose aerosolized Ad5-nCoV booster, 50 received a high-dose aerosolized Ad5- nCoV booster, 50 received homologous booster and 14 received the ZF2001 booster. This study assessed whether heterologous immunization with aerosol inhalation induces robust antibody immune response. Anti-RBD IgG levels for the low dose aerosolized Ad5-nCoV booster was 691.4 (95% CI, 559.3–854.8), for the high-dose aerosolized Ad5- nCoV booster was 988.5 (95% CI, 755.2–1294) and for the homologous booster was 2963 (95% CI, 2219–3956). The anti-RBD IgG levels from participants with homologous booster were significantly higher than those of the heterologous booster. Neutralizing antibodies (NAbs) against Omicron for participants with low dose aerosolized Ad5-nCoV booster was 115.8 (95% CI, 48.63–73.86), for participants with high-dose aerosolized Ad5- nCoV booster was 115.8 (95% CI, 88.57–151.3) and 4.32 (95% CI, 4.00–4.84) for participants who received homologous booster. The conventional virus neutralizing assay confirmed that Ad5-nCoV booster induced higher titer of neutralizing antibodies than ZF2001 booster (116.80 (95% CI, 84.51–161.5) vs 4.40 (95% CI, 4.00–4.83)). [Zhong J, 2022 ]

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 trial 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 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

Comparative studies
No comparative study reported or evaluated this outcome.

Non-comparative studies
Núñez I et al. was a retrospective observational study reporting the incidence of seizures among recipients of COVID-19 vaccines in Mexico, including 2,979,697 recipients of the CanSino vaccine. Based on data from the official databases provided by the Mexican Ministry of Health from December 24, 2020, to October 29, 2021. The analysis revealed 3 events of seizures, 2 of them were new-onset seizure events and one recipient had a history of epilepsy [Núñez I, 2022 ].

Toledo-Salinas et al. conducted a nationwide observational study among recipients of 61,414,803 doses of seven different COVID-19 vaccines, between December 2020 - October 2021 in Mexico, to identify the observed incidence of anaphylaxis in recipients of different anti-SARS-CoV-2 vaccines. The unadjusted incidence of anaphylaxis per million doses administered was 1.36 (95% CI 0.69–2.67) for Ad5-nCoV. [Toledo-Salinas C, 2022 ].

García-Grimshaw M was a non-comparative study conducted in Mexico that reported the incidence of Guillain-Barré syndrome (GBS) following COVID-19 vaccination. The study informed the adverse events of 81,842,426 first or second doses of seven COVID-19 vaccines (Coronavac, Moderna, Pfizer, AstraZeneca, Sputnik V, CanSino, and Janssen), with 2,979,697 doses corresponding to the CanSino vaccine. 97 cases of GBS were identified through passive epidemiological surveillance, 5 of them related to the CanSino vaccination, with an unadjusted incidence of 1.68 (95% CI 0.72-3.93) per million doses administered [García-Grimshaw M, 2022 ].

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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