Sinovac COVID-19 vaccine

Extended version of the vaccine

Sinovac COVID-19 vaccine

Authorization

World Health Organization Emergency Use Listing Procedure
Listed for emergency use on June 1, 2021 [WHO, 2021 ]
EUL/WHO Authorization: Authorized for emergency use in individuals 18-59 years of age [WHO, 2021 ].
SAGE/WHO Recommendation: Individuals aged 18 years and above [WHO, 2021 ]

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

China's National Medical Products Administration
Authorized
6 February 2021
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)
Not authorized

Brazilian Health Regulatory Agency (ANVISA, Brazil)
Authorized
17 January 2021
Authorized for emergency use [Agencia Nacional de Vigilancia Sanitaria (ANVISA). Brasil, 2021 ].

Health Canada
Not authorized

Public Health Institute (ISP, Chile)
Authorized
20 January 2021
Authorized for emergency use [Instituto de Salud Publica. Ministerio de salud de Chile, 2021 ].

National Institute of Food and Drug Monitoring (INVIMA, Colombia)
Authorized
22 February 2021
Authorized for emergency use [Ministerio de salud y protección social. Colombia, 2021 ].

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
10 February 2021
Authorized for emergency use [Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS). Mexico, 2021 ].

Authorization in other jurisdictions in the Americas
Bolivia
Dominican Republic
Ecuador
Panama
Paraguay
Uruguay
El Salvador
Saint Vincent and the Grenadines
Authorization in other jurisdictions
Albania
Armenia
Azerbaijan
Bangladesh
Benin
Cambodia
Egypt
Georgia
Hong Kong
Indonesia
Kazakhstan
Laos
Malaysia
Nepal
Oman
Pakistan
Philippines
South Africa
Sri Lanka
Tajikistan
Tanzania
Thailand
Timor-Leste
Togo
Tunisia
Turkey
Ukraine
Zimbabwe
San Marino
Serbia
Seychelles
Slovakia
Sri Lanka
Syria
Tunisia
Turkey
Turkmenistan
United Arab Emirates
Uzbekistan
Vietnam
West Bank
Zimbabwe

Manufacturing

Manufacturer
Sinovac Research and Development Co.Ltd; China. Sinovac has four installations across China that house its research, development, and manufacturing facilities for vaccine production.

Other manufacturers
Sinovac Life Sciences Co.Ltd.; China
Sinovac Research and Development Co. Ltd.; China
Egyptian Holding Company for Biological Products & Vaccines (VACSERA); Egipt. Local production of the inactivated vaccine against COVID-19 [Xinhua, 2021 ].

Filling and packaging
Instituto Butantan; Brazil. Filling and packaging of Sinovac vaccine [Agência Brasil, 2021 ].

General characteristics

Sinovac COVID-19 vaccine is an inactivated virus vaccine, derived from the CZ02 strain of coronavirus. The virus is cultivated in African green monkey kidney cells (Vero Cells), later it is harvested and inactivated to prevent its replication, to finally be concentrated, purified and adsorbed with aluminum hydroxide that acts as an adjuvant agent, which stimulates the host immune response [Palacios R, 2020 ].
Isolated SARS-CoV-2 strains were collected from infected patients. Strain CN2 was chosen for purified inactivated SARS-CoV-2 virus vaccine development [Qiang Gao, 2020 ],[Gao Q, 2020 ].
Viruses were cultured in large-scale Vero cells factories, and inactivated with β-propiolactone for 24 hours, followed by purification with Ion-exchange Chromatography (IEC) and Size Exclusion Chromatography (SEC) method. The purified viruses were mixed with Al(OH)3 adjuvant and served as SARS-CoV-2 vaccine candidate [Qiang Gao, 2020 ].

Dosage form and ingredients
The pharmaceutical form is a suspension for intramuscular injection, that is provided in a multidose vial (vial: 10 doses of 0,5 ml per vial), or as a monodose of 0,5 mL

The vaccine contains the following ingredients:
Active ingredient:
Each dose contains 600 standard units of inactivated SARS-CoV-2 antigen
Adjuvant:
Aluminum hydroxide
Excipients:
Dibasic sodium phosphate
Monobasic sodium phosphate
Sodium chloride
Sodium hydroxide
Water for injections.

Risk considerations

Purified inactivated viruses have been traditionally used for vaccine development and such vaccines have been found to be safe and effective for the prevention of diseases caused by viruses like influenza and poliovirus [Gao Q, 2020 ].
Inactivated vaccines are composed of inactivated virus, and contain different immunogenic components of the original virus. Compared with attenuated viruses, they carry no risk of viral reactivation if properly inactivated. Although they are considered safer than live attenuated vaccines, immunogenic properties of inactivated viruses may be structurally deformed during the inactivation process, which can affect the protection they may provide[Li YD, 2020 ].
Studies performed in mouse models on SARS-CoV and MERS-CoV showed that animals exposed to whole inactivated vaccines exhibited an immunopathologic-type lung disease.
[Tseng CT, 2012 ].

Previous experiences with the development of vaccine candidates against SARS-CoV and MERS-CoV had raised concerns about pulmonary immunopathology, probably caused by a response from type 2 (Th2) helper T cells. Although the cellular response can be elicited by many vaccines, protection against subsequent coronavirus infections is largely mediated for humoral immunity. The 'cytokine storm' induced by excess T cells has been shown to accentuate the pathogenesis of COVID-19 [Qiang Gao, 2020 ].

Dosification and schedule

Dose-finding studies
PRO-nCOV-1001 trial evaluated 744 healthy adults aged 18 to 59 years who received a low dose of the vaccine (3 µg per 0.5 mL of aluminium hydroxide diluent per dose), with a schedule of 0 and 14 days between each dose, or a high-dose (6 µg per 0.5 mL of aluminium hydroxide diluent per dose) with a schedule of 0 and 28 days between each dose.
The study showed that taking safety and immunogenicity into account, the 3 µg dose was the suggested dose for efficacy assessment in phase 3 trials [Zhang, Yanjun, 2021 ].

There is no evidence yet about the effects of the coadministration of Sinovac COVID-19 vaccine with other vaccines included in routine vaccination programs. There is however, one trial ongoing with influenza vaccine [Sinovac Research and Development Co., Ltd., 2021 ].

Indications and contraindications

Indications
Sinovac COVID-19 vaccine is indicated in adults 18 years and older [WHO, 2021 ].
Contraindications
Sinovac COVID-19 vaccine is contraindicated in individuals with a known history of a severe allergic reaction to any component of Sinovac COVID-19 vaccine [Ministerio de Salud Gobierno de Chile, 2021 ].
The second dose of the vaccine should NOT BE GIVEN to those who have experienced anaphylaxis to the first dose.
Precautions
Severe allergic reaction (e.g., anaphylaxis) to a previous dose of any vaccine (not including Sinovac 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.
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 [Ministerio de Salud Gobierno de Chile, 2021 ].
The available data on Sinovac COVID-19 vaccine on pregnant women are insufficient to assess vaccine efficacy in pregnancy, since no clinical trial evaluating vaccines to prevent COVID-19 has included pregnant women.
The available data on Sinovac COVID-19 vaccine on lactating women are insufficient to assess whether the vaccine is excreted in human milk or if there is any associated risk.
The available data on Sinovac COVID-19 vaccine on children are insufficient to assess vaccine efficacy since no clinical trial evaluating vaccines to prevent COVID-19 has included children.
The interaction of concomitant administration of Sinovac COVID-19 vaccine with other vaccines has not been studied [Ministerio de Salud Gobierno de Chile, 2021 ].
The immune response to the vaccine may be reduced in patients who have received immunosuppressive or immunodeficient therapy. Vaccination should be postponed until term treatment and it should be ensured that patients are well protected to minimize probability of contagion. Vaccination should be recommended for patients with stable chronic immune conditions [Ministerio de Salud Gobierno de Chile, 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
Sinovac COVID-19 vaccine is provided as a refrigerated suspension stored between 2°C to 8°C (36°F to 46°F) [WHO, 2021 ].
The shelf life of Sinovac COVID-19 vaccine of up to 12 months stored between 2 ° C and 8 ° C (36 ° F to 46 ° F) [WHO, 2021 ]
Keep the vaccine vials in their carton and place them in the storage unit.
Protect from light.
Logistic at the time of administration
Inspect the vial to be used. Sinovac vaccine is an opalescent, injectable suspension with possible precipitate formation that must be resuspended by inverting the vial several times to mix.
The vial should be discarded if particles or differences are observed in the described appearance of the vaccine.
Do not shake the vial roughly.

Storage after first puncture
After the first puncture of the vial, preferably use immediately.
Record the date and time the vial should be discarded.
To improve traceability, the name and batch number of the administered product should be clearly recorded [WHO, 2021 ].

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. Another option is to 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
PROFISCOV, also known as COV-02-IB, is a randomized phase 3 trial (registered with the number NCT04456595 [Butantan Institute, 2020 ]) sponsored by the Butantan Institute, that is being conducted in Brazil [Palacios R, 2021 ].The aim is to assess the efficacy and safety of two doses of the vaccine. It was first registered in July 2020 and has enrolled 12688 participants aged 18 years or older that received the vaccine or a placebo vaccine in a 1:1 ratio. It is expected to run through February 2022. The results of the trial have not been formally published in a scientific journal but a preprint version reporting on 12396 participants was released in April 2021.
9026-ASI is a randomized phase 3 trial (registered with the number NCT04582344 [Health Institutes of Turkey, 2020 ]), it is sponsored by The Health Institutes of Turkey and is being conducted in Turkey. It was first registered in October 2020 and enrolled 13000 participants aged 18 to 59 years of age that received two doses of the vaccine or placebo separated by two weeks. It ended in April 2021 [Tanriover MD, 2021 ].

CoronaVac3CL is a randomized phase 3 trial (registered with the number NCT04651790 [Pontificia Universidad Catolica de Chile, 2020 ]) sponsored by Pontificia Universidad Catolica de Chile that is being conducted in Chile. The aim is to compare the efficacy, safety, and immunogenicity of two vaccination schedules. It was first registered in December 2020 and has enrolled participants aged 18 years or older that received two doses of CoronaVac separated by 2 weeks or 4 weeks in a 1:1 ratio. It is expected to run through March 2022. The results of the trial have not been formally published in a scientific journal but a preprint version of an interim report on 434 participants was released in April 2021 [Susan M Bueno, 2021 ].

PRO-nCOV-1001 was a randomized phase 1/2 trial (registered with the number NCT04352608 [Sinovac Biotech Co., Ltd, 2020 ]), sponsored by Sinovac Research and Development Co., Ltd., that was conducted in China. It was first registered in April 2020 and enrolled 744 healthy adults aged 18-59 years old. In phase 1, the participants were assigned in a 1:1 ratio, with no specific randomization, into two vaccination schedule cohorts (days 0 and 14, and days 0 and 28). Within each cohort the participants were randomly assigned to low dose (3 µg) or high-dose (6 µg) of the vaccine. In the phase 2, participants were assigned in a 1:1 ratio, with no specific randomization, into two vaccination schedule cohorts (days 0 and 14, and days 0 and 28). Within each cohort the participants were randomly assigned in a 2:2:1 ratio to two doses of either low-dose vaccine, high-dose vaccine, or placebo. The results of the trial were published in a scientific journal in November 2020. [Zhang, Yanjun, 2021 ].
PRO-nCOV-1002 was a randomized phase 1/2 trial (registered with the number NCT04383574 [Sinovac Research and Development Co., Ltd., 2020 ]) sponsored by Sinovac Research and Development Co., Ltd. that was conducted in China. It was first registered in May 2020 and included 422 healthy adults aged 60 years or older that in the phase 1 were assigned in a 2:1 ratio to receive the vaccine or placebo, and in the phase 2 to receive either the vaccine at 1.5 µg, 3 µg, or 6 µg per dose, or placebo in a 2:2:2:1 ratio. The results of the trial were published in a scientific journal in February 2021 [Wu Z, 2021 ].

PRO-nCOV-1003 is a randomized phase 1/2 trial (registered with the number NCT04551547 [Sinovac Research and Development Co., Ltd., 2020 ]) sponsored by Sinovac Research and Development Co., Ltd., that is being conducted in China. It was first registered in September 2020 and includes healthy children and adolescents aged 3-17 years old that, in the phase 1, were assigned in a 3:1 ratio to receive the vaccine (1.5 ug) or placebo, and, in the phase 2, to receive either the vaccine at 1.5 µg, 3 µg per dose, or placebo in a 2:2:1 ratio. It is expected to run through September 2021. The results of the trial have not been formally published in a scientific journal, but a preprint version based on information from 522 participants was released in April 2021 [Bihua Han, 2021 ].

Ongoing randomized trials
Projeto S is an ongoing stepped-wedge cluster randomized trial (phase 4) (registered with the number NCT04747821 [Butantan Institute, 2021 ]) sponsored by Butantan Institute, that is being conducted in Brazil. It was first registered in February 2021 and plans to enrol 27711 adults 18 years and older who will receive the vaccine in a two-dose schedule with four-weeks interval administered in 4 steps (first, second, third and fourth week of the study). The study ended in February 2022. The results of the trial have not been formally published in a scientific journal but a press release was issued in March 2021 [Instituto Butantan, 2021 ].

PRO-QINF-4001 is an ongoing randomized phase 4 trial (registered with the number NCT04801888 [Sinovac Research and Development Co., Ltd., 2021 ]) sponsored by Sinovac Research and Development Co. Ltd., that is being conducted in China. It was first registered in March 2021 and plans to enrol 480 adults aged from 18 to 59 years, who will receive concomitant administration of the vaccine with a quadrivalent influenza vaccine. It is expected to run until July 2021.
TURKOVAC is an ongoing randomized, observer-blinded, phase III">phase III clinical trial (registered with the number NCT04942405 [Health Institutes of Turkey, 2021 ]) sponsored by Health Institutes of Turkey that is being conducted in Turkey. It was first registered in June 2021 and plans to enroll 40800 adults aged 18-55 years. The study will evaluate two doses of experimental vaccine or CoronaVac on the schedule of day 0,28. It is expected to run until May 2023.

PRO-nCOV-4001 is an ongoing double-blind, randomized clinical trial (registered with the number NCT04894227 [Sinovac Research and Development Co., Ltd., 2021 ]) sponsored by Sinovac Research and Development Co., Ltd. that is being conducted in China. It was first registered in May 2021 and plans to enroll 1080 health adults aged 26-45 years. The study will evaluate two doses of vaccine (CoronaVac) on day 0 and day 28. It is expected to run until July 2021.
PRO-nCOV-2001 is an ongoing randomized, double-blinded, placebo-controlled, phase II-b clinical trial(registered with the number NCT04884685 [Sinovac Research and Development Co., Ltd., 2021 ]) sponsored by Sinovac Research and Development Co., Ltd. that is being conducted in China. It was first registered in May 2021 and plans to enroll 500 individuals aged from 3 to 17 years. The study will evaluate two doses of experimental vaccine (CoronaVac) or placebo on day 0 and day 28. It is expected to run until January 2022.
PRO-nCOV-MA4004-SD is an ongoing phase 4, randomized, placebo-controlled and opened clinical trial(registered with the number NCT04953325 [Sinovac Research and Development Co., Ltd., 2021 ]) sponsored by Sinovac Research and Development Co., Ltd. that is being conducted in China. It was first registered in July 2021 and plans to enroll 270 healthy individuals aged 18 years and older. The study will evaluate two doses of CoronaVac on day 0 and day 28, one dose of 23-valent Pneumococcal Polysaccharide vaccine on day 0 and one dose of inactivated Hepatitis A vaccine on day 28. It is expected to run until January 2022.
PRO-nCOV-4003 is an ongoing open-label phase Ⅳ clinical trial (registered with the number NCT04962308 [Sinovac Research and Development Co., Ltd., 2021 ]) sponsored by Sinovac Research and Development Co., Ltd that is being conducted in China. It was first registered in July 2021 and plans to enroll 1400 healthy adults aged 18-59 years that will receive CoronaVac. It is expected to run until December 2021.
CoronaVacTND is an ongoing multisite, grouped test-negative case-control, phase Ⅳ clinical trial (registered with the number NCT04974164 [Sinovac Research and Development Co., Ltd., 2021 ]) sponsored by Sinovac Research and Development Co., Ltd that is being conducted in Dominican Republic. It was first registered in July 2021 and plans to enroll 1400 population aged 18 years and older that will receive two doses of CoronaVac vaccine for primary immunization with an interval of 21 days. It is expected to run until April 2022.

Other studies providing efficacy or safety data
Zhang et al was a study based on a self-administered online survey to monitor adverse reactions post vaccination. It included 1526 staff in a tertiary hospital who received one or two doses of the vaccine. The study was conducted in China from February 2021 to March 2021. The results were published in a scientific journal on May 2021 [Zhang MX, 2021 ].
Other ongoing registered studies
IDOR_VAC_01 is an ongoing non-comparative phase 4 study (registered with the number NCT04756830 [D'Or Institute for Research and Education, 2021 ]) sponsored by D'Or Institute for Research and Education, that is being conducted in Brazil. It was first registered in February 2021 and plans to enrol 1200 adults 18 years and older who will receive two doses of the vaccine with 14-days interval. It is expected to run until June 2023.
CoronavRheum is an ongoing non-randomized phase 4 study (registered with the number NCT04754698 [University of Sao Paulo General Hospital, 2021 ]), sponsored by University of Sao Paulo General Hospital, that is being conducted in Brazil. It was first registered in February 2021 and plans to enrol 2067 patients with chronic rheumatic diseases (such as systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, poly/dermatomyositis, systemic sclerosis, systemic vasculitis and primary Sjögren's syndrome) and people living with HIV/AIDS, who will receive CoronaVac 2-dose schedule with 21-28-day interval. It is expected to run until May 2022.

TXCoronavac is an ongoing non-comparative phase 4 study (registered with the number NCT04801667 [Hospital do Rim e Hipertensão, 2021 ]) sponsored by Hospital do Rim e Hipertensão, that is being conducted in Brazil. It was first registered in March 2021 and plans to enrol 3780 kidney transplant recipients who will receive the vaccine. It is expected to run until March 2022.

Ozdemir et al is an ongoing single group assignment study (registered with the number NCT04751721 [Izmir Bakircay University, 2021 ]) sponsored by Izmir Bakircay University that is being conducted in Turkey. It was first registered in February 2021 and plans to enroll 20 healthy women that will receive the vaccine will inoculated in 2 doses with an interval of 24 days. It is expected to run until April 2021.

CHEMOCOVAC is an ongoing case-control study (registered with the number NCT04765215 [Asoc. Prof. Erdoğan Selçuk Şeber, 2021 ]) sponsored by Asoc. Prof. Erdoğan Selçuk Şeber that is being conducted in Turkey. It was first registered in February 2021 and plans to enroll 291 cancer patients with active chemotherapy and healthy adults that will receive CoronaVac vaccine. It is expected to run until March 2022.

PRO-nCOV-MA4002 is an ongoing non-randomized phase 4 study (registered with the number NCT04911790 [Sinovac Research and Development Co., Ltd., 2021 ]) sponsored by Sinovac Research and Development Co., Ltd. that is being conducted in China. It was first registered in June 2021 and plans to enroll 121000 individuals aged 18 years and older. The study will evaluate two doses of inactivated SARS-CoV-2 vaccine (CoronaVac). It is expected to run until December 2022.

2021-04-30T1 is an ongoing observational, non-randomized study (registered with the number NCT04895007 [Karamanoğlu Mehmetbey University, 2021 ]) sponsored by Karamanoğlu Mehmetbey University that is being conducted in Turkey. It was first registered in May 2021 and plans to enroll 1500 individuals vaccinated with Sinovac, Sputnik V, or Pfizer/BionTEC COVID-19 vaccine. The study will evaluate anti-SARS-CoV-2 IgG antibody and neutralizing antibody response in different vaccine groups: Sinovac, Sputnik V, and Pfizer/BionTEC. It is expected to run until June 2022.

HHCTC_COVID-19_VACCINE_Ab is an ongoing phase 4, non-randomized study (registered with the number NCT04775069 [Humanity & Health Medical Group Limited, 2021 ]) sponsored by Humanity & Health Medical Group Limited that is being conducted in Hong Kong, China. It was first registered in March 2021 and plans to enroll 900 adults with chronic liver disease or Underlying CLD, aged 18 years and older that will receive mRNA vaccine (Pfizer-Biontech), inactivated SARS Cov-2 (Sinovac), or adenovirus-vector COVID-19 vaccine (Astrazeneca-Oxford). It is expected to run until March 2022.
Balcells et al is an ongoing cohort study (registered with the number NCT04888793 [Pontificia Universidad Catolica de Chile, 2021 ]) sponsored by Pontificia Universidad Catolica de Chile that is being conducted in Chile. It was first registered in May 2021 and plans to enroll 516 patients with cancer, HIV, solid organ transplant and patients receiving immunomodulatory agents for rheumatic diseases. The study will evaluate the serological immune response after receiving Coronavac vaccine. It is expected to run until December 2021.
COVA is an ongoing non-randomized study (registered with the number NCT04800133) sponsored by The University of Hong Kong that is being conducted in Hong Kong, China [The University of Hong Kong, 2021 ]. It was first registered in March 2021 and plans to enroll 900 healthy or clinically stable participants aged 11 years and older that will receive BNT162b2 and CoronaVac. It is expected to run for until March 2025.
EC 022/2564 is an ongoing phase ii, non-randomized study (registered with the number TCTR20210517006) sponsored by Chulabhorn Royal Academy that is being conducted in Thailand [Chulabhorn Royal Academy, 2021 ]. It was first registered in May 2021 and plans to enroll 3000 healthy adults 18 years of age and older that will receive COVID-Vac 0.5 ml intramuscular at deltoid muscle for 2 doses with a 3-week interval; CoronaVac 0.5 ml intramuscular at deltoid muscle for 2 doses with a 3-week interval; or ChAdOx1 0.5 ml intramuscular at deltoid muscle for 2 doses with a 12-week interval. It is expected to run for until July 2022.
Acar Sevinç S et al is an ongoing non-randomized study(registered with the number NCT04956562 [Sisli Hamidiye Etfal Training and Research Hospital, 2021 ]) sponsored by Sisli Hamidiye Etfal Training and Research Hospital that is being conducted in Turkey. It was first registered in July 2021 and plans to enroll 96 patients who were vaccinated with Sinovac at least 14 days before enrollment to the study and not vaccinated 65 years and older. It is expected to run until May 2021.
Poovorawan Y et al is an ongoing non-randomized study (registered with the number TCTR20210520004 [The National Research Council of Thailand, 2021 ]) sponsored by The National Research Council of Thailand that is being conducted in Thailand. It was first registered in May 2021 and plans to enroll 120 healthy adults who had been previously infected with COVID-19, above 18 years of age. Participants will receive virus vector ChAdOx-1 nCoV-19 and inactivated vaccine CoronaVac . It is expected to run until June 2022.

Methods used to assess efficacy and effectiveness

The following methods were used to assess efficacy in the phase 3 trials evaluating the vaccine:
PROFISCOV trial [Palacios R, 2021 ]
Primary efficacy endpoint
Incidence of COVID-19 cases after two-doses immunization schedule measured with the number of virologically confirmed symptomatic COVID-19 cases two weeks after second dose of vaccine

9026-ASI trial [Tanriover MD, 2021 ]
Primary efficacy endpoint
Incidence of symptomatic COVID-19 cases confirmed by RT-PCR at least 14 days after the second dose of vaccination, assessed in the per protocol population.

Methods used to assess safety

The following methods were used to assess safety in the phase 3 trials evaluating the vaccine:
PROFISCOV trial [Palacios R, 2021 ]
Primary safety endpoint
Frequency of adverse events up to seven days after immunization, measured by frequency of adverse reaction in the seven days following each immunization per age group (18 to 59, and 60 or older).
Incidence of solicited and unsolicited AEs that occur at least 7 days after each injection.
Incidence of solicited and unsolicited AEs that occur at least 28 days after each injection.
Incidence of serious adverse events and events of special interest at any moment described during the essay.

Efficacy and effectiveness of the vaccine

Efficacy of the vaccine in preclinical studies

The immunogenicity of the vaccine was assessed in 10 groups of BALB/c mice that were injected at day 0 and day 7 with different doses of the vaccine mixed with alum adjuvant (0, 1.5 or 3 or 6 µg per dose, and a sham group). Spike and RBD IgG developed quickly in the vaccinated mice and peaked at the titer of 819,200 (>200 µg/ml) and 409,600 (>100 µg/ml), respectively, at week 6 [Gao Q, 2020 ].
Immunogenic evaluations were also conducted in Wistar rats, with the same immunization strategy described for BALB/c mice, with similar results [Gao Q, 2020 ].
Immunogenicity and protective efficacy was additionally tested in rhesus macaques, a non-human primate species that shows a COVID-19-like disease caused by SARS-CoV-2 infection. Macaques were immunized three times via the intramuscular route with medium (3 µg per dose) or high doses (6 µg per dose) of inactivated vaccine at day 0, 7 and 14 (n=4). S-specific IgG and NAb were induced at week 2 and rose to ~12,800 and ~50, respectively at week 3 in both vaccinated groups. All vaccinated macaques were largely protected against SARS-CoV-2 infection and had no detectable viral loads in pharynx, crissum and lung at day 7 after infection [Gao Q, 2020 ].

Efficacy of the vaccine in clinical trials

Main immunogenicity outcomes

Seroconversion rates were measured independently with specific IgG against S1-RBD and the N protein of SARS-CoV-2 using ELISA assays.
A total of 32 participants aged 18 to 59 years (23 in the vaccine arm and 9 in the placebo arm), were analyzed for IgG presence. Seroconversion rates for IgG were 48% measured 14 days post vaccination and 96% measured between 28 and 42 days post injection in participants aged 18 to 59.
A total of 14 participants aged 60 years or older were evaluated (11 in the vaccine arm and 3 in the placebo arm) for IgG presence. Seroconversion rates were 18% measured 14 days post vaccination and 100% measured between 28 and 42 days post injection in participants aged 60 years or older [Susan M Bueno, 2021 ].

Main efficacy outcomes of Sinovac COVID-19 vaccine

Key messages

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

Sinovac COVID-19 vaccine probably reduces the risk of contracting severe COVID-19

The efficacy of Sinovac COVID-19 presented here was estimated from the PROFISCOV trial [Palacios R, 2021 ], based on information from 12396 participants.

The efficacy of Sinovac COVID-19 presented here was estimated from the 9026-ASI trial [Tanriover MD, 2021 ], based on information from 10029 participants.


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

The relative risk of contracting COVID-19 in the group that received Sinovac COVID-19 vaccine, versus the group that received placebo vaccine was 0.29 (95% CI 0.09 to 0.93). This means Sinovac COVID-19 vaccine reduced the risk of contracting COVID-19 by 71%, compared with placebo vaccine.

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

In the trials identified in this review, 200 people not receiving Sinovac COVID-19 vaccine out of 8340 presented this outcome (24 per 1000) versus 94 out of 11512 in the group that did receive it (7 per 1000). In other words, 17 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 1.7%, or that the intervention reduced the risk of contracting COVID-19 by 1.7 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 59. Which means that 59 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 the second injection)

The relative risk of contracting severe COVID-19 in the group that received Sinovac COVID-19 vaccine versus the group that received placebo vaccine was 0.06 (95% CI 0.01 to 0.42). This means Sinovac COVID-19 vaccine reduced the risk of contracting severe COVID-19 by 94%, compared with placebo vaccine.

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

In the trials identified in this review, 12 people not receiving Sinovac COVID-19 vaccine out of 8340 presented this outcome (1 per 1000) versus 0 out of 11512 in the group that did receive it (0 per 1000). In other words, 1 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 0.1%, or that the intervention reduced the risk of contracting severe COVID-19 by 0.1 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 1000. Which means that 1000 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 certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: Low number of events; Publication bias: No concerns.

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

The relative risk of contracting severe COVID-19 after the first dose (more than 14 days) in the group that received Sinovac COVID-19 vaccine versus the group that received placebo was 0.43 (95% CI 0.34 to 0.54). This means Sinovac COVID-19 vaccine reduced the risk of contracting severe COVID-19 after the first dose (more than 14 days) by 57%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting severe COVID-19 after the first dose (>14 days). Comparison: Sinovac COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 219 people out of 5714 not receiving Sinovac COVID-19 vaccine presented this outcome (38 per 1000) versus 94 out of 5717 in the group that did receive it (16 per 1000). In other words, 22 fewer people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to a 2.2% of absolute risk reduction of contracting severe COVID-19 after the first dose (>14 days). Another way of presenting the same information about the absolute effects is the number of participants who need to receive the intervention for one of them to experience the outcome (NNTB/H). In this case, the NNT is 45, which means that 45 people need to receive the vaccine for one of them to not contract COVID-19 after the first dose.

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 Sinovac 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 the second injection)

The relative risk of contracting COVID-19 (≥60y) in the group that received Sinovac COVID-19 vaccine versus the group that received placebo vaccine was 0.49 (95% CI 0.09 to 2.64). This means Sinovac COVID-19 vaccine reduced the risk of contracting COVID-19 (≥60y) by 51%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (≥60y). Comparison: Sinovac COVID-19 vaccine versus placebo vaccine

In the trials identified in this review, 4 people not receiving Sinovac COVID-19 vaccine out of 207 presented this outcome (19 per 1000) versus 2 out of 212 in the group that did receive it (9 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 (≥60y) 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 moderate.The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: Low number of events; Publication bias: No concerns.

Summary of findings table (iSoF)


Efficacy and effectiveness of the vaccine on subgroups

Sex

Randomized trials
The proportion of females in the PROFISCOV trial was 64.2% (7955 out of 12396 participants) [Palacios R, 2021 ].
Vaccine efficacy for this subgroup in the PROFISCOV trial has not yet been reported [Palacios R, 2021 ].
The proportion of females in the 9026-ASI trial was 43% (4307 out of 10214 participants) [Tanriover MD, 2021 ].
Vaccine efficacy for this subgroup in the 9026-ASI trial has not yet been reported [Tanriover MD, 2021 ].
Non-comparative studies
The single group assignment study Ozdemir et al is currently evaluating healthy women that will receive the vaccine inoculated in 2 doses with an interval of 24 days [Izmir Bakircay University, 2021 ].
Age

Randomized trials
The proportion of people 60 years of age and older in the PROFISCOV trial was 5.1% (632 out of 12396 participants) [Palacios R, 2021 ].
The relative risk reduction of contracting COVID-19 (14 days after the 2nd dose) in the people 60 years of age and older that received the vaccine versus those in the control group was 51.1% (95% CI -166.9 to 91.0). This estimate is not statistically different from the estimate for this outcome in the overall population of the trial.
The phase 1/2 trial PRO-nCOV-1002 assessed 72 healthy adults aged 60 years or older (mean age 65.8 years) in the phase 1 and 350 in the phase 2 (mean age 66.6 years). In the phase 1, seroconversion after the second dose was 100.0% (95% CI 85.8 to 100) in the 3 µg group, and 95.7% (78.1 to 99.9) in the 6 µg group. In the phase 2, seroconversion was 90.7% (83.1 to 95.7) in the 1.5 µg group, 98.0% in the 3 µg group, and 99% (94.5 to 100.0) in the 6 µg group. There were no detectable antibody responses in the placebo groups.
Non-comparative studies
Alencar CH et al is a cross sectional study that included 313,328 elderly people that received one or two doses of a vaccine (Oxford-AstraZeneca or CoronaVac). The occurrence of deaths among the unvaccinated elderly was more than 132 times higher, as compared to those who had received two doses of a vaccine, with a protection ratio for deaths of 99.2%. After two dose of Sinovac vaccine, the protection ratio was 113.17 (95%CI: 93.50-136.99). The effect was more pronounced with increasing age [Alencar CH, 2021 ].
Children and adolescents

Randomized trials
Children and adolescents have been excluded from the phase 3 randomized trials PROFISCOV [Palacios R, 2021 ], CoronaVac3CL [Susan M Bueno, 2021 ] and 9026-ASI [AP, 2020 ], so they do not provide efficacy data for this subgroup.
The phase 1/2 randomized trial PRO-nCOV-1003 assessed 72 healthy children and adolescents aged 3-17 years old in the phase 1 and 480 in the phase 2. In phase 1, seroconversion after the second dose was 100% (95% CI 87.3 to 100) in the 1.5 µg group and 100% (86.8 to 100) in the 3 µg group. In phase 2, seroconversion was 96.8% (93.1 to 98.8) in the 1.5 µg group and 100% (98 to 100) in the 3 µg group. There were no detectable antibody responses in the placebo groups [Bihua Han, 2021 ].
Pregnancy

Randomized trials
Pregnant females were excluded from the phase 3 randomized trials PROFISCOV [Palacios R, 2021 ], CoronaVac3CL [Susan M Bueno, 2021 ] and 9026-ASI [AP, 2020 ], so they do not provide efficacy data for this subgroup.
There are no published or ongoing studies evaluating Sinovac COVID-19 vaccine to prevent COVID-19 in pregnant women.
Breast-feeding

Randomized trials
Breast-feeding females were excluded from the phase 3 randomized trials PROFISCOV [Palacios R, 2021 ], CoronaVac3CL [Susan M Bueno, 2021 ] and 9026-ASI [AP, 2020 ], so they do not provide efficacy data for this subgroup.
There are no published or ongoing studies evaluating Sinovac COVID-19 vaccine to prevent COVID-19 in breast-feeding women.
Immunocompromised persons

Randomized trials
Vaccine efficacy for this subgroup in the PROFISCOV trial has not yet been reported [Palacios R, 2021 ].
Other studies
The non-comparative phase 4 study TXCoronavac is currently evaluating the efficacy of the vaccine on kidney transplant recipients [Hospital do Rim e Hipertensão, 2021 ].
The non-randomized phase 4 study CoronavRheum is currently evaluating the efficacy of the vaccine in patients with chronic rheumatic diseases (such as systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, poly/dermatomyositis, systemic sclerosis, systemic vasculitis and primary Sjögren's syndrome) and people living with HIV/AIDS [University of Sao Paulo General Hospital, 2021 ].
The cohort study Balcells et al is currently evaluating this population [Pontificia Universidad Catolica de Chile, 2021 ].
Individuals with recent COVID-19

Individuals with recent COVID-19 infection were excluded from the phase 3 trials and there are no other studies assessing this subgroup. However, most guidelines recommend that individuals who have had COVID-19 should receive an identical vaccine regimen as those who have not had the infection.

Other data from vaccine efficacy and effectiveness

Duration of protection

Randomized trials
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

Randomized trials
Individuals may not be fully protected until 14 days after their second dose. As with all vaccines, inoculation with Sinovac COVID-19 vaccine may not protect all vaccine recipients.
Comparative studies
None available
Non-comparative studies
None available
SARS-CoV-2 variants

Randomized trials
In a subset of participants in the PROFISCOV trial, neutralizing antibody assays showed similar seroconversion and geometric mean titres against B.1.128, P.1, and P.2 variants [Palacios R, 2021 ].
Other studies
de Souza et al measured neutralization of the P.1 virus in specimens from nasopharyngeal and bronchoalveolar lavage samples after incubation with the plasma of COVID-19 convalescent blood donors and recipients of the vaccine. The immune plasma of COVID-19 convalescent blood donors had 6-fold less neutralizing capacity against the P.1 than against the B-lineage. Moreover, five months after booster immunization with CoronaVac, plasma from vaccinated individuals failed to efficiently neutralize P.1 lineage isolates [William M. de Souza, 2021 ].

Safety of the vaccine

Safety of the vaccine in preclinical studies

Previous reports on the development of SARS and MERS inactivated virus vaccine candidates raised concerns about pulmonary immunopathology [Gao Q, 2020 ].
The safety of the vaccine was tested in groups of BALB/c mice and rhesus macaques, that were injected with various doses of Sinovac COVID-19 vaccine mixed with alum adjuvant. No inflammation or other adverse effects were observed [Gao Q, 2020 ]. Two groups of macaques (n=10) received intramuscular injection with low (1.5 µg) or high doses (6 µg) doses of vaccine, and 2 groups were used as placebo. Vaccination was performed three times, at day 0, 7 and 14. Neither fever nor weight loss was observed after immunization. Hematological and biochemical analysis showed no notable changes in vaccinated groups when compared to the placebo groups. In addition, histopathological evaluations of various organs, including lung, heart, spleen, liver, kidney and brain, from the 4 groups at day 29 demonstrated that inactivated vaccine did not cause any notable pathological changes in macaques [Gao Q, 2020 ].

Safety of the vaccine in clinical trials


Key messages

The safety data support a favourable safety profile without any specific safety concerns.

Main safety outcomes of Sinovac COVID-19 vaccine

Any adverse event (at least 28 days after 2nd dose)

The relative risk of any adverse event in the group that received Sinovac COVID-19 vaccine versus the group that received placebo vaccine was 1.16 (95% CI 1.13 to 1.18). This means Sinovac COVID-19 vaccine increased the risk of any adverse event by 16%, compared with placebo vaccine.

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

In the trials identified in this review, 4714 people not receiving Sinovac COVID-19 vaccine out of 9762 presented this outcome (483 per 1000) versus 6041 out of 12848 in the group that did receive it (560 per 1000). In other words, 77 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 7.7%, or that the intervention increased the risk of any adverse event by 7.7 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 13. Which means that 13 people need to receive the vaccine for one of them to experience an adverse event.

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


Serious adverse events (median follow-up from 1,5 to 4,5 months)

The relative risk of serious adverse events in the group that received Sinovac COVID-19 vaccine versus the group that received placebo vaccine was 0.99 (95% CI 0.63 to 1.55). This means Sinovac COVID-19 vaccine reduced the risk of serious adverse events by 1%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: serious adverse events. Comparison: Sinovac COVID-19 vaccine versus placebo vaccine

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: Low number of events; Publication bias: no concerns.

Local adverse events after the 2nd dose (28 days)

The relative risk of local adverse events after the 2nd dose in the group that received Sinovac COVID-19 vaccine versus the group that received placebo vaccine was 1.78 (95% CI 1.71 to 1.85). This means that, in relative terms, Sinovac COVID-19 vaccine increased the risk of local adverse events after the 2nd dose by 78%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: local adverse events after the 2nd dose. Comparison: Sinovac COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 2143 people out of 6194 not receiving Sinovac COVID-19 vaccine, presented this outcome (346 per 1000), versus 3815 out of 6202 in the group that did receive it (615 per 1000). In other words, 269 more people per 1000 did develop the outcome because of the vaccine. This is the same as saying that the intervention led to an increase of 26.9% of absolute risk of local adverse events after the 2nd dose. Another way of presenting the same information about the absolute effects is the number of participants who need to receive the intervention for one of them to experience the outcome (NNTB/H). In this case, the NNH is 4, which means that 4 people need to receive the vaccine for one of them to experience a local adverse event.

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

Systemic adverse events after the 2nd dose (28 days)

The relative risk of systemic adverse events after the 2nd dose in the group that received Sinovac COVID-19 vaccine versus the group that received placebo vaccine was 1.02 (95% CI 0.98 to 1.05). This means that, in relative terms, Sinovac COVID-19 vaccine increased the risk of systemic adverse events after the 2nd dose by 2%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: systemic adverse events after the 2nd dose. Comparison: Sinovac COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 2947 people out of 6194 not receiving Sinovac COVID-19 vaccine presented this outcome (476 per 1000), versus 2999 out of 6202 in the group that did receive it (484 per 1000). In other words, 8 more people per 1000 did develop the outcome because of the vaccine. This is the same as saying that the intervention led to an increase of 0.8% of the absolute risk of systemic adverse events after the 2nd dose. Another way of presenting the same information about the absolute effects is the number of participants who need to receive the intervention for one of them to experience the outcome (NNTB/H). In this case, the NNH is 125, which means that 125 people need to receive the vaccine for one of them to experience a systemic adverse event.

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

Summary of findings table (iSoF)


Safety of the vaccine in subgroups

Sex

Randomized trials
The proportion of females in the PROFISCO was 64.2% (7955 out of 12396 participants) [Palacios R, 2021 ].
Safety profile of Sinovac COVID-19 vaccine was not evaluated across sex groups.
The proportion of females in the 9026-ASI trial was 43% (4307 out of 10214 participants) [Tanriover MD, 2021 ].
Vaccine safety for this subgroup in the 9026-ASI trial has not yet been reported [Tanriover MD, 2021 ].
Non-comparative studies
In a cross sectional study conducted in Turkey, Abanoub Riad, 2021 reported adverse events of 780 healthcare workers. The study showed, females (67.9%) were significantly more affected by AEs compared to males (51.4%) [Abanoub Riad, 2021 ]
The single group assignment study Ozdemir et al is currently evaluating healthy women that will receive the vaccine inoculated in 2 doses with an interval of 24 days[Izmir Bakircay University, 2021 ].

Age

Randomized trials
The proportion of patients 60 years or older in the PROFISCOV was 5.1% (632 out of 12396 participants) [Palacios R, 2021 ].
The proportion of patients 60 years of age and older in the CoronaVac3CL trial was 25% (37 out of 434 participants) [Susan M Bueno, 2021 ].
Significant differences were observed between age groups regarding the frequency of local and systemic AEs; where AEs occur more frequently in the younger group. Pain at the injection site was present in 47.1% of the 18 to 59 years old group, in contrast to 29.7% in the 60 years or older group (p-value = 0.009), while headache was present in 42.4% and 27.0%, respectively (p-value = 0.026) [Susan M Bueno, 2021 ].
PRO-nCOV-1002 was a study phase 1/2, sponsored by Sinovac Research and Development Co., Ltd. and conducted in Hebei Provincial Center for Disease Control and Prevention (CDC) in Renqiu (Hebei, China). It was registered with trial registry number ClinicalTrials.gov, NCT04383574.
The trial included healthy adults aged 60 years or older. The sample size was 350 participants and their median age was 66.6 years. The proportion of fermales was 51%.
Participants were randomly assigned in a 1:1 ratio, and Phase 1 of the trial was a dose-escalation study of 72 participants. The first group (36 participants) was randomly assigned to receive either 3 µg of vaccine or placebo. The second group (36 participants) was randomly assigned to receive either 6 µg vaccine or placebo. Phase 2 considered vaccine doses of 1.5 µg, 3 µg, or 6 µg and were compared with placebo. [Wu Z, 2021 ]
Children and adolescents

Randomized trials
Children were excluded from the CoronaVac3CL trial, so no safety data are available from participants 17 years old and younger [Susan M Bueno, 2021 ].
Pro-nCOV-1003 is a phase 1/2 randomized, double-blind, placebo-controlled clinical trial sponsored by Sinovac Research and Development Co., Ltd. and conducted in China. It was registered under the registration number NCT04551547. The trial included healthy children and adolescents. The sample size was 552 participants, aged 3 to 17 years [Sinovac Research and Development Co., Ltd., 2020 ].
Pregnancy

Randomized trials
Pregnant females were excluded from the CoronaVac3CL trial, so no safety data is available [Susan M Bueno, 2021 ].
No clinical trial evaluating vaccines to prevent COVID-19 has included pregnant females.
Breast-feeding

Randomized trials
No clinical trial evaluating vaccines to prevent COVID-19 has included breast-feeding females.
Immunocompromised persons

Randomized trials
Available data are currently insufficient to assess safety in severely immunocompromised people.
Comparative studies
The cohort study Balcells et al is currently evaluating this population [Pontificia Universidad Catolica de Chile, 2021 ].
Non-comparative studies
Txcoronavac is a prospective study sponsored by the Kidney and Hypertension Hospital, that is being conducted in Brazil between March 2021 and March 2022. It is registered in ClinicalTrials.gov, NCT04801667.
The trial includes kidney transplant recipients older than 18 years of age, who received the vaccine to assess its impact, safety, tolerability, and immunogenicity against transplant recipients [Hospital do Rim e Hipertensão, 2021 ].
The cohort study Balcells et al is currently evaluating this population [Pontificia Universidad Catolica de Chile, 2021 ].
Persons living with HIV

Randomized trials
Available data are currently insufficient to evaluate safety for indivuduals living with HIV.
Comparative studies
CoronavRheum is a non-randomized, open label, clinical trial sponsored by University of Sao Paulo General Hospital, conducted in Brazil from February 9,2021 through March, 2023. It was registered with ClinicalTrials.gov, NCT04754698.
The trial will include patients with autoimmune rheumatic diseases and people living with HIV/AIDS. This study will evaluate the immunogenicity and safety of Sinovac COVID-19 vaccine in immunocompromised patients. The sample size is 2067 participants. The participants are adults of 18 years of age and older [University of Sao Paulo General Hospital, 2021 ].
Persons with autoimmune conditions

Randomized trials
Available data are currently insufficient to assess safety in patients with autoimmune conditions.
Comparative studies
CoronavRheum is a non-randomized, open label, clinical trial sponsored by University of Sao Paulo General Hospital and conducted in Brazil from February 9,2021 through March, 2023. It was registered with ClinicalTrials.gov, NCT04754698.
The trial will include patients with autoimmune rheumatic diseases and people living with HIV/AIDS. This study will evaluate the immunogenicity and safety of Sinovac COVID-19 vaccine in immunocompromised patients. The sample size is 2067 participants. The participants are adults of 18 years or older [University of Sao Paulo General Hospital, 2021 ].

Safety of the vaccine post-authorization

Post-authorization studies

Comparative studies
None available
Non-comparative studies
Abanoub Riad, 2021 reported a cross sectional study conducted in Turkey. 780 healthcare workers were included in this study; 62.5% of them experienced at least one side effects after Sinovac COVID-19 vaccine [Abanoub Riad, 2021 ].

Case reports and case series
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.

In Chile, inoculation against Sars-CoV-2 began on December 24, 2020. To date, 21 notifications of suspected anaphylactic reaction following vaccination with Sinovac COVID-19 vaccine have been reported. On March 2, 2021, the Vaccine Pharmacovigilance Expert group evaluated 17 of the 21 reported cases to determine the causal association between the adverse event and the vaccine. From the 17 cases, 12 did not meet the criteria of the international organization, Brighton Collaboration for case definition of anaphylaxis. The remaining cases failed to be classified due to lack of data [ISP, 2021 ].

Monitoring

WHO recommends the following research and post-authorization monitoring activities [World Health Organization, 2021 ]:
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.

References

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[Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS). Mexico, 2021] Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS). Mexico. Cofepris autoriza vacuna fabricada por Sinovac para uso de emergencia contra COVID-19. 2021; Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS). Mexico. Cofepris autoriza vacuna fabricada por Sinovac para uso de emergencia contra COVID-19. 2021;
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[Tseng CT, 2012] Tseng CT, Sbrana E, Iwata-Yoshikawa N et al. Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus. PloS one. 2012;7(4):e35421. Tseng CT, Sbrana E, Iwata-Yoshikawa N et al. Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus. PloS one. 2012;7(4):e35421.
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