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 1 June 2021 [WHO, 2021 ].
EUL/WHO Authorization: Authorized for emergency use in individuals 18-59 years of age [WHO, 2021 ].
SAGE/WHO Recommendation: Authorized for emergency in individuals aged 18 years and older [WHO, 2022 ].

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

China's National Medical Products Administration
Authorized on 6 February 2021 (Marketing authorization in individuals 18 years of age and older).
3 June 2021: Authorized for emergency use in individuals 12 - 15 years of age [china.org.cn, 2021 ].

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 for emergency use in individuals 6 years of age and older on 17 January 2021 [Agencia Nacional de Vigilancia Sanitaria (ANVISA). Brasil, 2021 ].
13 July 2022: Authorized for emergency use in individuals 3 years of age and older [ANVISA, 2022 ].

Health Canada
Not authorized.

Public Health Institute (ISP, Chile)
Authorized for emergency use on 20 January 2021 [Instituto de Salud Publica. Ministerio de salud de Chile, 2021 ].
30 November 2021: Authorized for emergency use in individuals 3 years of age and older [Gobierno de Chile, 2021 ].

National Institute of Food and Drug Monitoring (INVIMA, Colombia)
Authorized for emergency use on 22 February 2021 [Ministerio de salud y protección social. Colombia, 2021 ].
22 October 2021: For emergency use in individuals 6 years of age and older [INVIMA, 2021 ].

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

U.S. Food and Drug Administration (FDA)
Not authorized.

Federal Commission for the Protection against Sanitary Risk (COFEPRIS, Mexico)
Authorized for emergency use on 10 February 2021 [Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS). Mexico, 2021 ].

Authorization in jurisdictions in Latin America and the Caribbean
Bolivia
Dominican Republic
Ecuador
El Salvador
Panama
Paraguay
Peru
Trinidad and Tobago
Uruguay
Venezuela

Authorization in other jurisdictions
Albania
Algeria
Armenia
Azerbaijan
Bangladesh
Benin
Bosnia and Herzegovina
Botswana
Burkina Faso
Cambodia
Djibouti
Egypt
Guinea
Georgia
Hong Kong
Indonesia
Kazakhstan
Laos
Libya
Malawi
Malaysia
Mali
Moldova
Montenegro
Nepal
Oman
Pakistan
Philippines
Saudi Arabia
Singapore
South Africa
Sri Lanka
Tajikistan
Tanzania
Thailand
Timor-Leste
Togo
Tunisia
Turkey
Uganda
Ukraine
Zimbabwe

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

Manufacturing

Manufacturers
Sinovac Research and Development Co.Ltd., China. Sinovac has four installations across China that house its research, development, and manufacturing facilities for vaccine production [WHO, 2021 ].

Other manufacturers [WHO, 2021 ].
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 [Agência Brasil, 2021 ].

General characteristics

The 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 ].

 

Ingredients

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 ].

Dosing 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

The Sinovac COVID-19 vaccine is indicated for individuals 18 years and over [WHO, 2022 ].

Contraindications

The 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 [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.

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

As for all COVID-19 vaccines, there should be an observation period of 15 minutes after vaccination [Ministerio de Salud Argentina, 2021 ].

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

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

Breastfeeding [WHO, 2022 ].
WHO recommends using the Sinovac-CoronaVac 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) Sinovac-CoronaVac is not a live virus vaccine, and it is biologically and clinically unlikely to pose a risk to the breastfeeding child.
WHO does not recommend discontinuing breastfeeding after vaccination.

Persons living with HIV [WHO, 2022 ].
Data on the administration of the Sinovac-CoronaVac 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 with the standard primary series of two doses. Counseling should be provided to inform the individual benefit-risk assessment.

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

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

Other precautions

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

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

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

Storage and logistics

Storage

The 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 the 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.

Administration logistics

Inspect the vial to be used.
The 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 monodose vial, use immediately.

Once the multidose vial of the vaccine is opened, it can be stored between 2°C and 8°C (36 ° F to 46 ° F) for up to 6 hours or until the last dose is used, whichever occurs first.

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 12,396 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 13,000 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 27,711 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 1,400 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.

Curumim is an ongoing phase 3 randomized study (registered with the number NCT05225285 [Federal University of Espirito Santo, 2022 ]) sponsored by Federal University of Espirito Santo that is being conducted in Brazil. It was first registered in February 2022 and plans to enroll 1120 healthy children and adults between 3 and 49 years old that will receive either the inactivated Coronavac/Butantan vaccine (VACC) or the immunizing BNT162b2 (Pfizer) (BNTC). The VACC group will also be compared to a group of adults aged 18 to 49 who received Coronavac (ADU). It is expected to run until March 2023.

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 1,526 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 ].

Yasin AI et al. was a cohort study conducted in Turkey [Yasin AI, 2022 ], evaluating the efficacy and safety of Sinovac COVID-19 vaccine in cancer patients who have completed the primary vaccination series.

Suntronwong N et al. was a comparative cohort study conducted in Thailand [Nungruthai Suntronwong, 2022 ], evaluating immunogenicity results from adult individuals who had received two doses of Sinovac COVID-19 vaccine and a booster dose of AstraZeneca COVID-19 vaccine.

Perez-Then et al. was a comparative cohort study conducted in Dominican Republic [Pérez-Then E, 2022 ], evaluating immunogenicity results from adult individuals who had received two doses of Sinovac COVID-19 vaccine and a booster dose of Pfizer COVID-19 vaccine.

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

Huang et al. was a retrospective cohort study conducted in China [Huang J, 2022 ] at the Center for Reproductive Medicine, Jiangxi Maternal and Child Health Hospital (JMCHH) affiliated with Nanchang University School of Medicine. This study investigated the effect of female inactivated SARS-CoV-2 vaccination on cycle characteristics, laboratory parameters and pregnancy outcomes during in vitro fertilization (IVF) treatment. Participants included women who underwent fresh IVF cycles between June 1st and September 13th 2021 and who were followed up to October 18th 2021. The number of oocytes retrieved (9.9 ± 7.1 vs 9.9 ± 6.7), good-quality embryo rate (33.5 ± 29.8% vs 29.9 ± 28.6%) and clinical pregnancy rate (59.1% vs 63.6%) were all similar between the vaccine group and the control group. Additionally, no significant differences were observed regarding other cycle characteristics, laboratory parameters and pregnancy outcomes such as: stimulation duration, total gonadotropin dose, serum sex hormone level, endometrial thickness, number of ≥14 mm follicles on trigger day, mature oocyte rate, fertilization rate, cleavage rate, blastocyst formation rate, available blastocyst rate, biochemical pregnancy (65.2% vs 73.7%) and implantation (45.4% vs 46.7%). Results were also similar when vaccinated patients were subdivided into three categories based on the time interval from complete vaccination to cycle initiation: ≤1 month, >1–2 months, and >2 months. The authors suggest that inactivated SARS-CoV-2 vaccines in females did not result in any measurable detrimental effects on IVF treatment. However, further prospective studies with larger cohort size and longer follow-up are needed to validate this conclusion [Huang J, 2022 ].

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 1,200 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 2,067 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 3,780 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. Erdo?an Selçuk ?eber, 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 121,000 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 [Karamano?lu 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. 

PRO-nCOV-MA4007-SD is an ongoing phase 4 non-randomized study (registered with the number NCT05198336 [Sinovac Research and Development Co., Ltd., 2022 ]) sponsored by Sinovac Research and Development Co., Ltd. that is being conducted in China. It was first registered in January 2022 and plans to evaluate the immunogenicity of the vaccine in 400 children aged 3-11 years old that have already completed the primary vaccination series of Sinovac COVID-19 vaccine. It is expected to run until June 2022.

IIT-LKM-2021-NCV03-02 is an ongoing phase 1/2 non-randomized study (registered with the number NCT05205096 [Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd., 2021 ]) sponsored by Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd. that is being conducted in China. It was first registered in January 2022 and plans to enroll 480 adults 18 years old and over who have completed the primary vaccination series of Sinovac COVID-19 vaccine. The participants will receive a booster dose of Anhui Zhifei Longcom COVID-19 vaccine 3-9 months after the primary vaccination series. It is expected to run until June 2022. 

Tong Y et al is an ongoing phase 3 non-randomized study (registered with the number NCT05216484 [Chinese Academy of Medical Sciences, 2022 ]) sponsored by Chinese Academy of Medical Sciences that is being conducted in China. It was first registered in January 2022 and plans to enroll 480 adults 18 years old and over who have completed the primary vaccination series of Sinovac or Sinopharm/BIBP COVID-19 vaccine. Participants will receive a booster dose of Sinovac COVID-19 vaccine 6 months after the primary vaccination series. It is expected to run until December 2022.

 

Methods used to assess efficacy

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 a two-doses immunization schedule was 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.

Safety evaluation methods

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.

 

9026-ASI trial [Tanriover MD, 2021 ]

Primary safety endpoint

Incidence of adverse reactions from the day of first vaccination to 28 days after the second dose; the incidence of adverse reactions and adverse events within 7 days after each dose; and the incidence of serious adverse events from the first vaccination to 1 year after the second dose.

Vaccine efficacy and effectiveness

Efficacy of preclinical studies on the vaccine

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 ].

The immune response was evaluated from the first injection (Day 0) to 14 days after the second injection. The IgG antibody seropositivity rate against SARS-CoV-2 in the vaccinated group 14 days after the second injection was 99.74%. The seropositive rate in the vaccine group was significantly increased compared to the placebo group. Seroconversion rates measured on day 14 after the second injection increased by 97.48%, while in the placebo group there was a seroconversion rate of 0.75%. There was a 23.5-fold increase in GMT of IgG antibodies 14 days after the second injection in the vaccine group, while there was no significant increase in GMT in the placebo group [Fadlyana E, 2021 ].

Seropositivity for neutralizing antibodies was defined as a titer ≥ 1:4, and seroconversion was defined as a change from a titer < 1:8 to a titer ≥ 1:8; or a 4-fold increase from baseline, if the baseline titer is ≥ 1:8. After complete administration of the vaccine, the SARS-CoV-2 seropositivity rate 14 days after the second injection in the vaccine group was 87.15% with no seroconversion in the placebo group. There was a 7.88-fold increase in neutralizing antibody titers at 14 days after the second injection [Fadlyana E, 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 0.23 (95% CI 0.08 to 0.61). This means Sinovac COVID-19 vaccine reduced the risk of contracting COVID-19 by 77%, 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, 218 people not receiving Sinovac COVID-19 vaccine out of 8571 presented this outcome (25 per 1000) versus 101 out of 11996 in the group that did receive it (6 per 1000). In other words, 19 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 1.9%, or that the intervention reduced the risk of contracting COVID-19 by 1.9 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 53. Which means that 59 people need to receive the vaccine for one of them to not contracting 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 8473 presented this outcome (1 per 1000) versus 0 out of 11909 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 contracting severe 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.

Contracting COVID-19 (18-59y) (measured at least 14 days after the second injection)

The relative risk of contracting COVID-19 (18-59y) in the group that received Sinovac COVID-19 vaccine versus the group that received placebo vaccine was 0.5 (95% CI 0.38 to 0.65). This means Sinovac COVID-19 vaccine reduced the risk of contracting COVID-19 (18-59y) by 50%, 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 trials identified in this review, 164 people not receiving Sinovac COVID-19 vaccine out of 4663 presented this outcome (35 per 1000) versus 83 out of 4741 in the group that did receive it (17 per 1000). In other words, 175 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 reduction of 1.8%, or that the intervention reduced the risk of contracting COVID-19 (18-59y) by 1.8 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 56. 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 in subgroups

Sex

Randomized trials

The proportion of females in the PROFISCOV trial was 64.2% (7955 out of 12,396 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 10,214 participants) [Tanriover MD, 2021 ].

Vaccine efficacy for this subgroup in the 9026-ASI trial has not yet been reported [Tanriover MD, 2021 ].

 

 

Age

Randomized trials

The proportion of people 60 years of age and older in the PROFISCOV trial was 5.1% (632 out of 12,396 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.

Other studies

Alencar CH et al. is a comparative 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 ].

Suah JL et al. was a retrospective cohort study conducted in Malaysia. The study included 9,926,361 participants fully vaccinated with either Pfizer-BioNTech or Sinovac. Based on national data on COVID-19 vaccination and outcomes, and used cases from 1 to 30 September 2021 to compare VE between the 'early' (fully vaccinated in April to June 2021) and 'late' (July to August 2021) groups. In the 60 and above age group the effectiveness of Sinovac against infection in the late group was 78.6% (95% CI 74.4 to 82.2) and -38.6% (95% CI -68.4 to -14.1) in the early group. The effectiveness of Sinovac against ICU admission and death in the late group was 46% (95% CI 37.1 to 53.8) and 76.3% (95% CI 72.7 to 79.4) respectively, and for the early group it was 30.3% (95% CI 7.7 to 47.4) and 75.4% (95% CI 66.7 to 81.9) respectively. [Suah JL, 2022 ]

 

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 ].

Other comparative studies


Araos R was a cohort study conducted in Chile. The study analyzed a population-based cohort of children aged 3 to 5 years and aimed to estimate the effectiveness of the complete primary immunization schedule (two doses, 28 days apart) of an inactivated SARS-CoV2 vaccine (CoronaVac) to prevent laboratory confirmed COVID-19 hospitalization and admission to an intensive care unit. The study included 490,694 children aged 3 to 5 years affiliated to the Fondo Nacional de Salud (FONASA). It was conducted between December 6, 2021 and February 26, 2022 during the omicron outbreak in Chile. The estimated vaccine effectiveness was 38.2% (95% CI 36.5 to 39.9) against COVID-19, 64.6% (95% CI 49.6 to 75.2) against hospitalization, and 69.0% (95%CI 18.6 to 88.2) to prevent intensive care unit admission. The effectiveness was modest; however, protection against severe disease remained high [Araos R, 2022 ].

 

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.

Other studies

The test-negative design study conducted in Brazil assessed the effectiveness of the vaccine in 19838 pregnant females aged 18 to 49 years [Enny S. Paixão, 2021 ]. Based on data from the national surveillance system for RT-PCR test for Covid-19 (e-SUS Notifica); the information system for severe acute respiratory illness (SIVEP-Gripe) and the national immunization system (SIPNI). Results showed that a single dose of the Sinovac vaccine was not effective at preventing symptomatic COVID-19. Effectiveness of two doses of Sinovac was 41% (95% CI 27.1- 52.2) against symptomatic COVID-19, 85% (95% CI 59.5-94.8) against severe COVID-19, and 75% (95% CI 27.9- 91.2) in preventing progression to severe COVID-19 among those infected. Authors conclude that a complete regimen of Sinovac in pregnant women was effective in preventing symptomatic COVID-19 and highly effective against severe illness in a setting that combines high disease burden and elevated COVID-19 related maternal deaths.

 

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 ].

 Yasin AI et al. included 776 cancer patients and 715 non-cancer controls. The median follow-up period after vaccination was 3 months. The study showed that the seropositivity rate (85.2% versus 97.5% ) and antibody levels (363.9 AU/ml versus 656.5 AU/ml) were significantly lower in the cancer patients group than in the non-cancer group. Age and chemotherapy were associated with lower seropositivity in cancer patients [Yasin AI, 2022 ].

 

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 on vaccine efficacy and effectiveness

Main effectiveness outcomes of CoronaVac COVID-19 vaccine (Other studies)

Contracting COVID-19 

Ranzani OT et al. was a comparative study conducted in Brazil. The study enrolled 43,774 participants (> 70 years) with two doses of the Sinovac COVID-19 vaccine. Based on data from residents of São Paulo State and underwent SARS-CoV-2 RT-PCR testing from January 17 to April 29, 2021. The outcome was measured ≥14 days after the second dose. Results showed vaccine effectiveness of 41.6% (95% CI, 26.9 to 53.3). [Otavio T. Ranzani, 2021 ].

Cerqueira-Silva T et al. was a comparative study conducted in Brazil. The study enrolled 75,919,840 participants (>18 years old) with at least one dose of the Sinovac or AstraZeneca vaccine. Based on electronic health records from the Brazilian Ministry of Health vaccination campaign, between January 18 and July 24, 2021. The outcome was measured ≥14 days after vaccination. The results showed an effectiveness of 52.7% after the second dose [Cerqueira-Silva, T., 2021 ].

Anton Suryatma et al. was a case-control study conducted in Indonesia. The study enrolled 14,168 participants and was based on linked individual health electronic databases that included SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) test results from the national laboratory testing database, between January 13 and June 30, 2021. The outcome was measured ≥14 days after the vaccination. The study results showed a vaccine effectiveness against laboratory-confirmed infection of 14.5% (95% CI 11 to 34.2) after first dose and 66.7% (95% CI 58.1 to 73.5%) after the second dose [Anton Suryatma, 2022 ].

Cerqueira-Silva T et al was a case control study conducted in Brazil. The study enrolled 7,314,318: 3,279,280 participants with two doses of Sinovac, 4,035,038 participants in the control group. Based on electronic health records from the Brazilian Ministry of Health vaccination campaign. The study assessed the effectiveness of two doses of CoronaVac against confirmed SARS-CoV-2 infection and severe COVID-19 outcomes (hospitalization and death). Also estimated the effectiveness of the BNT162b2 mRNA vaccine as a booster dose. The vaccine effectiveness 14 to 30 days after the second dose was 55% (95% CI 54.3 to 55.7) [Cerqueira-Silva T, 2022 ].

Can G et al. was a retrospective cohort study conducted in Turkey. The study enrolled 3,174 healthcare workers: 2,267 were fully vaccinated with Sinovac, 907 were unvaccinated. Data obtained between March 1 and May 31, 2021 in Cerrahpasa Faculty of Medicine university hospital in Istanbul, Turkey employing 4067 healthcare workers.The follow-up period was defined as starting either 14 days after receiving the second dose. The vaccine effectiveness against symptomatic infection was 39% (95% CI 20 to 54) based on the adjusted HR from a Cox regression [Can G, 2022 ].

Suah JL et al. was a retrospective cohort study conducted in Malaysia. The study included 9,926,361 participants fully vaccinated with either Pfizer-BioNTech or Sinovac. Based on national data on COVID-19 vaccination and outcomes, and used cases from 1 to 30 September 2021 to compare VE between the 'early' (fully vaccinated in April to June 2021) and 'late' (July to August 2021) groups. The effectiveness of Sinovac against infection in the late group was 30.4% (95% CI 18.8 to 40.3) and 30.4% (95% CI 18.8 to 40.3) in the early group [Suah JL, 2022 ].

 

Marra AR et al was a retrospective cohort study conducted in Brazil. The study included 13,813 health care workers (aged ≥18 years) working in a private healthcare system in Brazil between January 1, 2021 and August 3, 2021, to assess vaccine effectiveness. In total, 13,813 HCWs met the inclusion criteria for this analysis. Among them, 6,385 (46.2%) received the CoronaVac vaccine, 5,916 (42.8%) received the ChAdOx1 vaccine, and 1,512 (11.0%) were not vaccinated. Vaccine effectiveness against COVID-19 infection was 50.3% (95% CI 36.2 to 61.3) [Marra AR, 2022 ].

 

Contracting severe COVID-19

Alencar CH et al. was a comparative study conducted in Brazil. The study enrolled 313,328 participants (>75 years) with one or two doses of Oxford-Astrazeneca (139,322 participants) or Sinovac (174,066 participants) COVID-19 vaccines. Based on data from the National Mortality System (SIM) and from the Immunization Program (SIPNI), between 17 January and 11 May 2021. The outcome was defined as people who died 21 days or later after the first dose of the vaccine. Results showed an Attributable Protection Ratio of 99.1% (95% CI 98.9 to 99.3). [Alencar CH, 2021 ].

Ranzani OT et al. was a comparative study conducted in Brazil. The study enrolled 43,774 participants (> 70 years) with two doses of the Sinovac COVID-19 vaccine. Based on data from residents of São Paulo State and underwent SARS-CoV-2 RT-PCR testing from January 17 to April 29, 2021. The outcome was measured ≥14 days after the second dose. Results showed vaccine effectiveness of 59.0% (95% CI, 44.2 to 69.8) for Hospitalizations and 71.4% (95% CI, 53.7 to 82.3) for deaths. [Otavio T. Ranzani, 2021 ].

Cerqueira-Silva T et al was a comparative study conducted in Brazil. The study enrolled 75,919,840 participants (>18 years old) with at least one dose of Sinovac or AstraZeneca vaccine. Based on electronic health records from the Brazilian Ministry of Health vaccination campaign, between January 18 and July 24, 2021. Outcome was measured ≥14 days after vaccination. The results showed an effectiveness of 52.7% after the second dose [Cerqueira-Silva, T., 2021 ].

Anton Suryatma et al. was a case-control study conducted in Indonesia. The study enrolled 14,168 participants and was based on linked individual health electronic databases that included SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) test results from the national laboratory testing database, between January 13 and June 30, 2021. The outcome was measured ≥14 days after the vaccination. The study results showed a vaccine effectiveness against COVID-19 related hospitalization and death of 71.1% (95% CI 62.9% to 77.6%) and 87.4% (95% CI 65.1% to 95.4%) respectively [Anton Suryatma, 2022 ].

Arregocés-Castillo et al was a retrospective cohort study conducted in Colombia. The study included 2,828,294 participants: 1,414,147 fully vaccinated (any vaccine) and 1,414,147 unvaccinated. The study evaluated the effectiveness of vaccines against COVID-19-related hospitalization and death in people aged 60 years and older. Participant follow-up was done between March 11, 2021, and Oct 26, 2021.It was estimated the overall effectiveness of being fully vaccinated, as well as effectiveness for each vaccine. The aim results showed that vaccine effectiveness against hospitalization without death was 47.3% (95% CI 41.9 to 52.3) in adults > 60 years. Effectiveness against death after hospitalization was 72.1% (95% CI 70.1 to 73.9) and against death without hospitalization was 64.9% (95% CI 61.2 to 68.2) in adults > 60 years. [Arregocés-Castillo L, 2022 ]

Suah JL et al. was a retrospective cohort study conducted in Malaysia. The study included 9,926,361 participants fully vaccinated with either Pfizer-BioNTech or Sinovac. Based on national data on COVID-19 vaccination and outcomes, and used cases from 1 to 30 September 2021 to compare VE between the 'early' (fully vaccinated in April to June 2021) and 'late' (July to August 2021) groups. The effectiveness of Sinovac against ICU admission and death in the late group was 56% (95% CI 51.2 to 60.2)
and 79.2% (95% CI 76.8 to 81.4) respectively, and for the early group it was 28.7% (95% CI 12.2 to 42.1) and 76.2% (95% CI 68.8 to 81.9) respectively [Suah JL, 2022 ].

Transmission 

No studies reported or assessed this outcome.

 

SARS-CoV-2 variants

Immunogenicity outcomes

Palacios R et al. conducted a non-comparative study in Brazil, which included 45 participants. In the study, for neutralization assays, seroconversion was defined as a person with a 10 post-vaccination titre ≥20 with a baseline negative result. Differences in seroconversion rates between age groups were not significant for the gamma variant (p = 0.337). Differences in geometric mean titers (GMT) between age groups were significant for the gamma variant (p = 0.029). Adults from 18 to 59 years old: 17/22 have seroconversion (77.3%; geometric mean titles 60.9) and adults aged 60 years or more: 14/23 have seroconversion (60.9%; geometric mean titles 34.5) [Palacios R, 2021 ].

Suntronwong N et al. included 458 fully vaccinated participants (2 doses Sinovac=248; 2 doses Sinovac plus AstraZeneca booster=210). Data were collected 34 days after infection. The study showed that binding antibody levels in sera from patients with breakthrough infection were significantly higher than those in individuals who had received AstraZeneca as a booster dose. However, neutralizing activities against wild-type and variants including alpha, beta, and delta were similar between patients with breakthrough infections and those who received a booster vaccination with AstraZeneca. Omicron was neutralized less effectively by serum from breakthrough infection patients, with a 6.3-fold reduction compared to delta variants [Nungruthai Suntronwong, 2022 ].

Angkasekwinai N et al. was a cohort study conducted Thailand . Based on data from a single-center, tertiary care university-based hospital in Bangkok, between July to September 2021. Results showed that for both the Sinovac-prime and AstraZeneca-prime groups, the PRNT50 GMT against the Delta and Beta variant were significantly higher among those who received a booster dose of Pfizer (30µg or 15µg) compared to those who received AstraZeneca or Sinopharm/ BIBP. In addition, there was no statistical difference in PRNT50 between boosting with 30µg and 15µg- Pfizer regardless of the primary series vaccine and the type of variants. However, the PRNT50 against the Beta variant was in general around 1.5-fold lower than the Delta variants for both CoronaVac-prime and ChAdOx1-prime groups. The GMRs of the PRNT50 between post-boost and post-primary series were highest among the participants who received Pfizer boosting vaccination in bothSinovac-prime and AstraZeneca-prime groups. The SARS-CoV-2 RBD IgG levels and the neutralizing titers against Delta variant or Beta variant were strongly correlated.[ ].

Perez-Then et al, was a cohort study conducted in the Dominican Republic. The study compared the neutralizing capabilities of plasma from 101 non hospitalized adults who received two doses of CoronaVac plus a Pfizer vaccine booster dose to a cohort of healthcare workers immunized with two doses of an mRNA vaccine (Pfizer or Moderna). The results showed increased neutralizing activity against the Omicron variant of the boosted cohort (1.4 fold increase) compared to the mRNA and CoronaVac only regimens. Neutralization against the Delta variant was similar in the boosted and mRNA groups but lower in the CoronaVac only group [Pérez-Then E, 2022 ].

Biyan Zhang et al. was a cohort study conducted in Singapore. The study enrolled 52 participants and evaluated the levels of antibodies for Omicron variant and compared to the ancestral strain (Wuhan-Hu-1) and Delta variant, in four groups of volunteers receiving 1) Two doses of mRNA vaccines plus an mRNA vaccine booster (Homologous mRNA vaccine booster) 2) Two doses of inactivated virus vaccines plus an inactivated virus vaccine booster (Homologous inactivated virus vaccine booster) 3) Two doses of mRNA vaccines plus an inactivated virus vaccine booster (Heterologous inactivated virus vaccine booster) and 4) Two doses of inactivated virus vaccines plus an mRNA vaccine booster (Heterologous mRNA vaccine booster). The study results showed that only the mRNA vaccine booster was able to effectively increase the median levels of neutralizing capabilities against the Omicron variant (Group 1, median 90.45% [IQR 78.71-94.33%]; Group 4, median 77.85% [IQR 47.80-92.18%]) by 4.5-fold and 3-fold, respectively. Inactivated virus booster shot was unable to significantly increase the median levels of neutralizing capabilities against the Omicron variant regardless of whether the individuals received 2 priming doses of mRNA vaccines (Group 3, median 30.65% [IQR 19.98- 36.03%]) or 2 priming doses of inactivated virus vaccines (Group 4, median 26.80% [IQR 18.35- 36.15%]) [Biyan Zhang, 2022 ].

Schultz et al. studied 186 participants who received a booster dose of CoronaVac vaccine. The study found the booster dose generates an increase in antibody concentrations 3 fold higher than the concentration achieved 2 weeks after the second dose. In respect to the cellular response, the study found a slight but insignificant increase in CD4 T cell activation after the booster dose. No CD8 T cell activation could be detected even after the booster dose [Schultz, B. M., 2022 ].

Lu et al. was a prospective cohort study conducted in Hong Kong. The study assessed the immune response generated by one or two doses of the Sinovac and Pfizer vaccine on COVID-19 recovered individuals. Lu et al, recruited 135 COVID-19 recovered individuals who were scheduled to receive either a Sinovac or Pfizer vaccine. The study compared the neutralizing response against the Beta, Delta and Omicron variants of the vaccinated individuals to the unvaccinated ones. The study found 1 dose of the Sinovac vaccine increased the titers of neutralizing antibodies against the Beta and Delta variants as well as the seropositivity rate. There was an increase in neutralizing titers against the Omicron variant for vaccinated individuals, however this was not significant [Lu Lu, 2022 ]. 

Zhe Z et al, was a comparative study conducted in China. The study compared antibody levels and pseudovirus-based neutralizing titers measured before and 7, 14 and 28 days after the booster vaccination.  The results showed greater generation of neutralizing antibodies against the Omicron variant was increased after a booster vaccination. Both Cansino booster groups had higher levels of neutralizing titers than the other two groups. This levels are lower than for the wildtype virus [Zhe Zhang, 2022 ].

Lu et al. was a prospective cohort study conducted in Hong Kong. The study assessed the immune response generated by one or two doses of the Sinovac and Pfizer vaccine on COVID-19 recovered individuals. Lu et al, recruited 135 COVID-19 recovered individuals who were scheduled to receive either a Sinovac or Pfizer vaccine. The study compared the neutralizing response against the Beta, Delta and Omicron variants of the vaccinated individuals to the unvaccinated ones. The study found 1 dose of the Sinovac vaccine increased the titers of neutralizing antibodies against the Beta and Delta variants as well as the seropositivity rate. There was an increase in neutralizing titers against the Omicron variant for vaccinated individuals, however this was not significant [Lu Lu, 2022 ].

Kanokudom et al. recruited 222 adults with a complete CoronaVac regimen who received a booster dose of 15μg Pfizer-BioNTech vaccine (n=59), 50μg Moderna vaccine (n=51), standard Pfizer-BioNTech vaccine (n=54)or standard Moderna vaccine (n=58). The study found no significant differences in binding antibody levels between standard and reduced doses. 28 days after the booster dose binding antibody levels were 28,413 U/mL and 31,793 U/mL for the reduced and standard Pfizer-BioNTech vaccines respectively and 41,171 U/mL and 51,979 U/mL for the reduced and standard Moderna vaccines. Boosting elicited an increase in median IFN-γ CD4+ T cell and CD4+ CD8+ T cell counts; there were no differences in T cell counts between the standard and reduced dose groups. The booster dose induced a neutralizing response against the Delta and Omicron variants in previously seronegative participants that was not affected by dosage. At day 28 the GMT of neutralizing antibodies against the Delta variant increased to 1 505 and 2 088 in the reduced dose Pfizer-BioNTech and Moderna vaccine groups, GMTs against Omicron variant reached 343.3 and 541.2 for the same vaccine groups  [Sitthichai Kanokudom, 2022 ].

Niyomnaitham et al. was a comparative study conducted in Thailand. The study recruited 210 participants equally divided (n=30) to receive Sinovac, AstraZeneca and Pfizer-BioNTech vaccines either as a first or second dose. Participants who received only Sinovac or AstraZeneca first and second doses also received a booster dose with Pfizer-BioNTech. The study found antibody levels were highest among the groups that received Pfizer-BioNTech as a second dose, levels were similar between homologous and heterologous regimens. These levels were significantly higher compared with the groups who received AstraZeneca or Sinovac as a second dose.  The groups who were given Pfizer-BioNTech as second dose had significantly higher neutralizing titers against Delta and Beta than the groups that received AstraZeneca or Sinovac as the second dose. Neutralizing titers against the Beta variant were reduced by 2 to 5-fold compared to the Delta variant. Overall, neutralization against Omicron was low across the groups and were 28- to 229-fold lower than Delta, depending on the vaccine schedules. Neutralization against both the Delta and Omicron variants were significantly lower among groups who received Sinovac as a second dose compared to the other groups. Seropositivity rate for the Omicron variant was : 80% (45/56), 50% (30/60) and 21% (21/58) for the groups that received  Pfizer-BioNTech, AstraZeneca and: Sinovac as a second dose respectively [Suvimol Niyomnaitham, 2022 ].

 

Randomized trials

Currently, there are no randomized trials that assess vaccine efficacy against SARS-CoV-2 variants.

 

Other studies

Lin XN et al. conducted a case-control study (test-negative) in China, which included 74 positive cases for SARS-COV-2 and 292 controls. In the study, they evaluated the efficacy of the Sinovac and Sinopharm vaccines (BIBP and WIBP) against COVID-19 infection for 14 days or more after receiving the second dose. The results showed that the efficacy against COVID-19 infection was 59.0% (95% CI 16.0 to 81.6) and the efficacy against severe COVID-19 infection was 100% [Li XN, 2021 ].

Min Kang et al. was a comparative cohort study in China, which included 10,813 healthy adults. The study evaluated the efficacy of the inactivated Sinovac, Sinopharm (BIBP and WIBP) and Biokangtai vaccine against COVID-19 infection for 14 days or more after receiving the second dose. The results showed an effectiveness against symptomatic COVID-19 infection of 69.5% (95% CI 42.8 to 96.3) and an efficacy against severe COVID-19 infection of 100% [Min Kang, 2021 ].

Hitchings MDT et al. conducted a case-control study (test-negativa) in Brazil, which included 418 cases of SARS-COV-2 infection and 418 controls. The study estimated the effectiveness of the two-dose vaccine against all SARS-CoV-2 infections for 14 days or more after receiving the second dose. The results confirmed an effectiveness against COVID-19 infection of 38% approximately (OR 0.62; 95% CI 0.26 to 1.46) and an effectiveness against symptomatic COVID-19 infection of 37% approximately (OR 0.63, 95% CI 0.26 to 1.53) [Hitchings MDT, 2021 ].

Ranzani OT et al. was a case-control study (test-negative) in Brazil, which included 26,433 cases of SARS-COV-2 infection in the elderly population and 17,622 controls. The study evaluated the effectiveness of the Sinovac vaccine against symptomatic COVID-19 ≥14 days after the second dose. The results showed an effectiveness against symptomatic COVID-19 infection of 41.6% (95% CI: 26.9 to 53.3) and an efficacy against severe COVID-19 infection of 59% (95% CI %: 44.2 to 69.8) [Ranzani OT, 2021 ].

Kang et al. was a comparative cohort study in China that included 10,805 healthy adults. The study evaluated the efficacy of the inactivated virus vaccines Sinovac and Sinopharm/BIBP against COVID-19 infection for 14 days or more after receiving the second dose. Results show an effectiveness against symptomatic COVID-19 infection of 63.5% (CI, 37.2% to 89.8%) and 100.0% (CI, 98.4% to 100.0%) against severe COVID-19 infection [Kang M, 2022 ].

 

Ranzani O et al was a case control study (test negative design) conducted in Brasil. It was a nationwide study of adults who were tested for SARS-CoV-2 infection. We evaluated vaccine effectiveness against symptomatic Covid-19 and severe Covid-19 (hospital admission or deaths) for the primary series of CoronaVac and homologous and heterologous (BNT162b2) booster doses. Vaccine effectiveness against Symptomatic COVID-19 after Two doses > 180 days was 3.7% (95% CI 2.5 to 5.0). Vaccine effectiveness after the third dose of CoronaVac (8-59 days) was 13.8% (95% CI 10.3 to 17.2) and after the third dose of Pfizer (8-59 days) was 57.2% (95% CI 56.6 to 57.8). Vaccine effectiveness against hospitalization or death after Third dose of CoronaVac (8-59 days) was 71.9% (95% CI 41.9 to 86.4) and after Third dose of Pfizer (8-59 days) was 90.8% (95% CI 88.5 to 92.7) [Otavio T. Ranzani, 2022 ].

 

Booster dose

Immunogenicity outcomes

PRO-nCOV-1002 is a phase 1/2 randomized trial sponsored by Sinovac Research and Development Co., Ltd. and conducted in China. The study included 303 participants: 85 1.5 μg group; 90 3 μg group; 81 6 μg group; 47 Placebo group. The immunogenicity was assessed by the geometric mean titre (GMT) and seropositivity rate of neutralizing antibodies to live SARS-CoV-2 on day 180 after two-dose primary vaccination, and on days 7, 14, and 28 after the third dose. Result showed neutralizing antibody titres declined substantially six months after two doses of CoronaVac among older adults. A booster dose rapidly induces robust immune responses. GMT increased to 305 (95% CI 215.3 to 432.0) on day 7 following the third dose, an approximately 7-fold increase compared with the GMT 28 days after the second dose [Minjie Li, 2021 ].

PRO-nCOV-1001 is a phase 1/2 randomized trial sponsored by Sinovac Research and Development Co., Ltd. and conducted in China. The study included 540 participants: Schedule 1: Days 0, 14, 42 vaccination cohort; Schedule 2: Days 0, 14, 194 vaccination cohort; Schedule 3: Days 0, 28, 56 vaccination cohort; Schedule 4: Days 0, 28, 208 vaccination cohort. Result showed a third dose of Sinovac administered 6 or more months after a second dose effectively recalled specific immune responses to SARS-CoV-2, resulting in a remarkable increase in antibody levels. GMTs assessed 14 days later increased to 137.9 (95% CI 99.9-190.4) for Schedule 2, and 143.1 (95%CI 110.8-184.7) for Schedule 4, approximately 3-fold above Schedule 1 and Schedule 3 GMTs after third doses. Similar patterns were observed for the 6 μg group [Pan, H., 2021 ].

Vargas L et al. was a comparative study conducted in Chile. The study included blood samples from different individuals; healthcare personnel volunteers from Hospital La Florida, and adult healthy volunteers aged 18 years and over. This study describes the production of IgG antibodies directed against the ancestral SARS-CoV-2 S protein induced by the two-dose scheme of the Coronavac vaccine in a Health Service of the Hospital La Florida, Santiago. In addition, The study analyzed the impact of the booster doses of Sinovac, Pfizer, or AstraZeneca COVID-19 vaccines, administered to individuals vaccinated with the two-dose scheme with CoronaVac six months earlier. Study results showed that two doses of Sinovac induce antibody titers against the SARS-CoV-2 ancestral strain which are lower in magnitude than those induced by the Pfizer vaccine. However, the response induced by Sinovac can be greatly potentiated with a heterologous booster scheme with Pfizer or AstraZeneca vaccines. Furthermore, the heterologous booster regimes induce a durable antibody response that does not show signs of decay 3 months after the booster dose [Leonardo Vargas, 2022 ].

Cheng SMS et al. was a study conducted in China. The study included subsets of sera from 7 groups of vaccinated individuals, convalescent individuals, and individuals with breakthrough infections. The study evaluated sera from a) vaccinated individuals with no evidence of prior COVID-19 infection 3-5 weeks after receiving two doses of Pfizer or two doses of Sinovac b) individuals 3-5 weeks after receiving a third dose of Sinovac or a heterologous booster dose of Pfizer after two prior doses of Sinovac. Study results showed that showed markedly reduced serum antibody titres against the Omicron variant (GMT)<10) as compared to wild-type virus 3-5 weeks after two doses of Pfizer (GMT 218.8) or Sinovac vaccines (GMT 32.5). A Pfizer booster dose elicited Omicron PRNT50 titres ≥25.6 in 88% of individuals who previously received 2 doses of Pfizer and 80% of individuals who previously received Sinovac. However, few (3%) previously infected individuals or those vaccinated with three doses of Sinovac met this threshold [Cheng SMS, 2022 ].

Li et al. is an ongoing, randomized, observer-blinded, parallel-controlled phase 4 trial. The study analysed blood samples from 300 participants, 100 receiving booster dose, and evaluated the safety and immunogenicity of the homologous booster in adults previously vaccinated with CoronaVac, measuring Geometric mean titers (GMTs) of neutralizing antibodies against live wild-type SARS-CoV-2 virus at 14 d after booster vaccination. The study results showed Geometric mean fold increase (GMFI) of homologous booster of 15.2 in neutralizing antibody levels against wild-type SARS-CoV-2. [Li J, 2022 ].

Biyan Zhang et al. was a cohort study conducted in Singapore. The study enrolled 52 participants and evaluated the levels of antibodies for Omicron variant and compared to the ancestral strain (Wuhan-Hu-1) and Delta variant, in four groups of volunteers receiving 1) Two doses of mRNA vaccines plus an mRNA vaccine booster (Homologous mRNA vaccine booster) 2) Two doses of inactivated virus vaccines plus an inactivated virus vaccine booster (Homologous inactivated virus vaccine booster) 3) Two doses of mRNA vaccines plus an inactivated virus vaccine booster (Heterologous inactivated virus vaccine booster) and 4) Two doses of inactivated virus vaccines plus an mRNA vaccine booster (Heterologous mRNA vaccine booster). The study results showed that only the mRNA vaccine booster was able to effectively increase the median levels of neutralizing capabilities against the Omicron variant (Group 1, median 90.45% [IQR 78.71-94.33%]; Group 4, median 77.85% [IQR 47.80-92.18%]) by 4.5-fold and 3-fold, respectively. Inactivated virus booster shot was unable to significantly increase the median levels of neutralizing capabilities against the Omicron variant
regardless of whether the individuals received 2 priming doses of mRNA vaccines (Group 3, median 30.65% [IQR 19.98- 36.03%]) or 2 priming doses of inactivated virus vaccines (Group 4, median 26.80% [IQR 18.35- 36.15%]) [Biyan Zhang, 2022 ].

Schultz et al. studied 186 participants who received a booster dose of CoronaVac vaccine. The study found the booster dose generates an increase in antibody concentrations 3 fold higher than the concentration achieved 2 weeks after the second dose. In respect to the cellular response, the study found a slight but insignificant increase in CD4 T cell activation after the booster dose. No CD8 T cell activation could be detected even after the booster dose [Schultz, B. M., 2022 ]. 

Heterologous vaccine regimens

Immunogenicity outcomes

JSVCT116 is a phase 4 randomized trial sponsored by Jiangsu Province Centers for Disease Control and Prevention and conducted in China. The study included 101 participants: 51 heterologous regimen (one dose of Sinovac + one dose of Cansino); 50 homologous regimen (two doses of Sinovac). The immunogenicity was assessed by the geometric mean titres (GMTs) of neutralizing antibodies against live SARS-CoV-2 virus at 14 days after the booster vaccination. Result showed the heterologous immunization with Cansino induced higher live viral neutralizing antibodies than did the homogeneous immunization with Sinovac[Jingxin Li, 2021 ].

Niyomnaitham et al. was a comparative study conducted in Thailand. The study recruited 210 participants equally divided (n=30) to receive Sinovac, AstraZeneca and Pfizer-BioNTech vaccines either as a first or second dose. Participants who received only Sinovac or AstraZeneca first and second doses also received a booster dose with Pfizer-BioNTech. The study found antibody levels were highest among the groups that received Pfizer-BioNTech as a second dose, levels were similar between homologous and heterologous regimens. These levels were significantly higher compared with the groups who received AstraZeneca or Sinovac as a second dose.  The groups who were given Pfizer-BioNTech as second dose had significantly higher neutralizing titers against Delta and Beta than the groups that received AstraZeneca or Sinovac as the second dose. Neutralizing titers against the Beta variant were reduced by 2 to 5-fold compared to the Delta variant. Overall, neutralization against Omicron was low across the groups and were 28- to 229-fold lower than Delta, depending on the vaccine schedules. Neutralization against both the Delta and Omicron variants were significantly lower among groups who received Sinovac as a second dose compared to the other groups. Seropositivity rate for the Omicron variant was : 80% (45/56), 50% (30/60) and 21% (21/58) for the groups that received  Pfizer-BioNTech, AstraZeneca and: Sinovac as a second dose respectively [Suvimol Niyomnaitham, 2022 ].

Effectiveness outcomes 

Sritipsukho P et al. was a case-control study conducted in Thailand. The study enrolled 3,353 participants. Based on a test negative design of consecutive individuals (age ≥18 years) at-risk for COVID-19 who presented for nasopharyngeal real-time polymerase chain reaction (RT-PCR) testing between 5 July 2021 and 23 October 2021 that were prospectively enrolled and followed up for disease development, the study results showed a vaccine effectiveness (one dose of sinovac+ one dose of Astrazeneca vaccine) of 74% (95% CI 43 to 88%) [Sritipsukho P, 2022 ].
  

Heterologous-booster regimens

Immunogenicity outcomes

JSVCT116 is a phase 4 randomized trial sponsored by Jiangsu Province Centers for Disease Control and Prevention and conducted in China. The study included 198 participants: 96 two doses of Sinovac + booster dose of Cansino; 102 two doses of Sinovac + booster dose of Sinovac. The immunogenicity was assessed by the geometric mean titres (GMTs) of neutralizing antibodies against live SARS-CoV-2 virus at 14 days after the booster vaccination. Result showed the heterologous immunization with Cansino induced higher live viral neutralizing antibodies than did the homogeneous immunization with Sinovac [Jingxin Li, 2021 ].

Suntronwong N et al. included 458 fully vaccinated participants (2 doses Sinovac=248; 2 doses Sinovac plus AstraZeneca booster=210). Data were collected 34 days after infection. The study showed that binding antibody levels in sera from patients with breakthrough infection were significantly higher than those in individuals who had received AstraZeneca as a booster dose. However, neutralizing activities against wild-type and variants including alpha, beta, and delta were similar between patients with breakthrough infections and those who received a booster vaccination with AstraZeneca. Omicron was neutralized less effectively by serum from breakthrough infection patients, with a 6.3-fold reduction compared to delta variants [Nungruthai Suntronwong, 2022 ].

Angkasekwinai N et al. was a cohort study conducted Thailand . Based on data from a single-center, tertiary care university-based hospital in Bangkok, between July to September 2021. Results showed that heterologous boosting vaccination with Pfizer following Sinovac or AstraZeneca primary series is the most immunogenic against SARS-CoV-2 variants. A lower dose Pfizer may be used as a booster in settings with limited vaccine supply [ ].

Vargas L et al. was a comparative study conducted in Chile. The study included blood samples from different individuals; healthcare personnel volunteers from Hospital La Florida, and adult healthy volunteers aged 18 years and over. This study describes the production of IgG antibodies directed against the ancestral SARS-CoV-2 S protein induced by the two-dose scheme of the Coronavac vaccine in a Health Service of the Hospital La Florida, Santiago. In addition, The study analyzed the impact of the booster doses of Sinovac, Pfizer, or AstraZeneca COVID-19 vaccines, administered to individuals vaccinated with the two-dose scheme with CoronaVac six months earlier. Study results showed that two doses of Sinovac induce antibody titers against the SARS-CoV-2 ancestral strain which are lower in magnitude than those induced by the Pfizer vaccine. However, the response induced by Sinovac can be greatly potentiated with a heterologous booster scheme with Pfizer or AstraZeneca vaccines. Furthermore, the heterologous booster regimes induce a durable antibody response that does not show signs of decay 3 months after the booster dose [Leonardo Vargas, 2022 ].

Cheng SMS et al. was a study conducted in China. The study included subsets of sera from 7 groups of vaccinated individuals, convalescent individuals, and individuals with breakthrough infections. The study evaluated sera from a) vaccinated individuals with no evidence of prior COVID-19 infection 3-5 weeks after receiving two doses of Pfizer or two doses of Sinovac b) individuals 3-5 weeks after receiving a third dose of Sinovac or a heterologous booster dose of Pfizer after two prior doses of Sinovac. Study results showed that showed markedly reduced serum antibody titres against the Omicron variant (GMT)<10) as compared to wild-type virus 3-5 weeks after two doses of Pfizer (GMT 218.8) or Sinovac vaccines (GMT 32.5). A Pfizer booster dose elicited Omicron PRNT50 titres ≥25.6 in 88% of individuals who previously received 2 doses of Pfizer and 80% of individuals who previously received Sinovac. However, few (3%) previously infected individuals or those vaccinated with three doses of Sinovac met this threshold [Cheng SMS, 2022 ].

Perez-Then et al. was a cohort study conducted in the Dominican Republic. The study compared the neutralizing capabilities of plasma from 101 non hospitalized adults who received two doses of CoronaVac plus a Pfizer vaccine booster dose to a cohort of healthcare workers immunized with two doses of an mRNA vaccine (Pfizer or Moderna). The results showed increased neutralizing activity against the Omicron variant of the boosted cohort (1.4 fold increase) compared to the mRNA and CoronaVac only regimens. Neutralization against the Delta variant was similar in the boosted and mRNA groups but lower in the CoronaVac only group [Pérez-Then E, 2022 ].

Biyan Zhang et al. was a cohort study conducted in Singapore. The study enrolled 52 participants and evaluated the levels of antibodies for Omicron variant and compared to the ancestral strain (Wuhan-Hu-1) and Delta variant, in four groups of volunteers receiving 1) Two doses of mRNA vaccines plus an mRNA vaccine booster (Homologous mRNA vaccine booster) 2) Two doses of inactivated virus vaccines plus an inactivated virus vaccine booster (Homologous inactivated virus vaccine booster) 3) Two doses of mRNA vaccines plus an inactivated virus vaccine booster (Heterologous inactivated virus vaccine booster) and 4) Two doses of inactivated virus vaccines plus an mRNA vaccine booster (Heterologous mRNA vaccine booster). The study results showed that only the mRNA vaccine booster was able to effectively increase the median levels of neutralizing capabilities against the Omicron variant (Group 1, median 90.45% [IQR 78.71-94.33%]; Group 4, median 77.85% [IQR 47.80-92.18%]) by 4.5-fold and 3-fold, respectively. Inactivated virus booster shot was unable to significantly increase the median levels of neutralizing capabilities against the Omicron variant regardless of whether the individuals received 2 priming doses of mRNA vaccines (Group 3, median 30.65% [IQR 19.98- 36.03%]) or 2 priming doses of inactivated virus vaccines (Group 4, median 26.80% [IQR 18.35- 36.15%]) [Biyan Zhang, 2022 ].

Zhe Z et al. was a comparative study conducted in China. The study compared antibody levels and pseudovirus-based neutralizing titers measured before and 7, 14 and 28 days after the booster vaccination.  The results showed greater generation of neutralizing antibodies against the Omicron variant was increased after a booster vaccination. Both Cansino booster groups had higher levels of neutralizing titers than the other two groups. This levels are lower than for the wildtype virus [Zhe Zhang, 2022 ].

Kanokudom et al. reclutaron a 222 adultos con un régimen completo de CoronaVac que recibieron una dosis de refuerzo de 15 μg de vacuna Pfizer-BioNTech (n=59), 50 μg de vacuna Moderna (n=51), vacuna estándar Pfizer-BioNTech (n=54) o vacuna estándar Moderna (n =58). El estudio no encontró diferencias significativas en los niveles de anticuerpos de unión entre las dosis estándar y reducida. 28 días después de la dosis de refuerzo, los niveles de anticuerpos de unión fueron de 28 413 U/mL y 31 793 U/mL para las vacunas reducidas y estándar de Pfizer-BioNTech, respectivamente, y de 41 171 U/mL y 51 979 U/mL para las vacunas reducidas y estándar de Moderna. El refuerzo provocó un aumento en la mediana de los recuentos de células T CD4+ de IFN-γ y de células T CD4+ CD8+; no hubo diferencias en los recuentos de células T entre los grupos de dosis estándar y reducida. La dosis de refuerzo indujo una respuesta neutralizante frente a las variantes Delta y Omicron en participantes previamente seronegativos que no se vio afectada por la dosis. En el día 28, el GMT de anticuerpos neutralizantes contra la variante Delta aumentó a 1 505 y 2 088 en los grupos de vacunas de dosis reducida Pfizer-BioNTech y Moderna, los GMT contra la variante Omicron alcanzaron 343,3 y 541,2 para los mismos grupos de vacunas [Sitthichai Kanokudom, 2022 ].

RHH-001 was a phase 4 randomized study, conducted in Brazil and El Salvador, that analyzed the immune response generated by homologous and heterologous booster vaccines based on a primary vaccination regimen with the Sinovac vaccine. The study recruited 1240 participants randomly assigned to receive a booster dose with Janssen (n=306), Pfizer-BioNTech (n=340), AstraZeneca (n=304), and Sinovac (n=290) vaccines at least 6 months after the second dose. Results found all booster doses substantially increased binding and neutralizing antibody levels, the geometric fold-rise at day 28 post booster was 77 (67–88) for Janssen, 152 (134–173) for Pfizer-BioNTech, 90 (95% CI 77–104) for AstraZeneca, and 12 (11–14) for Sinovac. Heterologous booster regimens were superior to the homologous regimen with GMRs of 8.7 (5.9–12.9) for Janssen, 21.5 (14.5–31.9) for Pfizer-BioNTech, and 10.6 (7.2–15.6) for AstraZeneca. Neutralizing antibody titres were above the lower limit of detection in 75 (94%) of 80 participants tested at day 28 for the delta variant and in 61 (76%) of 80 participants for the omicron variant [Costa Clemens SA, 2022 ].

Effectiveness outcomes

Sritipsukho P et al. was a case-control study conducted in Thailand. The study enrolled 3,353 participants. Based on a test negative design of consecutive individuals (age ≥18 years) at-risk for COVID-19 who presented for nasopharyngeal real-time polymerase chain reaction (RT-PCR) testing between 5 July 2021 and 23 October 2021 that were prospectively enrolled and followed up for disease development, the study results showed a vaccine effectiveness with two doses of sinovac+ one dose of Astrazeneca vaccine of 86% (95% CI, 74–93) and with two doses of Sinovac+one dose of Pfizer vaccine of 98% (95% CI, 87–100) [Sritipsukho P, 2022 ].

Silva T et al. was a case-control study conducted in Brazil. The study included 7,314,318 participants: 3,279,280 in the vaccine group and 4,035,038 in the control group. Based on national Brazilian databases, the study assessed the effectiveness of two doses of CoronaVac against confirmed SARS-CoV-2 infection and severe COVID-19 outcomes (hospitalization and death). Also estimated the effectiveness of the BNT162b2 mRNA vaccine as a booster dose. The main results showed that Vaccine effectiveness with booster (BNT162b2) was 92.7% (95% CI 91.0–94.0) 14-30 days after receiving the booster dose. Effectiveness against hospitalization or death with booster (BNT162b2) was 97.3% (95% CI 96.1–98.1) 14–30 days after booster dose [Cerqueira-Silva T, 2022 ].

Vaccine safety

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 the 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 [44cd825404297d3dcfed9fa79d7bc5a78009e3c2].

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 0.71 (95% CI 0.38 to 1.33). This means Sinovac COVID-19 vaccine reduced the risk of serious adverse events by 29%, compared with placebo vaccine.

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

In the trials identified in this review, 47 people not receiving Sinovac COVID-19 vaccine out of 9895 presented this outcome (5 per 1000) versus 53 out of 13245 in the group that did receive it (4 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 serious adverse events 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 experience serious adverse events.

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

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 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 trials identified in this review, 2195 people not receiving Sinovac COVID-19 vaccine out of 9762 presented this outcome (225 per 1000) versus 3995 out of 12848 in the group that did receive it (400 per 1000). In other words, 175 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 17.5%, or that the intervention increased the risk of local adverse events after the 2nd dose by 17.5 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 NNH is 6. Which means that 6 people need to receive the vaccine for one of them to experience local adverse events after the 2nd dose.

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 (95% CI 0.97 to 1.14). This means Sinovac COVID-19 vaccine increased the risk of systemic adverse events after the 2nd dose by 5%, 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 trials identified in this review, 3518 people not receiving Sinovac COVID-19 vaccine out of 9762 presented this outcome (360 per 1000) versus 4178 out of 12848 in the group that did receive it (378 per 1000). In other words, 18 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 1.8%, or that the intervention increased the risk of systemic adverse events after the 2nd dose by 1.8 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 NNH is 56. Which means that 56 people need to receive the vaccine for one of them to experience systemic adverse events after the 2nd dose.

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% (7,955 out of 12,396 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% (4,307 out of 10,214 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 12,396 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.

Huang et al. was a retrospective cohort study conducted in China [Huang J, 2022 ] at the Center for Reproductive Medicine, Jiangxi Maternal and Child Health Hospital (JMCHH) affiliated with Nanchang University School of Medicine. This study investigated the effect of female inactivated SARS-CoV-2 vaccination on cycle characteristics, laboratory parameters and pregnancy outcomes during in vitro fertilization (IVF) treatment. Participants included women who underwent fresh IVF cycles between June 1st and September 13th 2021 and who were followed up to October 18th 2021. The number of oocytes retrieved (9.9 ± 7.1 vs 9.9 ± 6.7), good-quality embryo rate (33.5 ± 29.8% vs 29.9 ± 28.6%) and clinical pregnancy rate (59.1% vs 63.6%) were all similar between the vaccine group and the control group. Additionally, no significant differences were observed regarding other cycle characteristics, laboratory parameters and pregnancy outcomes such as: stimulation duration, total gonadotropin dose, serum sex hormone level, endometrial thickness, number of ≥14 mm follicles on trigger day, mature oocyte rate, fertilization rate, cleavage rate, blastocyst formation rate, available blastocyst rate, biochemical pregnancy (65.2% vs 73.7%) and implantation (45.4% vs 46.7%). Results were also similar when vaccinated patients were subdivided into three categories based on the time interval from complete vaccination to cycle initiation: ≤1 month, >1–2 months, and >2 months. The authors suggest that inactivated SARS-CoV-2 vaccines in females did not result in any measurable detrimental effects on IVF treatment. However, further prospective studies with larger cohort size and longer follow-up are needed to validate this conclusion [Huang J, 2022 ].

 

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 ].

Yasin AI et al. included 776 cancer patients and 715 non-cancer controls. The median follow-up period after vaccination was 3 months. The study showed that there was no significant difference between the two groups in terms of the prevalence of side effects after the second dose. The most common adverse effect was the fatigue (6.4%) in the cancer patients group and local pain in the non-cancer group (9.7%) [Yasin AI, 2022 ].

 

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 the 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. A preprint with preliminary results was recently published [Rosa Maria Rodrigues Pereira, 2022 ].

 

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 the 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 2,067 participants. The participants are adults of 18 years or older.A preprint with preliminary results was recently published [Rosa Maria Rodrigues Pereira, 2022 ].

Safety of the vaccine post-authorization

Post-authorization studies

Comparative studies

Tsun Lai FT et al. was a case-control study conducted in China. The study enrolled 1,693 participants: 152 vaccine group; 1,541 control group. Based on health care records provided by the Hospital Authority (HA) of Hong Kong that were linked with population-based vaccination records at the Department of Health to allow identification of vaccination status as of 2 August 2021 with the objective of examining the association of Sinovac COVID-19 vaccine and Pfizer COVID-19 vaccine with carditis, the study results showed an adjusted odds ratio (OR) for Carditis of 1.21 (95% CI 0.53 to 2.75) in vaccinated individuals [Tsun Lai FT, 2022 ].

Xue Li, was a comparative cohort study conducted in China. The study included 721,588 participants. 332,707 received the Sinovac vaccine and 388,881 received the Pfizer vaccine. Based on electronic medical records of Hong Kong Hospital Authority users between February 23, 2021 and June 30, 2021 with the aim of describing the incidence of autoimmune diseases after vaccination with Pfizer-BioNTech and Sinovac and compare them with age-standardized incidence rates in unvaccinated people. The study showed that autoimmune disease 28 days after the second dose occurred with a cumulative incidence of less than 1 per 100,000 people [Xue Li, 2021 ].

Sing CW et al. was a case-control study conducted in China. The study enrolled 3,983,529 participants: 1,643,419 vaccine group; 2,340,110 control group and was based on data from the Hong Kong Hospital Authority and the Department of Health between 1 January 2018 and 31 July 2021, with the objective of evaluating the association between COVID-19 vaccines (CoronaVac and BNT162b2) and hematological abnormalities. The study results showed a risk of thrombocytopenia of OR 0.92 (95%CI 0.68 to 1.25), a risk of leukopenia of OR 0.90 (95% CI 0.58 to 1.39) and a risk of neutropenia of OR 0.69 (95% CI 0.22 to 2.15) in vaccinated individuals [Sing CW, 2022 ].

Lai FTT et al. was a retrospective cohort study conducted in China. The study enrolled 3,983,529 participants: 1,643,419 vaccine group; 2,340,110 control group. Based on electronic medical records of patients aged 16 years or older provided by the sole provider of public inpatient services in Hong Kong, between 1 January 2018 and 31 July 2021, the study objective was to examine the association between vaccination and the risk of AESI 28-day post-vaccination as well as the effect modification by multimorbidity status. The study results showed a Hazard Ratio (HR) for adverse events of 0.70 (95%CI 0.63 to 0.77) in vaccinated individuals [Lai FTT, 2022 ].

 

Non-comparative studies

Toniassoa SCC et al. was a non-comparative study conducted in Brazil, which included 7,523 participants with at least one dose of the vaccine (Sinovac or AstraZeneca). The study aimed to assess the prevalence of COVID-19 among healthcare workers after vaccination against SARS-CoV-2. The results showed that there was a 62% reduction in new COVID-19 cases among the institution's healthcare workers after seven weeks from the start of the vaccine launch [Toniassoa SCC, 2021 ].

Zhang MX et al. was a non-comparative study conducted in China, which included 1,526 healthcare workers with at least one dose of the Sinovac vaccine. The incidence of general adverse reactions after the first and second injections was 15.6% (238/1526) and 14.6% (204/1397), respectively. The most common adverse reaction was localized pain at the injection site, with an incidence of 9.6% and 10.7% after each dose, representing 61.8% and 73.0% of adverse reactions, respectively [Zhang MX, 2021 ]. 

 

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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