Sinovac COVID-19 vaccine

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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: Recommended for 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 ].
23 August 2022: Authorized for emergency use in individuals 6 months of age and older [Instituo de Salud Pública, 2022 ]

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

The Sinovac COVID-19 vaccine is administered as a series of two doses (0.5 mL each) with an interval of 2-4 weeks between the two doses according to the manufacturer’s product label.
WHO recommends an interval of 4 weeks [WHO, 2022 ].

The pharmaceutical form is a suspension for intramuscular injection provided in a multidose vial (2 doses of 0.5 mL per vial), or as a single dose of 0.5 mL. Additionally, it is presented as a monodose in a prefilled syringe [WHO, 2021 ].
The preferred site of injection is the deltoid muscle of the upper arm.

If administration of the second dose is inadvertently delayed beyond 4 weeks, it should be given as soon as possible.


Booster dose [WHO, 2022 ]

A booster dose is recommended for the highest and high priority-use groups (i.e. older adults, health workers, persons with comorbidities), administered 4–6 months after completion of the primary series.
Once high booster dose coverage has been achieved in the highest priority-use group, countries may also consider a booster for other lower priority-use groups.

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


Heterologous COVID-19 vaccine schedules [WHO, 2022 ]
WHO supports a flexible approach to using different EUL COVID-19 vaccine products for different doses (heterologous schedule), and considers a total of 2 doses of any combination of EUL COVID-19 vaccines (e.g. 1 dose of Sinovac-CoronaVac, and 1 dose of another EUL COVID-19 vaccine) to be a complete primary series.

Evidence suggests that immunogenicity and vaccine effectiveness are superior with a heterologous booster (COVID-19 vaccine from a different platform) following a primary series with CoronaVac compared to a homologous booster dose.
Any of the EUL COVID-19 vaccines can be used as a booster dose following a primary series of CoronaVac, preferably an mRNA-based or viral vector vaccine.

Heterologous vaccination should be implemented with careful consideration of current vaccine supply, vaccine supply projections, and other access considerations, alongside the potential benefits and risks of the specific products being used.


Vaccination schedule for immunocompromised persons [WHO, 2022 ]
WHO recommends and extended primary series including an additional (third) dose for immunocompromised persons aged 18 years and older, administered 1–3 months after the second dose in the standard primary series.
The most appropriate timing for the additional dose may vary depending on the epidemiological setting and the extent and timing of immune suppressive therapy and should be discussed with the treating physician. A heterologous additional (third) dose should be considered.

A booster (fourth) dose administered 3–6 months after the additional (third) dose should be considered for immunocompromised persons.

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.

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

Precautions

Allergic reactions [WHO, 2022 ].
Persons with a history of anaphylaxis to any other vaccine or injectable therapy should be observed 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 [WHO, 2022 ].

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.

Children and adolescents [WHO, 2022 ].
A phase 2 pediatric trial has been completed, but the Sinovac COVID-19 vaccine has not yet received the emergency listing authorization (EUL/WHO) for this age indication.

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

Persons living with HIV [WHO, 2022 ].
Data on the administration of the 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.

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

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


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

Storage and logistics

Storage

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

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

Phase 1/2:
The PRO-nCOV-1001 trial (NCT04352608 [Sinovac Biotech Co., Ltd, 2020 ]) conducted in China, initiated in April 2020, included 744 healthy adults aged 18 to 59 years. In phase 1, participants were assigned in a 1:1 ratio into two vaccination schedule cohorts (days 0 and 14, and days 0 and 28). Within each cohort, participants were randomly assigned to low-dose (3 μg) or high-dose (6 μg) of the vaccine. In phase 2, participants were assigned in a 1:1 ratio, into two vaccination schedule cohorts (days 0 and 14, and days 0 and 28). Within each cohort, participants were randomized in a 2:2:1 ratio to two doses of low-dose vaccine, high-dose vaccine, or placebo [Zeng G, 2021 ], [Xin Q, 2022 ], [Zhang, Yanjun, 2021 ]

Phase 2:
The trial conducted by Nanthapisal et al. (TCTR20210722003 [Health and Aging Platform, Chulalongkorn University, 2021 ]) in Thailand, started in July 2021, included 422 adults with a complete CoronaVac regimen. Of the participants, 206 received a low dose, and 208 received a standard dose of the AstraZeneca vaccine. [Aikawa NE, 2022 ], [Nanthapisal S, 2022 ], [Sira Nanthapisal, 2022 ]

The trial conducted by Niyomnaitham et al. (TCTR20210720007, [Faculty of Medicine Siriraj Hospital, 2021 ]) in Thailand, started in July 2021, including 210 individuals who were randomly assigned 1:1:1:1:1:1:1 to one of seven main booster groups: CoronaVac-AstraZeneca, CoronaVac-Pfizer, AstraZeneca-CoronaVac, AstraZeneca-Pfizer, Pfizer-CoronaVac, Pfizer-AstraZeneca, or Pfizer counterpart. [Aikawa NE, 2022 ], [Nanthapisal S, 2022 ], [Sira Nanthapisal, 2022 ]

The TVTN001 trial (NCT05049226 [Mahidol University, 2021 ]) conducted in Thailand, initiated in September 2021, included 1,320 participants in 2 arms (660 each) who received a third full or half-dose of AstraZeneca or Pfizer. Each group was stratified into 3 subgroups (1:1:1) of intervals in terms of days to receive the booster dose, after the second dose of Sinovac, at 60 and less than 90 days, 90 to less than 120 days, and 120 to 180 days [Suvimol Niyomnaitham, 2022 ]

The trial conducted by Puthanakit et al. (TCTR20210923012 [National Vaccine Institute, 2021 ]) in Thailand, initiated in October 2021, included 76 adolescents between 12 and 18 years old who were randomized 1:1:1:1 to receive CoronaVac followed by Pfizer 30 or 20 µg at an interval of 3 or 6 weeks [Puthanakit T, 2022 ]

Phase 3:
The 9026-ASI trial (NCT04582344 [Health Institutes of Turkey, 2020 ]) conducted in China started in September 2020 including 10,228 individuals aged 18 to 59 years separated into two cohorts. Cohort K1 consisted of healthcare workers (randomized 1:1), and cohort K2 non-healthcare workers (randomized 2:1). The study vaccine consisted of 3 μg of CoronaVac. Participants received either vaccine or placebo intramuscularly on days 0 and 14 [Akova M, 2021 ], [Tanriover MD, 2021 ]

The CoronaVac3CL trial (NCT04651790 [Pontificia Universidad Catolica de Chile, 2020 ]) conducted in Chile, initiated in December 2020, included 2,302 participants aged 18 years or older. Participants were randomly assigned (1:1) to two CoronaVac vaccination schedules, receiving two doses 14 (0-14) or 28 (0-28) days apart. [Schultz BM, 2022 ], [Susan M Bueno, 2021 ], [Bueno SM, 2021 ], [Duarte LF, 2021 ]

The trial conducted by Mok CKP et al. (NCT04611243 [Chinese University of Hong Kong, 2020 ]) in China, initiated in August 2021, included 260 CoronaVac recipients participants of a previous study who showed surrogate neutralization test (sVNT) results below 60% in their blood samples collected 1 month after the second dose and were randomly assigned to receive a third dose of Pfizer–BioNTech vaccine or CoronaVac [Mok CKP, 2022 ]

The PROFISCOV trial (NCT04456595 [Palacios R, 2021 ]) conducted in Brazil, started in July 2020 and involved 12,396 individuals over 18 years of age. 6,104 participants received 2 doses of the vaccine (3 μg in 0.5 mL) on days 0 and 14 and 6,202 individuals received a placebo [Priscilla Ramos Costa, 2022 ], [Palacios R, 2021 ], [Palacios R, 2020 ]

The PRO-nCOV-3002 trial (NCT04992260 [Sinovac Research and Development Co., Ltd., 2021 ]) conducted in Chile, started in September 2021 included 963 participants between 3 and 17 years of age were recruited, who received two doses (3 μg) of CoronaVac with an interval of 4 weeks. For the immunogenicity analysis, samples were collected from 158 volunteers. [Soto JA, 2022 ]

Phase 4:
The Cobovax study (NCT05057169 [The University of Hong Kong, 2021 ]) conducted in China, initiated in November 2021, included 219 adults who had received two doses of an inactivated vaccine (CoronaVac) or an mRNA vaccine (Pfizer) 6 or more months previously, were randomized in a proportion 1:1 ratio to receive a third dose of either vaccine [Nancy H. L. Leung, 2022 ]

The Projeto S trial (NCT04747821, [Butantan Institute, 2021 ]), conducted in Brazil, started in February 2021. The study included the Serrana population, the city was separated into 25 subareas, divided into four groups and randomized to receive CoronaVac in a two-dose schedule with an interval of four weeks. The intervention was started in each group with an interval of one week. [Marcos C. Borges, 2021 ]

The RHH-001 trial (RBR-9nn3scw, [Instituto D'Or de Pesquisa e Ensino, 2021 ]) conducted in Brazil and El Salvador since in August 2021, enrolled 1240 participants randomly assigned to receive a booster dose of Janssen (n= 306), Pfizer-BioNTech (n=340), AstraZeneca (n=304), or Sinovac (n=290) COVID-19 vaccines at least 6 months after the second dose [Costa Clemens SA, 2022 ], [Sue Ann Costa Clemens, 2021 ]

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

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

Vaccine efficacy and effectiveness

Efficacy of preclinical studies on the vaccine

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 ].

Circulating neutralizing antibodies measured by surrogate virus neutralization test (sVNT) were 50.9 IU/ml (95% CI, 37.4-59.1) and 178.2 IU/ml (95% CI, 133.5-238.1) for 0-14 days schedule and 0-28 schedule respectively. Circulating neutralizing antibodies measured by conventional virus neutralization test (cVNT) were 46.9 IU/ml (95% CI, 38.6-57.0) and 90.2 IU/ml (95% CI, 76.8-105.8) respectively.[Gálvez NMS, 2022 ]

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 
Los datos obtenidos en el ensayo PROFISCOV fue del 64,2% (7955 de 12396 participantes) no permiten realizar un análisis de subgrupo por sexo [Palacios R, 2021 ].
La eficacia de la vacuna para este subgrupo en el ensayo PROFISCOV aún no se ha informado [Palacios R, 2021 ].

La proporción de mujeres en el ensayo 9026-ASI fue del 43% (4307 de 10214 participantes) [Tanriover MD, 2021 ].
La eficacia de la vacuna para este subgrupo en el ensayo 9026-ASI aún no se ha informado [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 12396 participants).
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. [Palacios R, 2021 ]

Pengfei Jin et al. was a phase 4 randomized trial that included 299 participants aged 60 years and older: 99 primed with two doses of CoronaVac and Cansino COVID-19 vaccine booster, 100 primed with two doses of Coronavac and homologous booster, 50 primed with one dose of CoronaVac and received a Cansino booster and 50 primed with one dose of CoronaVac and homologous booster. In the group primed with two doses of CoronaVac and with a CoronaVac booster, GMT of neutralizing antibodies against wild-type SARS-CoV-2 was 48.2 (95% CI 39.5 to 58.7) 14 days post boost vaccination. Among participants who were primed with one dose of CoronaVac, a homologous second dose induced a GMT of neutralizing antibodies against wild-type SARS-CoV-2 of 9.3 (95% CI 6.2 to 13.9)[Pengfei Jin, 2022 ].

Other comparative studies
Alencar CH et al is a cross sectional study that included 313,328 elderly people that received one or two doses of a vaccine (Oxford-AstraZeneca or CoronaVac). The occurrence of deaths among the unvaccinated elderly was more than 132 times higher, as compared to those who had received two doses of a vaccine, with a protection ratio for deaths of 99.2%. After two dose of Sinovac vaccine, the protection ratio was 113.17 (95% CI 93.50–136.99). The effect was more pronounced with increasing age [Alencar CH, 2021 ].

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 ].

Puthanakit T et al was a phase 2 randomized clinical trial conducted in Thailand. The study included 80 participants aged 12 to 18 years without previous SARS-CoV-2 vaccination. Participants were randomized to be vaccinated with CoronaVac 3 ug as the first dose followed by BNT162b2 30 µg or 20 µg as the second dose, at 3-week (3w) or 6-week interval (6w). During the Omicron-predominant period, participants were offered a BNT162b2 booster dose 30, 15, or 10 µg. Neutralization tests (sVNT and pseudovirus neutralization test; pVNT) against Omicron strain were tested pre- and 14 days post-booster dose.  At day 14, the geometric mean (GM) of anti-S-RBD IgG in CoronaVac 3w/Pfizer 30µg was 4713 (95 %CI 4127–5382) binding-antibody unit (BAU)/ml, while geometric mean ratio(GMR) was 1.28 (1.09–1.51) in  CoronaVac 6w/Pfizer 30 µg. The GMs of sVNT against Delta variants at day 14 among participants in CoronaVac 3w/Pfizer 30µg and CoronaVac 6w/Pfizer 30 µg arms were 95.3 % and 99.7% inhibition, respectively [Puthanakit T, 2022 ].

PRO-nCOV-1003 (phase 1/2) was a clinical trial in China in healthy children and adolescents between 3 and 17 years of age. With the aim of reporting the safety, tolerability and immunogenicity of the CoronaVac vaccine. In phase 2, individuals were divided by age into groups of 3-5 years (120), 6-11 years (180) and 12-17 years (180), 192 individuals received two doses of 1.5 ug of vaccine (low dose or block 1), 192 individuals received two doses of 3 ug of vaccine (high dose or block 2, 192 individuals) and another 96 individuals received two doses of aluminum hydroxide (controls). Less than 1% of individuals reported serious severe reactions, the most common adverse reaction was pain at the puncture site 13% of the population, and fever 5%. After the second doses of vaccination, seroconversion rates were 180 (Ci 95%: 96-8% [93.1-98.8]) of 186 participants in the 1-5μg group (GMT 86-4 [73.9-101.0] ) and 180 (100-0% [98.0-1000]) of 180 participants in the 3-0μg group (142.2 [124.7-162.1]). The seroconversion rate and GMT of the 3.0μg group were higher than those of the 1.5μg group (p=0.030 and p<0.0001). Neutralizing antibodies in all alum-only recipients were negative after vaccination. [Han B, 2021 ]
In a study derived from the PRO-nCOV-1003 trial to assess the third safety and immunogenicity of a third dose of CoronaVac, 384 participants in the vaccine group were assigned to two cohorts. One received the third dose at a 10-months interval (cohort 1) and the other on at a 12-months interval (cohort 2). The severity of local and systemic adverse reactions reported within 28 days after the third dose was mild and moderate in both cohorts. A third dose of CoronaVac increased the geometric mean titer (GMT) to 681.0 (95% CI, 545.2–850.7) in Cohort 1 and to 745.2 (95% CI, 577.0 –962.3) in cohort 2. The seropositivity rates against the Omicron variant were 90.6% (cohort 1) and 91.5% (cohort 2). [Wang L, 2022 ]

The PRO-nCOV-3002 study was a phase 3 clinical trial conducted in Chile. 963 children and adolescents (3 to 17 years old) were recruited and inoculated with two doses of 3 μg of CoronaVac in a 4-week interval. 92 of 148 participants from the immunogenicity branch were included in the analysis. Seropositivity reached 96% for the 3 to 11-year age group, and 94.5% for the 12 to 17-year age group. However, in both groups, 100% of seropositivity was found for the samples analyzed by the surrogate virus neutralization test (sVNTs) 4 weeks after the second dose. Compared to the baseline samples, a significant increase in CD4+ T cell activation 4 weeks after the second dose of CoronaVac was observed upon stimulation with four mega pools (MPs) comprising peptides from the S, R (all but S), M, and N viral proteins. A significant increase in the activation of CD4+ T cells was found in the 12 to 17-year age group for all the MPs evaluated. In contrast, the increase in the activation of CD4+ T cells for the 3 to 11-year age group was statistically significant for the S and N stimuli only. Additionally, the induction of memory markers in activated CD4+ T cells induced 4 weeks after the second dose was compared to the baseline samples. An increase in the ratio of memory cells with respect to the baseline samples was observed in the 12 to 17-year age group in the presence of all stimuli. For the 3 to 11-year age group, an increase in the ratio of memory cells with respect to the baseline samples was observed only in the presence of the S and N stimuli [Soto JA, 2022 ].

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 ].

Florentino P et al was a case-control study conducted in Brazil, the study included 197,958 participants, 89,595 cases and 108,363 controls. Based on data from the national surveillance system for COVID-19 infection (e-SUS Notifica); the information system for severe acute respiratory illness (SIVEP-Gripe) and the the national immunization system (SI-PNI), comprising children 6-11 years with COVID-19  from January 21, 2022, to April 15, 2022. The study showed an effectiveness against symptomatic infection of 39.8 (95% CI 33.7 to 45.4), and 59.2 (95% CI 11.3 to 84.5) against hospital admission.[Florentino PTV, 2022 ]

Jara A et al was a cohort study conducted in Chile, including data from a population-based cohort of children aged 3–5 years from the public national healthcare system of Chile (FONASA), the study enrolled 490,694 children, 194,427 received 2 doses of CoronaVac and 189,523 remained unvaccinated between 6 December 2021 and 26 February 2022. The vaccine effectiveness during the Omicron variant outbreak was 38.2% (95% CI, 36.5–39.9) against COVID-19 infection, 64.6% (95% CI, 49.6–75.2) against hospitalization, and 69.0% (95% CI, 18.6–88.2) against ICU admission. [Jara A, 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.

Other comparative studies
A test-negative design study conducted in Brazil evaluated the efficacy of the vaccine in 19,838 pregnant women aged 18 to 49 years. Based on data from the national surveillance system for the RT-PCR test for COVID-19 (e-SUS Notifica), the information system for severe acute respiratory diseases (SIVEP-Gripe), and the national immunization system (SIPNI). The effectiveness of two doses of Sinovac was 41% (95% CI, 27.1% to 52.2%) against symptomatic COVID-19, 85% (95% CI, 59.5% to 94.8%) against severe COVID-19 and 75% (95% CI, 27.9% to 91.2%) in preventing progression to severe COVID-19 among infected ¿? (parece que falta una palabra) [Enny S. Paixão, 2021 ].

Breastfeeding
Randomized trials
Breastfeeding 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.

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-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 ].

Wing Tak Cheng et al. conducted a retrospective cohort study in Hong Kong in individuals with chronic kidney disease, of whom 28,374 were unvaccinated, 27,129 had received two doses of Pfizer, and 47,640 had two doses of CoronaVac. Vaccine effectiveness was 38% (95% CI, 34% to 41%) for BNT162b2 and 4% (95% CI, 0% to 8%) for CoronaVac, compared to the unvaccinated group [Tak Cheng FW, 2022 ].

Silva CA et al was a prospective longitudinal study conducted in Brazil. This study assessed anti-SARS-CoV-2 immunogenicity decay and incident cases six months after the second dose of CoronaVac inactivated vaccine in 828 autoimmune rheumatic disease patients compared with 207 control individuals. Anti-S1/S2 IgG positivity and titers reduced to 23.8% and 38% in patients during the six-month follow up and 20% and 51% in controls, respectively. Neutralizing antibodies positivity and percent inhibition declined to  41% and 54% in patients and 39.7% and 47% in controls, respectively. [Silva CA, 2022 ]

Medina-Pestana conducted a prospective, single-center cohort study included kidney transplant recipients without previous COVID-19. There were 307 patients in the heterologous group (2 CoronaVac + BNT26b2) and 777 in the homologous group (3 CoronaVac). At a median of 25 days after the heterologous BNT262b2 and 35 days after the homologous CoronaVac third-dose vaccine, the seroconversion rate was significantly higher in the heterologous group (48.9% versus 32.4%; p < 0.0001), resulting in a significantly higher seroprevalence rate (67.4% versus 55.5%; p = 0.0003). After the booster, the median antibody titers among seropositive patients were higher in those to whom the third heterologous BNT262b2 was administered (7771 versus 599 AU/mL; p < 0.0001). 444 individuals or 40.1% of the entire cohort (32.6% in the heterologous BNT262b2 and 44.2% in the homologous CoronaVac groups; p = 0.0003) remained seronegative even after 3 doses. When stratifying the immunogenicity analysis by serological status before the third dose, a 66-fold increase in antibody titers was observed in the heterologous group, compared to a 4-fold increase after the third homologous dose (p < 0.0001). Finally, among patients who seroconverted, median titers were approximately 10times higher after the third heterologous compared to homologous dose (1768 versus 189 AU/mL; p < 0.0001). [Medina-Pestana J, 2022 ]

Vaccine effectiveness (other comparative studies)

Contracting COVID-19
Cerqueira-Silva T et al was a comparative study conducted in Brazil that enrolled 75,919,840 participants (>18 years old) with at least one dose of the Sinovac or AstraZeneca vaccine. Data was based on electronic health records from the Brazilian Ministry of Health vaccination campaign, between January 18th and July 24th 2021. Outcome was measured ≥14 days after vaccination. Results showed an effectiveness of 53.2% after the second dose. [Cerqueira-Silva T, 2022 ]

Ranzani OT et al. was a comparative study conducted in Brazil that enrolled 43,774 participants (>70 years) with two doses of the Sinovac vaccine. Based on data from residents of São Paulo state who underwent SARS-CoV-2 RT-PCR testing from January 17th to April 29th 2021. The outcome was measured ≥14 days after the second dose. Results showed vaccine effectiveness of 46.8% (95% CI, 38.7% to 53.8%). [Ranzani OT, 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 health care 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 ].

Paternina-Caicedo A et al, was a cohort study carried out in Colombia, the study included 719,735 participants amongst which 76,729 received two-dose Sinovac and 539,010 were unvaccinated. Based on data from Mutual Ser, a health insurer in Colombia. The study included all insured subjects aged 40 and above, excluding those with a confirmed previous SARS-CoV-2 infection as of March 1st of 2021 to August 15th of 2021. The vaccine effectiveness against symptomatic infection was -44.0% (95% CI -54.1 to -34.6). [Paternina-Caicedo A, 2022 ]

Hitchings MDT et al. conducted a case-control study (test-negative design) using data from SARS-CoV-2 testing and vaccination of 202,741 participants, health care workers (HCW), and non-HCW, retrieved from four databases in São Paulo, Brazil, between January and December 2021. It estimated the association between the time from receipt of the second dose of the CoronaVac vaccine to the date of sample collection for RT-PCR and the odds of testing positive for SARS-CoV-2. The increase in adjusted odds of contracting COVID-19 between 0-13 days from the second dose and after 180 days was greater among the HCW group (from 1.36 [95% CI, 1.18-1.56] to 4.22 [95% CI, 3.39-5.26]) compared to non-HCW (from 1.41 [95% CI, 1.26-1.57] to 1.67 [95% CI, 1.24-2.26]) [Hitchings MDT, 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 that enrolled 43,774 participants (>70 years) with two doses of the Sinovac vaccine. Based on data from residents of São Paulo state who underwent SARS-CoV-2 RT-PCR testing from January 17th to April 29th 2021. The outcome was measured ≥14 days after the second dose. Results showed vaccine effectiveness of 55.5% (95% CI, 38.7% to 53.8%) for hospitalization and 61.2% (95% CI, 48.9% to 70.5%) for deaths. [Ranzani OT, 2021 ]

Cerqueira-Silva T et al was a comparative study conducted in Brazil that enrolled 75,919,840 participants (>18 years) with at least one dose of the Sinovac or AstraZeneca vaccine. Data based on electronic health records from the Brazilian Ministry of Health vaccination campaign, between January 18th and July 24th 2021. Outcome was measured ≥14 days after vaccination. Results showed an effectiveness of 71.2% (95% CI, 70% to 72.4%) against hospitalization, 72.2% (95% CI, 70.2% to 74%) against ICU admission and 73.7% (95% CI, 72.1% to 75.2%) against death. [Cerqueira-Silva T, 2022 ].

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 ].

Paternina-Caicedo A et al, was a cohort study carried out in Colombia, the study included 719,735 participants amongst which 76,729 received two-dose Sinovac and 539,010 were unvaccinated. Based on data from Mutual Ser, a health insurer in Colombia. The study included all insured subjects aged 40 and above, excluding those with a confirmed previous SARS-CoV-2 infection as of March 1st of 2021 to August 15th of 2021. The vaccine effectiveness against hospitalizacion was 3.3% (95% CI -15.1 to 18.7), and 18% (95% CI -10.6 to 39.2) against critical care admission. [Paternina-Caicedo A, 2022 ]

Yan VKC et al was a case-control study conducted in Hong Kong. The study included 14, 984 participants to evaluate the risk of severe complications following 1-3 doses of CoronaVac using electronic health records database. Cases were adults with their first COVID-19-related severe complications between 1 January and 31 March 2022. Vaccine effectiveness against severe complications after two doses CoronaVac was 58.9% (95% CI: 50.3-66.1)  in those aged ≥65, 67.1% (95% CI: 47.1-79.6) in those aged 50-64, 77.8% (95% CI: 49.6-90.2)  in those aged 18-50. Further risk reduction with the third dose was observed especially in those aged ≥65 years, against severe complications. [Yan VKC, 2022 ]

Transmission
No studies reported or assessed this outcome.

Efficacy and effectiveness against SARS-CoV-2 variants

Immunogenicity outcomes
Alpha (B.1.1.7)
Suntronwong N et al. included 457 fully vaccinated participants: 247 with 2 doses of Sinovac and 210 with 2 doses of Sinovac plus an AstraZeneca booster. 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. [Suntronwong N, 2022 ]

Beta (B.1.351)
Suntronwong N et al. included 457 fully vaccinated participants: 247 with 2 doses of Sinovac and 210 with 2 doses Sinovac plus an AstraZeneca booster. 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. [Suntronwong N, 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-primed 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.[ ].

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 ]

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 [Suvimol Niyomnaitham, 2022 ].

Gamma (P.1)
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 ].

Delta (B.1.617.2)
Suntronwong N et al. included 457 fully vaccinated participants: 247 with 2 doses of Sinovac and 210 with 2 doses of Sinovac plus an AstraZeneca booster. 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 the ancestral strain 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 6.2-fold reduction compared to the Delta variant. [Suntronwong N, 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-primed 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 ].

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 BM, 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 [Suvimol Niyomnaitham, 2022 ].

Pengfei Jin et al. was a phase 4 randomized trial that included 299 participants aged 60 years and older: 99 primed with two doses of CoronaVac and Cansino COVID-19 vaccine booster, 100 primed with two doses of Coronavac and homologous booster, 50 primed with one dose of CoronaVac and received a Cansino booster and 50 primed with one dose of CoronaVac and homologous booster. In the group primed with two doses of CoronaVac and with a CoronaVac booster, GMT of neutralizing antibodies against Delta variant was 7.3 (95% CI: 5.6 to 9.5) 14 days post boost vaccination. Among participants who were primed with one dose of CoronaVac, a homologous second dose induced a GMT of neutralizing antibodies against Delta variant of  4 (95% CI 2.4 to 6.7) [Pengfei Jin, 2022 ].

Buathong et al conducted an observational study to determine the levels of neutralizing antibodies against the SARS-CoV-2 ancestral strain, Delta and Omicron variants of concern (VOCs), in 125 healthcare workers who received CoronaVac as their primary vaccination and later received either a single ChAdOx1 or a combination of two consecutive boosters using either two ChAdOx1 doses or a ChAdOx1 or BNT162b2 as the primary and second boosters, respectively, or two doses of BNT162b2. Coronavac Coronavac + ChAdOx1: - 8.5% of subjects were NT positive against the Delta VOC at day 0 post-booster, with a MI of 1.9% (95% CI: 0.7–3.1%), but the percentage increased significantly (p < 0.0001) to 91.5% at week 1 post-booster with an MI of 76.8% (95% CI: 70.9–82.7%) and again to 98.1% at week 4 post-booster with an MI of 81.3% (95% CI: 76.9–85.7%). Coronavac Coronavac + ChAdOx1 ChAdOx1: - The rates of NT positivity against the Delta VOC, increased from 56% with an MI of 49% (95% CI: 35.3–62.7%) at Day 0 post second booster to 76% with an MI of 70.4% (95% CI: 58.9–81.9%, p = 0.005) at week 1 post second booster. Coronavac Coronavac + ChAdOx1 Pfizer: - The rates of NT positivity against the Delta VOC, % rates increased from 62.9% with an MI of 56.4% (95% CI: 45.5–67.3%) at Day 0 to 97% with an MI of 80.9% (95% CI: 76.8–85.1%) at week 1 post second booster. Coronavac Coronavac + Pfizer Pfizer: - 100% were NT positives against the Delta VOC at Day 0 (MI of 80.7%, 95% CI: 71.8–89.7%) and week 1 (MI of 84.1%, 95% CI: 70.7–97.5%) post second booster. [Buathong R, 2022 ]

Sira et al. (TCTR20210722003) conducted a randomized clinical trial in Thailand, with 422 adults with a mean age of 44 years. The aim of the study was to evaluate the immunogenicity and reactogenicity of standard-dose and low-dose boosters of Oxford-AstraZeneca vaccine, after the full CoronaVac schedule in healthy adults. 206 individuals received low dose and 208 individuals standard dose. At baseline, geometric means (GM) of sVNT against delta variant and anti-S-RBD IgG were 18.1% inhibition (95% CI 16.4-20.0) and 111.5 (105, 1-118.3) BAU/ml. GM of sVNT against delta variant and anti-S-RBD IgG in DS were 95.6% inhibition (95% CI 94.3-97.0) and 1975.1 (1841.7-2118.2) BAU /ml at day 14, and 89.4% inhibition (86.4-92.4) and 938.6 (859.9-1024.4) BAU/ml at day 90, respectively. The GMRs of sVNT against delta variant and anti-S-RBD IgG in LD compared to SD were 1.00 (95% CI: 0.98-1.02) and 0.84 (0.76-0, 93) at day 14, and 0.98 (0.94-1.03) and 0.89 (0.79-1.00) at day 90, respectively. [Sira Nanthapisal, 2022 ]

Niyomnaitham et al fue un ensayo clínico aleatorio de fase 2 realizado en Tailandia. El estudio incluyó a 1243 participantes con el esquema primario de CoronaVac: 312 en el grupo de refuerzo de AstraZeneca (media dosis), 307 en el grupo de refuerzo de AstraZeneca (dosis completa), 316 en el grupo de refuerzo de Pfizer (media dosis) y 308 en el grupo de refuerzo de Pfizer (media dosis). La inmunogenicidad inducida por la vacunación frente a las cepas Ancestral, Delta y Omicron BA.1 se evaluó mediante la valoración de los anticuerpos anti-espiga ('anti-S'), antinucleocápside, neutralización de pseudovirus ('PVNT'), títulos de microneutralización y ensayos de células T. Independientemente de la dosis o el esquema, las seroconversiones fueron superiores al 97%, y superiores al 90% para los anticuerpos neutralizantes contra el pseudovirus, pero similares contra las cepas de SARS-CoV-2. La inmunogenicidad según el título de anticuerpos neutralizantes de pseudovirus (PVNT50) frente a la variante delta en el día 28 fue de 468,3 (IC 95%, 409,8-535,2) para el grupo de media dosis de AstraZeneca, 530,6 (IC 95%, 470,4-598,5) para el grupo de dosis completa de AstraZeneca, 801,5 (IC 95%, 715,4-897,8) para el grupo de media dosis de Pfizer y 856,1 (IC 95%, 777,8-942,1) para el grupo de dosis completa de Pfizer. [Suvimol Niyomnaitham, 2022 ]

Filardi B et al was a comparative cohort study that included 293 participants with two doses of CoronaVac vaccine: 131 with AstraZeneca booster, 61 with CoronaVac booster and 101 with Pfizer booster. The aim was to evaluate virus-specific immune responses following different booster vaccines across age groups and to assess the potential risk of vaccine immune evasion by Omicron infection.  Increase in neutralization capacity 28 days after booster with Pfizer was 10.8-, 7.1- and 3.52-fold increase for the ancestral strain, Delta variant and Omicron (BA.1) variant, respectively. Increase in neutralization capacity 28 days after booster with AstraZeneca was 3.4-, 6.5- and 2.2-fold increase for the ancestral strain, Delta variant and Omicron (BA.1) variant, respectively. Increase in neutralization capacity 28 days after booster with CoronaVac was 2.6-, 3.4- and 1.2-fold increase for yhe ancestral strain, Delta variant and Omicron (BA.2.12.1) variant, respectively. [Bruno Andraus Filardi, 2022 ]

Li J et al was a cross-sectional study conducted in China that assessed the neutralizing antibody levels against ancestral SARS-CoV-2, Delta and Omicron variants of the primary vaccine schedule and the booster dose of CoronaVac vaccine. The GMT of neutralizing antibodies was 11.67 (95% CI, 10.75–12.66) with a seropositivity rate of 21.60% against the Delta variant, after the primary schedule. The overall GMT after the booster dose against the Delta variant were 40.33 (95% CI, 36.79–44.20) with a seropositivity rate of 70.82%. [Li J, 2022 ]

Omicron (B.1.1.529)
Suntronwong N et al. included 457 fully vaccinated participants: 247 with 2 doses of Sinovac and 210 with 2 doses of Sinovac plus an AstraZeneca booster. 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 the ancestral strain 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 6.2-fold reduction compared to the Delta variant. [Suntronwong N, 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 ].

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 ].

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 ].

Puthanakit T et al was a phase 2 randomized clinical trial conducted in Thailand. The study included 80 participants aged 12 to 18 years without previous SARS-CoV-2 vaccination. Participants were randomized to be vaccinated with CoronaVac 3 ug as the first dose followed by BNT162b2 30 µg or 20 µg as the second dose, at 3-week (3w) or 6-week interval (6w). During the Omicron-predominant period, participants were offered a BNT162b2 booster dose 30, 15, or 10 µg. Neutralization tests (sVNT and pseudovirus neutralization test; pVNT) against Omicron strain were tested pre- and 14 days post-booster dose.  At day 14, the geometric mean (GM) of anti-S-RBD IgG in CoronaVac 3w/Pfizer 30µg was 4713 (95 %CI 4127–5382) binding-antibody unit (BAU)/ml, while geometric mean ratio(GMR) was 1.28 (1.09–1.51) in  CoronaVac 6w/Pfizer 30 µg. The GMs of sVNT against Delta variants at day 14 among participants in CoronaVac 3w/Pfizer 30µg and CoronaVac 6w/Pfizer 30 µg arms were 95.3 % and 99.7% inhibition, respectively [Puthanakit T, 2022 ].

Pengfei Jin et al. was a phase 4 randomized trial that included 299 participants aged 60 years and older: 99 primed with two doses of CoronaVac and Cansino COVID-19 vaccine booster, 100 primed with two doses of Coronavac and homologous booster, 50 primed with one dose of CoronaVac and received a Cansino booster and 50 primed with one dose of CoronaVac and homologous booster. In the group primed with two doses of CoronaVac and with a CoronaVac booster, GMT of neutralizing antibodies against Omicron variant was 4.4 (95% CI: 3.2 to 5.9) 14 days post boost vaccination. Among participants who were primed with one dose of CoronaVac, a homologous second dose induced a GMT of neutralizing antibodies against Omicron variant of  3.7 (95% CI 2.2 to 6.1) [Pengfei Jin, 2022 ].

Cobovax study was a randomized clinical trial conducted in China. The study enrolled 219 adults who previously received two doses of CoronaVac and randomized to CoronaVac ("CC-C", n=101) or BNT162b2 ("CC-B", n=118) third dose; and 232 adults who previously received BNT162b2 and randomized to CoronaVac ("BB-C", n=118) or BNT162b2 ("BB-B", n=114). The aim was to assess immunogenicity and cell-mediated immune responses and vaccine efficacy against infections during follow-up. Third-dose vaccination increased PRNT50 titers against ancestral virus 315 by 14-, 94-, 3- and 19-fold, and against Omicron BA.2 by 1-, 16-, 1- and 13-fold, in CC-C, CC-B, BB-C and BB-B arms respectively. Antibody responses to a BNT162b2 third dose were substantially and statistically significantly greater than responses to a CoronaVac third dose regardless of prior two-dose vaccine type [Nancy H. L. Leung, 2022 ].

Buathong et al conducted an observational study to determine the levels of neutralizing antibodies against the SARS-CoV-2 ancestral strain, Delta and Omicron variants of concern (VOCs), in 125 healthcare workers who received CoronaVac as their primary vaccination and later received either a single ChAdOx1 or a combination of two consecutive boosters using either two ChAdOx1 doses or a ChAdOx1 or BNT162b2 as the primary and second boosters, respectively, or two doses of BNT162b2. Coronavac Coronavac + ChAdOx1: - NT positivity rate and titers against Omicron VOC at day 0 post-booster was 0% with an MI of 1.2% (95% CI: 1.0–1.3%), which increased significantly (p < 0.0001) at week 1 to 18.6% with an MI of 21.8% (95% CI: 13.3–30.3%) and to 21.2% with an MI of 22.2% (95% CI: 12.9–31.5%) at week 4. Coronavac Coronavac + ChAdOx1 ChAdOx1: - 4% were NT positive against the Omicron VOCs at Day 0 post second booster, with an MI of 7.4% (95% CI: 0–16.0%). NT positive rates increased to 16% at week 1 with an MI of 15.1% (95% CI: 2.6–27.7%). Coronavac Coronavac + ChAdOx1 Pfizer: -  NT positive against the Omicron VOCs went from 11.4% with an MI of 10.0% 95% CI: 0.2–19.8%) at Day 0 to 71.4% with an MI of 58.7% (95% CI: 45.4–72.0%) at week 1. - Subjects in the 2CoronaVac-ChAdOx1/BNT162b2 and 2CoronaVac-2BNT162b2 groups had significant higher MI against Omicron VOC than the CoronaVac(x2)/ChAdOx1(x2) group at week 1 post second booster (p = 0.034 and p < 0.0001, respectively). Coronavac Coronavac + Pfizer Pfizer:-  NT positive against the Omicron VOCs increased from 16% with an MI of 16.0% (95% CI: 0–55.4%) at Day 0 to 100% with a MI of 73.6% (95% CI: 61.2–86.1%) at week 1. - Subjects in the 2CoronaVac-ChAdOx1/BNT162b2 and 2CoronaVac-2BNT162b2 groups had significant higher MI against Omicron VOC than the CoronaVac(x2)/ChAdOx1(x2) group at week 1 post second booster (p = 0.034 and p < 0.0001, respectively). [Buathong R, 2022 ]

Niyomnaitham et al fue un ensayo clínico aleatorio de fase 2 realizado en Tailandia. El estudio incluyó a 1.243 participantes con el esquema primario de CoronaVac: 312 en el grupo de refuerzo de AstraZeneca (media dosis), 307 en el grupo de refuerzo de AstraZeneca (dosis completa), 316 en el grupo de refuerzo de Pfizer (media dosis) y 308 en el grupo de refuerzo de Pfizer (media dosis). La inmunogenicidad inducida por la vacunación frente a las cepas Ancestral, Delta y Omicron BA.1 se evaluó mediante la valoración de los anticuerpos anti-espiga ('anti-S'), antinucleocápside, neutralización de pseudovirus ('PVNT'), títulos de microneutralización y ensayos de células T. Independientemente de la dosis o el esquema, las seroconversiones fueron superiores al 97%, y superiores al 90% para los anticuerpos neutralizantes contra el pseudovirus, pero similares contra las cepas de SARS-CoV-2. Los títulos de anticuerpos neutralizantes de pseudovirus (PVNT50) frente a Omicron (GMT) fueron 118,9 (IC 95%, 97,3-145,2) para el grupo de dosis completa de AstraZeneca y 255,9 (IC 95%, 222,9-293,7) para el grupo de dosis completa de Pfizer.  [Suvimol Niyomnaitham, 2022 ]

Filardi B et al was a comparative cohort study that included 293 participants with two doses of CoronaVac vaccine: 131 with AstraZeneca booster, 61 with CoronaVac booster and 101 with Pfizer booster. The aim was to evaluate virus-specific immune responses following different booster vaccines across age groups and to assess the potential risk of vaccine immune evasion by Omicron infection.  Increase in neutralization capacity 28 days after booster with Pfizer was 10.8-, 7.1- and 3.52-fold increase for the ancestral strain, Delta variant and Omicron (BA.1) variant, respectively. Increase in neutralization capacity 28 days after booster with AstraZeneca was 3.4-, 6.5- and 2.2-fold increase for the ancestral strain, Delta variant and Omicron (BA.1) variant, respectively. Increase in neutralization capacity 28 days after booster with CoronaVac was 2.6-, 3.4- and 1.2-fold increase for the ancestral strain, Delta variant and Omicron (BA.2.12.1) variant, respectively. [Bruno Andraus Filardi, 2022 ]

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

Li J et al was a cross-sectional study conducted in China that assessed the neutralizing antibody levels against ancestral SARS-CoV-2, Delta and Omicron variants of the primary vaccine schedule and the booster dose of CoronaVac vaccine. The overall GMT after the primary schedule against Omicron was 8.51 (95% CI, 7.92–9.15) with a seropositivity rate of 12.65%. The overall GMT after the booster dose against the Omicron variant was 29.31 (95% CI, 26.75–32.11) with a seropositivity rate of 63.62%. [Li J, 2022 ]

Effectiveness outcomes
Alpha (B.1.1.7)
Copur B et al was a retrospective cohort study conducted in Turkey. This study included data from 1,911 health care workers: 1,160 vaccinated with 2 doses of CoronaVac vaccine and 751 unvaccinated. The aim was to assess the effectiveness of CoronaVac in preventing COVID19 in healthcare workers during the Alpha variant-dominant period. The adjusted effectiveness was 65.0% (95% CI, 0% to 75%) in the cohort. [Copur B, 2022 ]

Gamma (P.1)
Hitchings MDT et al. conducted a case-control study (test-negative) 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 ].

Delta (B.1.617.2)
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 effectiveness 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 effectiveness against COVID-19 infection was 59.0% (95% CI 16.0 to 81.6) and the effectiveness against severe COVID-19 infection was 100% [ d0b34b4760a7c20611147efa750eaf15c8176256].

Min Kang et al. was a comparative cohort study in China, which included 10,813 healthy adults. The study evaluated the effectiveness 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 ].

Omicron (B.1.1.529)
Ranzani O et al was a case-control study (test negative design) conducted in Brazil including 1,386,544 positive antigen/PCR SARS-CoV-2 tests and matched controls. The study estimated the vaccine effectiveness (VE) for homologous and heterologous (BNT162b2) booster doses in adults who received two doses of CoronaVac during the Omicron predominance period. VE against symptomatic COVID-19 for the homologous CoronaVac booster was 8.1% (95% CI, 4.6% to 11.4%) and 57.3% (95% CI, 56.8% to 57.9%) for the Pfizer heterologous booster, measured 8-59 days after the third dose. For hospitalization or death, VE was 86% (95% CI, 71.7% to 93.1%) and 92.1% (95% CI, 90.2% to 93.7%) after 8-59 days of the homologous and heterologous booster schedules, respectively [Ranzani OT, 2022 ].

Ng O et al, was a cohort study conducted in Singapore, the study included data from the Singapore Ministry of Health’s (MOH) official COVID-19 database, including individuals who had received 2 or 3 doses of mRNA vaccines (by Pfizer-BioNTech or Moderna) or inactivated vaccines (by Sinovac or Sinopharm) and notified infections from December 27, 2021, to March 10, 2022. The study showed an effectiveness during the Omicron wave with an incidence rate ratio for 2 doses of CoronaVac of 1.03% (95% CI 0.95-1.11) and 3 doses of 0.93% (95% CI 0.89-0.97) against confirmed infection. The incidence rate ratio for 2 doses of CoronaVac of 1.81% (95% CI 1.20 - 2.74) and 3 doses of 0.30% (95% CI 0.18 - 0.51) against severe infection. [Ng OT, 2022 ]

Jara A et al was a cohort study conducted in Chile, including data from a population-based cohort of children aged 3–5 years from the public national healthcare system of Chile (FONASA), the study enrolled 490,694 children, 194,427 received 2 doses of CoronaVac and 189,523 remained unvaccinated between 6 December 2021 and 26 February 2022. The vaccine effectiveness during the Omicron variant outbreak was 38.2% (95% CI, 36.5–39.9) against COVID-19 infection, 64.6% (95% CI, 49.6–75.2) against hospitalization, and 69.0% (95% CI, 18.6–88.2) against ICU admission. [Jara A, 2022 ]

Florentino P et al was a case-control study conducted in Brazil, the study included 197,958 participants, 89,595 cases and 108,363 controls. Based on data from the national surveillance system for COVID-19 infection (e-SUS Notifica); the information system for severe acute respiratory illness (SIVEP-Gripe) and the the national immunization system (SI-PNI), comprising children 6-11 years with COVID-19  from January 21, 2022, to April 15, 2022 during the Omicron predominance period. The study showed an effectiveness against symptomatic infection of 39.8 (95% CI 33.7 to 45.4), and 59.2 (95% CI 11.3 to 84.5) against hospital admission.[Florentino PTV, 2022 ]

Cerqueira-Silva T et al, was a case-control study with a test-negative design conducted in Brazil, the study enrolled 2,471,576 participants, including 1,431,108 cases and 1,040,468 controls, including data from the nationwide linked database during the Omicron period in Brazil, including participants who received CoronaVac plus a Pfizer-BioNTech booster, from January to April 2022. The vaccine effectiveness against symptomatic infection was 1.7% (95% CI 0.1 to 3.2) and 89.4% (95% CI 87.8 to 90.7) against severe infection. [Cerqueira-Silva T, 2022 ]

Bingyi et al. conducted a comparative study conducted in Hong Kong to estimate vaccine effectiveness against confirmed COVID-19 by RT-PCR or rapid self-reported antigen test during the period of the omicron BA.2 variant. 4993 participants were included of which 8% (386), 41% (2038), 43% (2141) had received 1, 2 or 3 doses respectively. Vaccine effectiveness for two doses of CoronaVac was 26% (95% CI -34 to 59), 28% (95% CI - 26 to 59) for two doses of Pfizer, and 52% (95% CI - 16 to 73) for the three-dose schedule with CoronaVac and/or Pfizer-BioNTech [Yang B, 2022 ].

Wan EYF was a case-control study conducted in China. The study included 82,587 cases of COVID-19 infection, 10,241 COVID-19 related hospital admission cases, 539 cases of ICU admission and 135 cases of post-infection incident. This study evaluated the vaccine effectiveness (VE) of each dose of BNT162b2 and CoronaVac against any COVID-19 infection, COVID-19-related hospital admission, ICU admission, and incident cardiovascular disease (CVD) in the Hong Kong Hospital Authority outbreak dominated by Omicron BA.2 sublineage. Vaccine effectiveness against COVID-19 infection was -0.3% (95% CI -2.7 to -2.1) with 2 doses of CoronaVac, 22.1% (95% CI 20.0 to 24.2) with 2 doses of Pfizer, 19.8% (95% CI 17.2 to 22.3) with 3 doses of CoronaVac, 54.2% (95% CI 52.4 to 55.9) with 3 doses of Pfizer, 12.1% (-15.8 to 33.3) with Pfizer primary schedule and CoronaVac booster, and 39.9% (95% CI 36.6 to 42.9) with CoronaVac primary schedule and Pfizer booster. Vaccine effectiveness against COVID-19 hospitalization was 64.2 (95% CI 61.8 to 66.4) with 2 doses of CoronaVac, 74.2 (95% CI 71.7 to 76.4) with 2 doses of Pfizer, 85.4% (95% CI 83.2 to 87.3) with 3 doses of CoronaVac, 91.4% (95% CI 89.5 to 92.9) with 3 doses of Pfizer and 89.5% (95% CI 85.9 to 92.2) with CoronaVac primary schedule and Pfizer booster. [Wan EYF, 2022 ]

Zee ST et al, was a retrospective study was performed to compare the rate and outcome of COVID-19 in healthcare workers with various vaccination regimes during a territory-wide Omicron BA.2.2 outbreak in Hong Kong between 1 February to 31 March 2022 . The study included 3167 healthcare workers. Compared two-dose vaccination, three-dose vaccination reduced infection risk by 31.7% and 89.3% in household contact and non-household close contact, respectively. Using two-dose BNT162b2 as reference, two-dose CoronaVac recipient had significantly higher risk of being infected (HR 1.69 p < 0.0001). Three-dose BNT162b2 (HR 0.4778 p< 0.0001) and two-dose CoronaVac + BNT162b2 booster (HR 0.4862 p = 0.0157) were associated with a lower risk of infection. Three-dose CoronaVac and two-dose BNT162b2 + CoronaVac booster were not significantly different from two-dose BNT162b2. [Zee ST, 2022 ]

Yan VKC et al was a case-control study conducted in Hong Kong. The study included 14, 984 participants to evaluate the risk of severe complications following 1-3 doses of CoronaVac using electronic health records database. Cases were adults with their first COVID-19-related severe complications between 1 January and 31 March 2022. Vaccine effectiveness against severe complications after two doses CoronaVac was 58.9% (95% CI: 50.3-66.1)  in those aged ≥65, 67.1% (95% CI: 47.1-79.6) in those aged 50-64, 77.8% (95% CI: 49.6-90.2)  in those aged 18-50. Further risk reduction with the third dose was observed especially in those aged ≥65 years, against severe complications. [Yan VKC, 2022 ]

Wan EYF was a case control study conducted in China. The study included data from 78,326 individuals: 7,293 death related to COVID-19 cases and 71,033 controls. This study analyzed data available between January and March 2022 from the electronic health databases in Hong Kong and enrolled individuals aged 60 or above. Vaccine effectiveness against COVID-19 infection (60-79 years old) was -16.2% (95% CI, -18.6- -13.9), 1.9% (95% CI, -0.3 - 4.0), -2.9% (95% CI, -24.0-14.6) and 30.9% (95% CI, 28.5-33.2) for 2 CoronaVac doses schedule, 3 CoronaVac doses schedule, pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule respectively. Vaccine effectiveness against COVID-19 related hospitalization was 62.5% (95% CI, 60-64.7), 82.3% (95% CI, 80.4-84), 87.4% (95% CI, 59.6-96.1) and 86.9%(95% CI, 84.3-89.1) for 2 CoronaVac doses schedule, 3 CoronaVac doses schedule, pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule respectively. [Wan EYF, 2022 ]

Cerqueira-Silva et al was a case control study conducted in Brazil. In this study 918,219 tests (899,050 individuals) were included: 476,901 cases and 441,318 controls. This study used data from national databases in Brazil between 1 January and 22 March 2022, during the period of predominant circulation of the Omicron variant. Those vaccinated received Janssen, Pfizer, AstraZeneca, or CoronaVac vaccines. Vaccine effectiveness against symptomatic infection was 27.3% (95% CI, 22.3-31.9) 2-9 weeks after the second dose of CoronaVac vaccine. Vaccine effectiveness against severe outcomes was 66.4% (95% CI, 37.6-81.9) 10-19 weeks after the second dose of Janssen vaccine [Thiago Cerqueira-Silva, 2022 ].

Vaccine efficacy and effectiveness for booster dose

Immunogenicity outcomes
PRO-nCOV-1002 is a phase 1/2   randomised 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. Results showed neutralizing antibody titers 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 randomised 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 ].

Xin Q et al was a follow up study of PRO-nCOV-1001 and PRO-nCOV-1002 phase 1/2 randomized trials sponsored by Sinovac Research and Development Co., Ltd. and conducted in China. The study included 514 participants, 129 from the 1a-14d-2m group, 135 from the 1b-14d-8m group, 126 from the  2a-28d-2m group and 124 participants from the 2b-28d-8m group. The immunogenicity was assessed by the geometric mean titre (GMT) of neutralizing antibodies to live ancestral SARS-CoV-2 after booster vaccination. A decrease in neutralizing antibody titers was observed across all groups. Results 6 months after booster vaccination showed a GMT of 52.9 (95% CI 40.1 to 70) in the 1b-14d-8m group and 62.8 (95% CI 47.1 to 83.8) in the 2b-28d-8m group. Results after 1 year showed GMTs of 8.9 (95% CI 7 to 11.5) and 9.4 (95% CI 7 to 12.6) in the 1a-14d-2m and the 2a-28d-2m groups respectively. [Jara A, 2022 ]

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 titers 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 titers ≥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 ].

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 ].

Pengfei Jin et al. was a phase 4 randomized trial that included 299 participants aged 60 years and older: 99 primed with two doses of CoronaVac and Cansino COVID-19 vaccine booster, 100 primed with two doses of Coronavac and homologous booster, 50 primed with one dose of CoronaVac and received a Cansino booster and 50 primed with one dose of CoronaVac and homologous booster. In the group primed with two doses of CoronaVac and with a CoronaVac booster, GMT of neutralizing antibodies against wild-type SARS-CoV-2 was 48.2 (95% CI 39.5 to 58.7) 14 days post boost vaccination. Among participants who were primed with one dose of CoronaVac, a homologous second dose induced a GMT of neutralizing antibodies against wild-type SARS-CoV-2 of 9.3 (95% CI 6.2 to 13.9)[Pengfei Jin, 2022 ].

Cobovax study was a randomized clinical trial conducted in China. The study enrolled 219 adults who previously received two doses of CoronaVac and randomized to CoronaVac ("CC-C", n=101) or BNT162b2 ("CC-B", n=118) third dose; and 232 adults who previously received BNT162b2 and randomized to CoronaVac ("BB-C", n=118) or BNT162b2 ("BB-B", n=114). The aim was to assessed immunogenicity and cell-mediated immune responses and vaccine efficacy against infections during follow-up. Third-dose vaccination increased PRNT50 titers against ancestral virus 315 by 14-, 94-, 3- and 19-folds, and against Omicron BA.2 by 1-, 16-, 1- and 13-folds, in CC-C, CC-B, BB-C and BB-B arms respectively. Antibody responses to a BNT162b2 third dose were substantially and statistically significantly greater than responses to a CoronaVac third dose regardless of prior two-dose vaccine type. [Nancy H. L. Leung, 2022 ]

Fadlyana et al was a randomized controlled trial conducted in Indonesia. The study included 949 participants primed with CoronaVac that received one booster dose: 193 Half-Dose ChAdOx1, 192 Full-Dose ChAdOx1, 190 Half-Dose BNT162b2, 193 Full-Dose BNT162b2 and 192 Full-Dose Parameter CoronaVac. The primary outcome was to evaluate the seroconversion rate and geometric mean titres (GMTs) of IgG anti S-RBD 28 days after the booster in the per-protocol population. Seroconversion rates were highest for BNT162b2 (97.8% and 92.0% for full and half-dose), followed by ChAdOx1-S (87.9% and 81.5% for full and half dose) and CoronaVac (41.3% to 66.3%). For participants primed within 6–9 months before booster, GMT values 28 days post-booster were highest for BNT162b2 (19999.84 and 17017.62 for full and half-dose), followed by ChAdOx1-S (11258 and 7853.04 for full and half-dose) and CoronaVac (1440.55). [Eddy Fadlyana, 2022 ]

Intapiboon P et al was a randomized clinical trial conducted in China. The study included 80 participants who had received two doses of CoronaVac: 40 with Pfizer booster and 40 with CoronaVac booster. The primary outcome was antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) measured by surrogate Virus Neutralization Test (sVNTs), plaque reduction neutralization tests (PRNTs), and N-terminal domain (NTD) ELISA in plasma samples collected 1 month after the third dose of vaccination. One month after the third dose of vaccination, the mean percentage of inhibition in the sVNT in the plasma for the BNT1626 and CoronaVac groups was 96.83% and 57.75%, respectively (P < 0.0001). The 90% plaque reduction neutralization (PRNT90) geometric mean titers in the BNT162b2 and CoronaVac groups were 207.49 and 16.53, respectively. PRNT50 geometric mean titers were 303.79 and 56.67, respectively. [Mok CKP, 2022 ]

Filardi B et al was a comparative cohort study that included 293 participants with two doses of CoronaVac vaccine: 131 with AstraZeneca booster, 61 with CoronaVac booster and 101 with Pfizer booster. The aim was to evaluate virus-specific immune responses following different booster vaccines across age groups and to assess the potential risk of vaccine immune evasion by Omicron infection. Increase in neutralization capacity 28 days after booster with Pfizer was 10.8-, 7.1- and 3.52-fold increase for the ancestral strain, Delta variant and Omicron (BA.1) variant, respectively. Increase in neutralization capacity 28 days after booster with AstraZeneca was 3.4-, 6.5- and 2.2-fold increase for ancestral strain, Delta variant and Omicron (BA.1) variant, respectively. Increase in neutralization capacity 28 days after booster with CoronaVac was 2.6-, 3.4- and 1.2-fold increase for ancestral strain, Delta variant and Omicron (BA.2.12.1) variant, respectively. [Bruno Andraus Filardi, 2022 ]

Zhong J et al was a comparative study conducted in China. The study included 150 participants with two doses of CoronaVac vaccine: 50 received a low-dose aerosolized Ad5-nCoV booster, 50 received a high-dose aerosolized Ad5-nCoV booster, 50 received homologous booster and 14 received the ZF2001 booster. This study assessed whether heterologous immunization with aerosol inhalation induces robust antibody immune response. Anti-RBD IgG levels for the low dose aerosolized Ad5-nCoV booster was 691.4 (95% CI, 559.3–854.8), for the high-dose aerosolized Ad5- nCoV booster was 988.5 (95% CI, 755.2–1,294) and for the homologous booster was 2,963 (95% CI, 2,219–3,956). The anti-RBD IgG levels from participants with homologous booster were significantly higher than those of the heterologous booster. Neutralizing antibodies against Omicron for participants with low dose aerosolized Ad5-nCoV booster was 115.8 (95% CI, 48.63–73.86), for participants with high-dose aerosolized Ad5- nCoV booster was 115.8 (95% CI, 88.57–151.3) and 4.32 (95% CI, 4.00–4.84) for participants who received homologous booster. The conventional virus neutralizing assay confirmed that Ad5-nCoV booster induced higher titer of neutralizing antibodies than ZF2001 booster (116.80 (95% CI, 84.51–161.5) vs 4.40 (95% CI, 4.00–4.83)). [Zhong J, 2022 ]

Vargas L et al was a comparative study conducted in Chile. The study included 428 participants distributed in 4 groups: the aim of group 1 was to study the immune response following two CoronaVac doses in healthcare personnel. Group 2 was designed to compare CoronaVac and BNT162b2 vaccination. The aim of group 3 was to analyze the homologous and heterologous booster response (6 months after CoronaVac vaccination) and for group 4 the aim was to study the persistence of the humoral response after >100days following the homologous and heterologous booster. The CoronaVac homologous booster vaccine generates an adequate but considerably milder antibody production (6-fold increase) than the antibody production induced by the AstraZeneca vaccine (12.4-fold increase) or the Pfizer booster vaccine (11.2-fold increase). [Vargas L, 2022 ]

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

Li J et al was a cross-sectional study conducted in China, the study assessed the neutralizing antibody levels against ancestral SARS-CoV-2, Delta and Omicron variants of the primary vaccine schedule and the booster dose of CoronaVac vaccine. The overall GMT after the booster dose against the ancestral strain were 61.48 (95% CI, 56.42–66.99) with a seropositivity of 88.52%, 40.33 (95% CI, 36.79–44.20) with a seropositivy of 70.82% against Delta variant, and 29.31 (95% CI, 26.75–32.11) with a seropositivity rate of 63.62% against Omicron variant. [Li J, 2022 ]

Medina-Pestana conducted a prospective, single-center cohort study included kidney transplant recipients without previous COVID-19. There were 307 patients in the heterologous group (2 CoronaVac + BNT26b2) and 777 in the homologous group (3 CoronaVac). At a median of 25 days after the heterologous BNT262b2 and 35 days after the homologous CoronaVac third-dose vaccine, the seroconversion rate was significantly higher in the heterologous group (48.9% versus 32.4%; p < 0.0001), resulting in a significantly higher seroprevalence rate (67.4% versus 55.5%; p = 0.0003). After the booster, the median antibody titers among seropositive patients were higher in those to whom the third heterologous BNT262b2 was administered (7771 versus 599 AU/mL; p < 0.0001). 444 individuals or 40.1% of the entire cohort (32.6% in the heterologous BNT262b2 and 44.2% in the homologous CoronaVac groups; p = 0.0003) remained seronegative even after 3 doses. When stratifying the immunogenicity analysis by serological status before the third dose, a 66-fold increase in antibody titers was observed in the heterologous group, compared to a 4-fold increase after the third homologous dose (p < 0.0001). Finally, among patients who seroconverted, median titers were approximately 10 times higher after the third heterologous compared to homologous dose (1768 versus 189 AU/mL; p < 0.0001). [Medina-Pestana J, 2022 ]

Ma Y et al was a prospective multicenter study conducted in China that included 97 solid cancer patients (SCP-N) with 279 positive controls as RRG (robust response group) and 82 negative controls as healthy controls (HC). The aim was to assess the immune response to the third dose and identify whether vitamin D deficiency is associated with serial serologic failure in patients with cancer. The seroconversion rate after third-dose vaccination was higher in SCP-N than in HC (70.6% vs. 29.4%, p < 0.01). The matched comparison showed that patients in the seronegative group had a significantly lower level of vitamin D and consumption rate than the robust response group, or robust response group with third-dose positive) (all p < 0.01). [Ma Y, 2022 ]

Effectiveness outcomes
Wan EYF was a case-control study conducted in China. The study included 82,587 cases of COVID-19 infection, 10,241 COVID-19 related hospital admission cases, 539 cases of ICU admission and 135 cases of post-infection incident. This study evaluated the vaccine effectiveness (VE) of each dose of BNT162b2 and CoronaVac against any COVID-19 infection, COVID-19-related hospital admission, ICU admission, and incident cardiovascular disease (CVD) in the Hong Kong Hospital Authority outbreak dominated by Omicron BA.2 sublineage. Vaccine effectiveness against COVID-19 infection was -0.3% (95% CI -2.7 to -2.1) with 2 doses of CoronaVac, 22.1% (95% CI 20.0 to 24.2) with 2 doses of Pfizer, 19.8% (95% CI 17.2 to 22.3) with 3 doses of CoronaVac, 54.2% (95% CI 52.4 to 55.9) with 3 doses of Pfizer, 12.1% (-15.8 to 33.3) with Pfizer primary schedule and CoronaVac booster, and 39.9% (95% CI 36.6 to 42.9) with CoronaVac primary schedule and Pfizer booster. Vaccine effectiveness against COVID-19 hospitalization was 64.2 (95% CI 61.8 to 66.4) with 2 doses of CoronaVac, 74.2 (95% CI 71.7 to 76.4) with 2 doses of Pfizer, 85.4% (95% CI 83.2 to 87.3) with 3 doses of CoronaVac, 91.4% (95% CI 89.5 to 92.9) with 3 doses of Pfizer and 89.5% (95% CI 85.9 to 92.2) with CoronaVac primary schedule and Pfizer booster. [Wan EYF, 2022 ]

Zee ST et al, was a retrospective study was performed to compare the rate and outcome of COVID-19 in healthcare workers with various vaccination regimes during a territory-wide Omicron BA.2.2 outbreak in Hong Kong between 1 February to 31 March 2022 . The study included 3,167 healthcare workers.  Compared two-dose vaccination, three-dose vaccination reduced infection risk by 31.7% and 89.3% in household contact and non-household close contact, respectively. Vaccine effectiveness against infections for CoronaVac homologous booster dose was (HR 0.9269  p < 0.6715), Three-dose CoronaVac and two-dose BNT162b2 + CoronaVac booster were not significantly different from two-dose BNT162b2. [Zee ST, 2022 ]

YYan VKC et al was a case-control study conducted in Hong Kong. The study included 14,984 participants to assess the risk of serious complications after 1 to 3 doses of CoronaVac using the electronic health record database. Cases were adults with their first serious COVID-19 related complications between January 1 and March 31, 2022. Vaccine effectiveness during the Omicron period after Sinovac primary schedule and Pfizer booster were 95.2% (95% CI: 80.5-98.8) in  ≥65 years , 88.6% (95% CI: 50.4-97.4) 51-64 years and 73.9% (95% CI: -106.8-96.7) 18-50 years inn those 18-50 years . The findings show that the CoronaVac vaccine was effective against serious complications related to COVID-19 against the Omicron BA.2 pandemic, with the risks further decreased with the third dose. [Yan VKC, 2022 ]

Ng O et al, was a cohort study conducted in Singapore, the study included data from the Singapore Ministry of Health’s (MOH) official COVID-19 database, including individuals who had received 2 or 3 doses of mRNA vaccines (by Pfizer-BioNTech or Moderna) or inactivated vaccines (by Sinovac or Sinopharm) and notified infections from December 27, 2021, to March 10, 2022. The study showed an effectiveness during the Omicron wave with an incidence rate ratio for 3 doses of CoronaVac of 0.93% (95% CI 0.89-0.97) against confirmed infection and 69.7% (95% CI 48.9 - 82.0) against severe infection. [Ng OT, 2022 ]

Jara A et al was a prospective cohort study conducted in Chile that analyzed data from 3,754,785 adults. This study assessed the effectiveness against COVID-19-related ICU admissions and death for four different three-dose regimes. The effectiveness analysis included data from 236,895 persons at risk with mRNA homologous booster, 840,136 persons at risk with CoronaVac primary schedule and mRNA booster, 137,002 persons at risk with CoronaVac homologous booster and 1,393,752 persons with CoronaVac primary schedule and AstraZeneca booster. Vaccine effectiveness against ICU admissions was 77.0% (95% CI, 69.7-83.0) for participants with CoronaVac primary schedule and mRNA booster, 74,2% (IC 95%, 54,8-85,2) for participants with CoronaVac homologous booster and 86.3% (95% CI, 83.2-88.8) for participants with CoronaVac primary schedule and AstraZeneca booster. [Alejandro Jara, 2022 ]

Wan EYF was a case control study conducted in China. The study included data from 78,326 individuals: 7,293 death related to COVID-19 cases and 71,033 controls. This study analyzed data available between January and March 2022 from the electronic health databases in Hong Kong and enrolled individuals aged 60 or above. Vaccine effectiveness against COVID-19 infection (60-79 years old) was -16.2% (95% CI, -18.6- -13.9), 1.9% (95% CI, -0.3-4), -2.9% (95% CI, -24-14.6) and 30.9% (95% CI, 28.5-33.2) for 2 CoronaVac doses schedule, 3 CoronaVac doses schedule, pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule respectively. Vaccine effectiveness against COVID-19 related hospitalization was 62.5% (95% CI, 60-64.7), 82.3% (95% CI, 80.4-84), 87.4% (95% CI, 59.6-96.1) and 86.9% (95% CI, 84.3-89.1) for 2 CoronaVac doses schedule, 3 CoronaVac doses schedule, pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule respectively. [Wan EYF, 2022 ]

Ranzani O et al was a case-control study (test negative design) conducted in Brazil including 1,386,544 positive antigen/PCR SARS-CoV-2 tests and matched controls. The study estimated the vaccine effectiveness (VE) for homologous and heterologous (BNT162b2) booster doses in adults who received two doses of CoronaVac during the Omicron predominance period. VE against symptomatic COVID-19 for the homologous CoronaVac booster was 8.1% (95% CI, 4.6% to 11.4%) and 57.3% (95% CI, 56.8% to 57.9%) for the Pfizer heterologous booster, measured 8-59 days after the third dose. For hospitalization or death, VE was 86% (95% CI, 71.7% to 93.1%) and 92.1% (95% CI, 90.2% to 93.7%) after 8-59 days of the homologous and heterologous booster schedules, respectively [Ranzani OT, 2022 ].

Vaccine efficacy and effectiveness for heterologous schedule

Immunogenicity outcomes
JSVCT116 is a phase 4 randomised trial sponsored by Jiangsu Province Centers for Disease Control and Prevention and conducted in China. The study included 101 participants: 51 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 titers (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 ].

Puthanakit T et al was a phase 2 randomized clinical trial conducted in Thailand. The study included 80 participants aged 12 to 18 years without previous SARS-CoV-2 vaccination. Participants were randomized to be vaccinated with CoronaVac 3 ug as the first dose followed by BNT162b2 30 µg or 20 µg as the second dose, at 3-week (3w) or 6-week interval (6w). During the Omicron-predominant period, participants were offered a BNT162b2 booster dose 30, 15, or 10 µg. Neutralization tests (sVNT and pseudovirus neutralization test; pVNT) against Omicron strain were tested pre- and 14 days post-booster dose.  At day 14, the geometric mean (GM) of anti-S-RBD IgG in CoronaVac 3w/Pfizer 30µg was 4713 (95 %CI 4127–5382) binding-antibody unit (BAU)/ml, while geometric mean ratio(GMR) was 1.28 (1.09–1.51) in  CoronaVac 6w/Pfizer 30 µg. The GMs of sVNT against Delta variants at day 14 among participants in CoronaVac 3w/Pfizer 30µg and CoronaVac 6w/Pfizer 30 µg arms were 95.3 % and 99.7% inhibition, respectively [Puthanakit T, 2022 ].

Niyomnaitham S et al was a randomized clinical trial conducted in Thailand. This study evaluated the immunogenicity and reactogenicity of heterologous COVID-19 primary schedules in healthy adults, as well as booster response to BNT162b2 following heterologous CoronaVac and ChAdOx1 nCoV-19 regimens. 210 adults participated in the study: 30 with CoronaVac/AstraZeneca primary schedule, 30 with CoronaVac/Pfizer, 30 with AstraZeneca/CoronaVac, 30 with  AstraZeneca/Pfizer, 30 with Pfizer/CoronaVac, 30 with Pfizer/AstraZeneca and 30 with Pfizer/Pfizer. At 2 weeks after the second dose, the anti-RBD IgG levels were  2181.8 BAU/mL (95%CI 1558.2 to 3055.1) for CoronaVac/Pfizer schedule, 2132.7 BAU/mL (95%CI 1696.1 to 2,681.7) for AstraZeneca/Pfizer schedule, 2248.8 BAU/mL (95% CI 1691.3 to 2,990.0) for Pfizer/Pfizer schedule, 851.4 BAU/mL (95% CI 649.5 to 1116.1) for CoronaVac/AstraZeneca schedule, 1201.2 BAU/mL (95%CI 947.9 to 1522.1) for Pfizer/AstraZeneca schedule, 137.04 BAU/mL (95% CI 103.6 to 186.4) for AstraZeneca/CoronaVac schedule and 225.2 BAU/mL (95% CI 177.1 to 286.4) for Pfizer/CoronaVac schedule. [Niyomnaitham S, 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 the Astrazeneca vaccine) of 74% (95% CI 43 to 88%) [Sritipsukho P, 2022 ].

Vaccine efficacy and effectiveness for heterologous booster schedule

Immunogenicity outcomes
JSVCT116 is a phase 4 randomised 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 titers (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 457 fully vaccinated participants: 247 with 2 doses of Sinovac and 210 with 2 doses of Sinovac plus an AstraZeneca booster. 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 ancestral strain 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 6.2-fold reduction compared to the Delta variant. [Suntronwong N, 2022 ]

Angkasekwinai N et al. was a cohort study conducted in 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 markedly reduced serum antibody titers 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 titers ≥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 ].

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 esquema 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 titers 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 ].

Puthanakit T et al was a phase 2 randomized clinical trial conducted in Thailand. The study included 80 participants aged 12 to 18 years without previous SARS-CoV-2 vaccination. Participants were randomized to be vaccinated with CoronaVac 3 ug as the first dose followed by BNT162b2 30 µg or 20 µg as the second dose, at 3-week (3w) or 6-week interval (6w). During the Omicron-predominant period, participants were offered a BNT162b2 booster dose 30, 15, or 10 µg. Neutralization tests (sVNT and pseudovirus neutralization test; pVNT) against Omicron strain were tested pre- and 14 days post-booster dose.  At day 14, the geometric mean (GM) of anti-S-RBD IgG in CoronaVac 3w/Pfizer 30µg was 4713 (95 %CI 4127–5382) binding-antibody unit (BAU)/ml, while geometric mean ratio(GMR) was 1.28 (1.09–1.51) in  CoronaVac 6w/Pfizer 30 µg. The GMs of sVNT against Delta variants at day 14 among participants in CoronaVac 3w/Pfizer 30µg and CoronaVac 6w/Pfizer 30 µg arms were 95.3 % and 99.7% inhibition, respectively [Puthanakit T, 2022 ].

Cobovax study was a randomized clinical trial conducted in China. The study enrolled 219 adults who previously received two doses of CoronaVac and randomized to CoronaVac ("CC-C", n=101) or BNT162b2 ("CC-B", n=118) third dose; and 232 adults who previously received BNT162b2 and randomized to CoronaVac ("BB-C", n=118) or BNT162b2 ("BB-B", n=114). The aim was to assessed immunogenicity and cell-mediated immune responses and vaccine efficacy against infections during follow-up. Third-dose vaccination increased PRNT50 titers against ancestral virus 315 by 14-, 94-, 3- and 19-folds, and against Omicron BA.2 by 1-, 16-, 1- and 13-folds, in CC-C, CC-B, BB-C and BB-B arms respectively. Antibody responses to a BNT162b2 third dose were substantially and statistically significantly greater than responses to a CoronaVac third dose regardless of prior two-dose vaccine type. [Nancy H. L. Leung, 2022 ]

Fadlyana et al was a randomized controlled trial conducted in Indonesia. The study included 949 participants primed with CoronaVac that received one booster dose: 193 Half-Dose ChAdOx1, 192 Full-Dose ChAdOx1, 190 Half-Dose BNT162b2, 193 Full-Dose BNT162b2 and 192 Full-Dose Parameter CoronaVac. The primary outcome was to evaluate the seroconversion rate and geometric mean titres (GMTs) of IgG anti S-RBD 28 days after the booster in the per-protocol population. Seroconversion rates were highest for BNT162b2 (97.8% and 92.0% for full and half-dose), followed by ChAdOx1-S (87.9% and 81.5% for full and half dose) and CoronaVac (41.3% to 66.3%). For participants primed within 6–9 months before booster, GMT values 28 days post-booster were highest for BNT162b2 (19999.84 and 17017.62 for full and half-dose), followed by ChAdOx1-S (11258 and 7853.04 for full and half-dose) and CoronaVac (1440.55). [Eddy Fadlyana, 2022 ]

Intapiboon P et al was a randomized clinical trial conducted in China. The study included 80 participants who had received two doses of CoronaVac: 40 with Pfizer booster and 40 with CoronaVac booster. The primary outcome was antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) measured by surrogate Virus Neutralization Test (sVNTs), plaque reduction neutralization tests (PRNTs), and N-terminal domain (NTD) ELISA in plasma samples collected 1 month after the third dose of vaccination. One month after the third dose of vaccination, the mean percentage of inhibition in the sVNT in the plasma for the BNT1626 and CoronaVac groups was 96.83% and 57.75%, respectively (P < 0.0001). The 90% plaque reduction neutralization (PRNT90) geometric mean titers in the BNT162b2 and CoronaVac groups were 207.49 and 16.53, respectively. PRNT50 geometric mean titers were 303.79 and 56.67, respectively. [Mok CKP, 2022 ]

Niyomnaitham S et al was a randomized clinical trial conducted in Thailand. This study evaluated the immunogenicity and reactogenicity of heterologous COVID-19 primary schedules in healthy adults, as well as booster response to BNT162b2 following heterologous CoronaVac and ChAdOx1 nCoV-19 regimens. 210 adults participated in the study: 30 with CoronaVac/AstraZeneca primary schedule, 30 with CoronaVac/Pfizer, 30 with AstraZeneca/CoronaVac, 30 with  AstraZeneca/Pfizer, 30 with Pfizer/CoronaVac, 30 with Pfizer/AstraZeneca and 30 with Pfizer/Pfizer. At two weeks after the booster dose with Pfizer, the anti-RBD IgG levels against the ancestral strain were 2518.8 BAU/mL ( 95%CI 1960.4 to 3236.4) for participants primed with CoronaVac/AstraZeneca and 2610.6 BAU/mL (95%CI 2037.7–3344.5) for participants primed with AstraZeneca/CoronaVac. GMR were 2.5 and 18.9 for CoronaVac/AstraZeneca/Pfizer  and AstraZeneca/CoronaVac/Pfizer groups, respectively. [Niyomnaitham S, 2022 ]

Intapiboon P et al was a randomized clinical trial conducted in Thailand. The study included 91 participants with 2 doses of CoronaVac who were randomized to receive Pfizer intramuscular full dose booster, Pfizer intramuscular half dose booster or Pfizer Intradermal dose. The aim was to assess immunogenicity in healthy adults who had received a conventional two dosage of inactivated SARS-CoV-2 vaccine (CoronaVac) with an intradermal booster, using a reciprocal dosage of BNT162b2. The antibody responses were significantly increased in sera of volunteers boosted with a full dose of the mRNA vaccines compared to the non-boosted group (median = 3884 and 52 BAU/mL, respectively). [Intapiboon P, 2021 ]

Buathong et al conducted an observational study to determine the levels of neutralizing antibodies against the SARS-CoV-2 ancestral strain, Delta and Omicron variants of concern (VOCs), in 125 healthcare workers who received CoronaVac as their primary vaccination and later received either a single ChAdOx1 or a combination of two consecutive boosters using either two ChAdOx1 doses or a ChAdOx1 or BNT162b2 as the primary and second boosters, respectively, or two doses of BNT162b2. Coronavac Coronavac + ChAdOx1: - When measured against the SARS-CoV-2 ancestral strain, 13.6% of subjects were NT (Neutralizing Antibodys) positive at the time of booster dose and a mean percentage inhibition (MI) of 14.3% (95% CI: 7.1–21.5%). 98.5% of subjects were NT positive at week 1 (p < 0.0001) with an MI of 81.9% (95% CI: 77.8–86.0%) and a 100% at week 4 post-booster, with an MI of 81.3% (95% CI: 78.2–84.4%). Coronavac Coronavac + ChAdOx1 ChAdOx1: - 96% of the subjects who received a second ChAdx1 booster dose were NT positive at the time of their second booster (day 0) with an MI of 88.1% (95% CI: 82.2–92.9%). All (100%) were NT positive at week 1 post second booster and an MI of 91.6% (95% CI: 87.5–95.7%). Coronavac Coronavac + ChAdOx1 Pfizer: - 100% of the subjects were NT positive against the ancestral strain at day 0 (MI of 84.5%, 95% CI: 80.5–88.6%; and MI of 84.6%, 95% CI: 73.2–95.9%, respectively) and at 1 week (MI of 85.2%, 95% CI: 81.8–88.7%; and MI of 93.3%, 95% CI: 86.3–100.3%, respectively) after their second booster dose. Coronavac Coronavac + Pfizer Pfizer: - 100% of the subjects were NT positive against the ancestral strain at day 0 (MI of 84.5%, 95% CI: 80.5–88.6%; and MI of 84.6%, 95% CI: 73.2–95.9%, respectively) and at 1 week (MI of 85.2%, 95% CI: 81.8–88.7%; and MI of 93.3%, 95% CI: 86.3–100.3%, respectively) after their second booster dose. [Buathong R, 2022 ]

Sira et al. (TCTR20210722003) conducted a randomized clinical trial in Thailand, with 422 adults with a mean age of 44 years old. The aim of the study was to evaluate the immunogenicity and reactogenicity of standard-dose and low-dose boosters of Oxford-AstraZeneca vaccine, after the full CoronaVac schedule in healthy adults. 206 individuals received low dose and 208 individuals standard dose. At baseline, geometric means (GM) of sVNT against delta variant and anti-S-RBD IgG were 18.1% inhibition (95% CI 16.4-20.0) and 111.5 (105, 1-118.3) BAU/ml. GM of sVNT against delta variant and anti-S-RBD IgG in DS were 95.6% inhibition (95% CI 94.3-97.0) and 1975.1 (1841.7-2118.2) BAU /ml at day 14, and 89.4% inhibition (86.4-92.4) and 938.6 (859.9-1024.4) BAU/ml at day 90, respectively. The GMRs of sVNT against delta variant and anti-S-RBD IgG in LD compared to SD were 1.00 (95% CI: 0.98-1.02) and 0.84 (0.76-0, 93) at day 14, and 0.98 (0.94-1.03) and 0.89 (0.79-1.00) at day 90, respectively. [Sira Nanthapisal, 2022 ]

Niyomnaitham et al was a phase 2 randomized clinical trial conducted in Thailand. The study included 1,243 participants with CoronaVac primary schedule: 312 in the AstraZeneca booster (half dose) group, 307 in the AstraZeneca booster (full dose) group, 316 in the Pfizer booster (half dose) group and 308 in the Pfizer booster (half dose) group. Vaccination-induced immunogenicity to Ancestral, Delta and Omicron BA.1 strains were evaluated by assessing anti-spike (‘anti-S’), anti-nucleocapsid antibodies, pseudovirus neutralization (‘PVNT’), micro-neutralization titers, and T-cells assays. Within platforms and irrespective of dose or platform, seroconversions were greater than 97%, and greater than 90% for neutralising antibodies against pseudovirus, but similar against SARS-CoV-2 strains. Anti Spike RBD IgG Geometric means concentration (U/mL) at day 28 were 8237.0 (95% CI, 7679.3-8835.2) for the AstraZeneca half dose group, 8973.6 (95% CI, 8328.1-9669.2) for the AstraZeneca full dose group, 14073.9 (95% CI, 13236.4-14964.4) for the Pfizer half dose group and 15920.7 (95% CI, 15135.7-16746.4) for the Pfizer full dose group. [Suvimol Niyomnaitham, 2022 ]

Filardi B et al was a comparative cohort study that included 293 participants with two doses of CoronaVac vaccine: 131 with AstraZeneca booster, 61 with CoronaVac booster and 101 with Pfizer booster. The aim was to evaluate virus-specific immune responses following different booster vaccines across age groups and to assess the potential risk of vaccine immune evasion by Omicron infection.  Increase in neutralization capacity (28 days after the booster) with Pfizer vaccine booster was 10.8, 7.1 and 3.52 fold increase for ancestral strain, delta variant and omicron (BA.1) variant respectively. Increase in neutralization capacity (28 days after the booster) with AstraZeneca vaccine booster was 3.4, 6.5 and 2.2 fold increase for ancestral strain, delta variant and omicron (BA.1) variant respectively. Increase in neutralization capacity (28 days after the booster) with CoronaVac vaccine booster was 2.6, 3.4 and 1.2 fold increase for ancestral strain, delta variant and omicron (BA.2.12.1) variant respectively. [Bruno Andraus Filardi, 2022 ]

Zhong J et al was a comparative study conducted in China. The study included 150 participants with two doses of CoronaVac vaccine: 50 received a low-dose aerosolized Ad5-nCoV booster, 50 received a high-dose aerosolized Ad5- nCoV booster, 50 received homologous booster and 14 received the ZF2001 booster. This study assessed whether heterologous immunization with aerosol inhalation induces robust antibody immune response. Anti-RBD IgG levels for the low dose aerosolized Ad5-nCoV booster was 691.4 (95% CI, 559.3–854.8), for the high-dose aerosolized Ad5-nCoV booster was 988.5 (95% CI, 755.2–1,294) and for the homologous booster was 2,963 (95% CI, 22,19–3,956). The anti-RBD IgG levels of participants with homologous boosters were significantly higher. Neutralizing antibodies against Omicron for participants with low dose aerosolized Ad5-nCoV booster was 115.8 (95% CI, 48.63–73.86), for participants with high-dose aerosolized Ad5- nCoV booster was 115.8 (95% CI, 88.57–151.3) and 4.32 (95% CI, 4.00–4.84) for participants who received homologous booster. The conventional virus neutralizing assay confirmed that Ad5-nCoV booster induced higher titer of neutralizing antibodies than ZF2001 booster (116.80 (95% CI, 84.51–161.5) vs 4.40 (95% CI, 4.00–4.83)). [Zhong J, 2022 ]

Vargas L et al was a comparative study conducted in Chile. The study included 428 participants distributed in 4 groups: the aim of group 1 was to study the immune response following two CoronaVac doses in healthcare personnel. Group 2 was designed to compare CoronaVac and BNT162b2 vaccination. The aim of group 3 was to analyze the homologous and heterologous booster response (6 months after CoronaVac vaccination) and for group 4 the aim was to study the persistence of the humoral response after >100days following the homologous and heterologous booster. The CoronaVac homologous booster vaccine generates an adequate but considerably milder antibody production (6-fold increase) than the antibody production induced by the AstraZeneca vaccine (12.4-fold increase) or the Pfizer booster vaccine (11.2-fold increase). [Vargas L, 2022 ]

Tawinprai K et al was a randomized controlled trial conducted in Thailand. The study included 125 participants with 2 doses of CoronaVac: 41 received AstraZeneca intramuscular standard dose, 41 received AstraZeneca intradermal fractional dose and 43 received AstraZeneca intradermal fractional dose (20%). The primary endpoint was the geometric mean ratio of anti-receptor binding domain antibody in the ID1/ID2 vs. the IM groups 14 days post-vaccination. Geometric mean concentration of anti-SARS-CoV-2 spike protein RBD antibodies 2 weeks after ChAdOx1/AZD1222 vaccination were 6,414.62 (95% CI, 5,107.56–8,056.17), 5,669.49 (95% CI, 4,560.30–7,048.45) and 8,230.37 (95% CI, 6,697.04-10,114.8) for the intramuscular standard dose group, intradermal fractional dose group and intradermal fractional dose (20%) group respectively. [Tawinprai K, 2022 ]

Medina-Pestana conducted a prospective, single-center cohort study included kidney transplant recipients without previous COVID-19. There were 307 patients in the heterologous group (2 CoronaVac + BNT26b2) and 777 in the homologous group (3 CoronaVac). At a median of 25 days after the heterologous BNT262b2 and 35 days after the homologous CoronaVac third-dose vaccine, the seroconversion rate was significantly higher in the heterologous group (48.9% versus 32.4%; p < 0.0001), resulting in a significantly higher seroprevalence rate (67.4% versus 55.5%; p = 0.0003). After the booster, the median antibody titers among seropositive patients were higher in those to whom the third heterologous BNT262b2 was administered (7771 versus 599 AU/mL; p < 0.0001). 444 individuals or 40.1% of the entire cohort (32.6% in the heterologous BNT262b2 and 44.2% in the homologous CoronaVac groups; p = 0.0003) remained seronegative even after 3 doses. When stratifying the immunogenicity analysis by serological status before the third dose, a 66-fold increase in antibody titers was observed in the heterologous group, compared to a 4-fold increase after the third homologous dose (p < 0.0001). Finally, among patients who seroconverted, median titers were approximately 10 times higher after the third heterologous compared to homologous dose (1768 versus 189 AU/mL; p < 0.0001). [Medina-Pestana J, 2022 ]

Suntronwong et al conducted a cohort study to examine the capability of booster vaccination following CoronaVac/AZD1222 prime to induce neutralizing antibodies against Omicron (BA.1 and BA.2) and T cell responses. The cohort study started on November 30th 2021 and ended on January 24th 2022, in Thailand. A total of 167 participants received AZD1222 (n=60), BNT162b2(n=55) and mRNA-1273(n=52) as a booster dose. Comparing pre‐ and post‐boost, mRNA‐1273‐boosted individuals achieved an anti‐RBD IgG with a 23‐fold increase (126.9 vs. 2921 BAU/ml) and showed a higher level than the other vaccine groups, whereas BNT162b2 and AZD1222 groups were induced by 15.8‐fold (152.1 vs. 2404 BAU/ml) and 2.5‐fold (142 vs. 360.8 BAU/ml) higher than baseline. Between 90% and 97% of individuals boosted with BNT162b2 and mRNA‐1273 could induce IFN‐γ responses after stimulation with the spike protein of the ancestral strain. On the contrary, no difference was found in IFN‐γ response in those boosted with AZD1222 compared with baseline [Suntronwong N, 2022 ].

Zhu Y et al was a cohort study conducted in China, including 486 participants with heterologous prime-boost inactivated vaccine schedules: 48 received BBIBP+CoronaVac, 30 received CoronaVac+BBIBP, 30 received CoronaVac+WIBP, 34 received WIBP+CoronaVac, 25 received WIBP+BBIBP and 36 received BBIBP+WIBP. The study evaluated the immunogenic response of heterologous booster schedules with inactivated vaccines. The neutralization GMTs against the ancestral strain were 312 in the BBIBP+CoronVac group, 179 in the CoronaVac+BBIBP group, 335 in the CoronaVac+WIBP group, 444 in the WIBP+CoronaVac group, 130 in the WIBP+BBIBP group and 191 in the BBIBP+WIBP group. [Zhu Y, 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 ].

Cerqueira-Silva T et al, was a case-control study with a test-negative design conducted in Brazil, the study enrolled 2,471,576 participants, including 1,431,108 cases and 1,040,468 controls, including data from the nationwide linked database during the Omicron period in Brazil, including participants who received CoronaVac plus a Pfizer-BioNTech booster, from January to April 2022. The vaccine effectiveness against symptomatic infection was 1.7% (95% CI 0.1 to 3.2) and 89.4% (95% CI 87.8 to 90.7) against severe infection. [Cerqueira-Silva T, 2022 ]

Wan EYF was a case-control study conducted in China. The study included 82,587 cases of COVID-19 infection, 10,241 COVID-19 related hospital admission cases, 539 cases of ICU admission and 135 cases of post-infection incident. This study evaluated the vaccine effectiveness (VE) of each dose of BNT162b2 and CoronaVac against any COVID-19 infection, COVID-19-related hospital admission, ICU admission, and incident cardiovascular disease (CVD) in the Hong Kong Hospital Authority outbreak dominated by Omicron BA.2 sublineage. Vaccine effectiveness against COVID-19 infection was -0.3% (95% CI -2.7 to -2.1) with 2 doses of CoronaVac, 22.1% (95% CI 20.0 to 24.2) with 2 doses of Pfizer, 19.8% (95% CI 17.2 to 22.3) with 3 doses of CoronaVac, 54.2% (95% CI 52.4 to 55.9) with 3 doses of Pfizer, 12.1% (-15.8 to 33.3) with Pfizer primary schedule and CoronaVac booster, and 39.9% (95% CI 36.6 to 42.9) with CoronaVac primary schedule and Pfizer booster. Vaccine effectiveness against COVID-19 hospitalization was 64.2 (95% CI 61.8 to 66.4) with 2 doses of CoronaVac, 74.2 (95% CI 71.7 to 76.4) with 2 doses of Pfizer, 85.4% (95% CI 83.2 to 87.3) with 3 doses of CoronaVac, 91.4% (95% CI 89.5 to 92.9) with 3 doses of Pfizer and 89.5% (95% CI 85.9 to 92.2) with CoronaVac primary schedule and Pfizer booster. [Wan EYF, 2022 ]

Zee ST et al, was a retrospective study was performed to compare the rate and outcome of COVID-19 in healthcare workers with various vaccination regimes during a territory-wide Omicron BA.2.2 outbreak in Hong Kong between 1 February to 31 March 2022 . The study included 3167 healthcare workers.  Compared two-dose vaccination, three-dose vaccination reduced infection risk by 31.7% and 89.3% in household contact and non-household close contact, respectively. Vaccine effectiveness against infections for CoronaVac heterologous booster dose was (HR 0.4862 p = 0.0157) and  Three-dose CoronaVac and two-dose BNT162b2 + CoronaVac booster were not significantly different from two-dose BNT162b2. [Zee ST, 2022 ]

Yan VKC et al was a case-control study conducted in Hong Kong. The study included 14, 984 participants to evaluate the risk of severe complications following 1-3 doses of CoronaVac and BNT162b2 using electronic health records database. Cases were adults with their first COVID-19-related severe complications between 1 January and 31 March 2022. Vaccine effectiveness heterologus booster doses (Sinovac +  BNT162b2) was 95.2% (95% CI: 80.5-98.8) in those aged ≥65, 88.6% (95% CI: 50.4-97.4)  in those aged 50-64, 73.9% (95% CI: -106.8-96.7)  in those aged 18-50. Further risk reduction with the third dose was observed especially in those aged ≥65 years, against severe complications in the Omicron BA.2 pandemic. [Yan VKC, 2022 ]

Jara A et al was a prospective cohort study conducted in Chile that analyzed data from 3,754,785 adults. This study assessed the effectiveness against COVID-19-related ICU admissions and death for four different three-dose regimes. The effectiveness analysis included data from 236,895 persons at risk with mRNA homologous booster, 840,136 persons at risk with CoronaVac primary schedule and mRNA booster, 137,002 persons at risk with CoronaVac homologous booster and 1,393,752 persons with CoronaVac primary schedule and AstraZeneca booster. Vaccine effectiveness against ICU admissions was 77.0% (95% CI, 69.7-83.0) for participants with CoronaVac primary schedule and mRNA booster, 74,2% (95% CI, 54,8-85,2) for participants with CoronaVac homologous booster and 86.3% (95% CI, 83.2-88.8) for participants with CoronaVac primary schedule and AstraZeneca booster. [Alejandro Jara, 2022 ]

Wan EYF fue un estudio de casos y controles realizado en China. El estudio incluyó datos de 78 326 individuos: 7 293 casos de muerte relacionados con COVID-19 y 71 033 controles. Este estudio analizó los datos disponibles entre enero y marzo de 2022 de las bases de datos electrónicas de salud de Hong Kong e incluyó a individuos de 60 años o más. La efectividad de la vacuna contra la infección por COVID-19 (60-79 años) fue del -16,2% (IC 95%, -18,6- -13,9), del 1,9% (IC 95%, -0,3-4), del -2,9% (IC 95%, -24-14,6) y del 30,9% (IC 95%, 28,5-33,2) para el esquema de 2 dosis de CoronaVac, el esquema de 3 dosis de CoronaVac, el esquema primario de pfizer con refuerzo de CoronaVac y el esquema primario de CoronaVac con refuerzo de Pfizer, respectivamente. La efectividad de la vacuna contra la hospitalización relacionada con COVID-19 fue del 62,5% (IC 95%, 60-64,7), del 82,3% (IC 95%, 80,4-84), del 87,4% (IC 95%, 59,6-96,1) y del 86,9% (IC 95%, 84,3-89,1) para el esquema de 2 dosis de CoronaVac, el esquema de 3 dosis de CoronaVac, el esquema primario Pfizer con refuerzo de CoronaVac y el esquema primario de CoronaVac con refuerzo de Pfizer, respectivamente. [Wan EYF, 2022 ]

Ranzani O et al was a case-control study (test negative design) conducted in Brazil including 1,386,544 positive antigen/PCR SARS-CoV-2 tests and matched controls. The study estimated the vaccine effectiveness (VE) for homologous and heterologous (BNT162b2) booster doses in adults who received two doses of CoronaVac during the Omicron predominance period. VE against symptomatic COVID-19 for the homologous CoronaVac booster was 8.1% (95% CI, 4.6% to 11.4%) and 57.3% (95% CI, 56.8% to 57.9%) for the Pfizer heterologous booster, measured 8-59 days after the third dose. For hospitalization or death, VE was 86% (95% CI, 71.7% to 93.1%) and 92.1% (95% CI, 90.2% to 93.7%) after 8-59 days of the homologous and heterologous booster schedules, respectively [Ranzani OT, 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 1.05 (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 PROFISCOV trial was 64.2% (7955 out of 12396 participants) [Palacios R, 2021 ].
Safety outcomes were not reported separately between gender groups.

The proportion of females in the 9026-ASI trial was 43% (4307 out of 10214 participants) [Tanriover MD, 2021 ].
Vaccine safety for this subgroup in the 9026-ASI trial has not yet been reported [Tanriover MD, 2021 ].
      
Age
Randomized trials
The proportion of patients 60 years or older in the PROFISCOV was 5.1% (632 out of 12396 participants) [Palacios R, 2021 ].

The proportion of patients 60 years of age and older in the CoronaVac3CL trial was 25% (37 out of 434 participants) [Susan M Bueno, 2021 ].

Significant differences were observed between age groups regarding the frequency of local and systemic AEs; where AEs occur more frequently in the younger group. Pain at the injection site was present in 47.1% of the 18 to 59 years old group, in contrast to 29.7% in the 60 years or older group (p-value = 0.009), while headache was present in 42.4% and 27.0%, respectively (p-value = 0.026) [Susan M Bueno, 2021 ].

PRO-nCOV-1002 was a study phase 1/2, sponsored by Sinovac Research and Development Co., Ltd. and conducted in Hebei Provincial Center for Disease Control and Prevention (CDC) in Renqiu (Hebei, China). It was registered with trial registry number ClinicalTrials.gov, NCT04383574. The trial included healthy adults aged 60 years or older. The sample size was 350 participants and their median age was 66.6 years. The proportion of fermales was 51%. Participants were randomly assigned in a 1:1 ratio, and Phase 1 of the trial was a dose-escalation study of 72 participants. The first group (36 participants) was randomly assigned to receive either 3 µg of vaccine or placebo. The second group (36 participants) was randomly assigned to receive either 6 µg vaccine or placebo. Phase 2 considered vaccine doses of 1.5 µg, 3 µg, or 6 µg and were compared with placebo. [Wu Z, 2021 ]

Children and adolescents
Randomized trials
Children were excluded from the CoronaVac3CL trial, so no safety data are available from participants 17 years old and younger. [Susan M Bueno, 2021 ]

Pro-nCOV-1003 is a phase 1/2 randomized, double-blind, placebo-controlled clinical trial sponsored by Sinovac Research and Development Co., Ltd. and conducted in China. It was registered under the registration number NCT04551547. The trial included healthy children and adolescents. The sample size was 552 participants, aged 3 to 17 years. [Sinovac Research and Development Co., Ltd., 2020 ]

Other comparative studies
Puspitarani F et al. was a cross-sectional study conducted in Indonesia that included 1,093 children between 6 and 11 years old, who received 2 doses of CoronaVac. The prevalence of adverse events following immunization (AEFIs) was 16.7% after the first dose and 22.6% after the second dose. The most common symptoms were local site pain and fever for the first dose, and cough and cold for the second dose. [Puspitarani F, 2022 ]

Pregnancy
Randomized trials
Pregnant females were excluded from the CoronaVac3CL trial, therefore no safety data is available [Susan M Bueno, 2021 ]. 

Other comparative studies
Huang et al. was a retrospective cohort study conducted in China 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. [Huang J, 2022 ]

Paixao ES et al was a test negative case-control study conducted in Brazil that included 19,838 pregnant women, 7,424 test-positive and 12,414 test-negative. Based on data from e-SUS Notifica, SIVEP-Gripe and SI-PNI, the study included participants with COVID-19 related symptoms from March to October 2021. The adjusted effectiveness of CoronaVac among pregnant women against symptomatic infection was 5% (95% CI, –18.2% to 23.6%) for one dose and 40.9% (95% CI, 27% to 52.2%) for two doses, the effectiveness against severe COVID-19 was 67.7% (95% CI, 20% to 87%) for one dose and 85.3 (95% CI, 59.4% to 94.8%) for two doses. [Paixao ES, 2022 ]

Breastfeeding
Randomized trials
No clinical trial evaluating vaccines to prevent COVID-19 has included breastfeeding women.

Immunocompromised persons
Randomized trials
Available data are currently insufficient to assess safety in immunocompromised persons.

Other comparative studies
The cohort study Balcells et al is currently evaluating this population [Pontificia Universidad Catolica de Chile, 2021 ].

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. This report included patients with systemic autoimmune myopathies aged 18 years and older. Results showed that Sinovac-related adverse events were mild with similar frequencies in patients and control group [University of Sao Paulo General Hospital, 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 ].

Safety of the vaccine post-authorization

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 BNT162b2 and CoronaVac vaccination 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 ].

Chui CSL et al. was a retrospective cohort study conducted in Hong Kong. The study evaluated the incident thromboembolic events or hemorrhagic stroke within 28 days of covid-19 vaccination with CoronaVac or Pfizer-BioNTech or SARS-CoV-2 positive test from February to September, 2021. The study included 4,492,167 vaccinated individuals (2,862,245 vaccinated with BNT162b2 and 1,629,922 vaccinated with CoronaVac) and 11,632 SARS-CoV-2 positive cases. The results showed that the crude incidence of thromboembolic events and hemorrhagic strokes per 100,000 administered doses of both COVID-19 vaccines was lower than per 100,000 SARS-CoV-2 test-positive cases. The risk of thromboembolic events following vaccination with CoronaVac was IRR 1.03 (95% CI: 0.83 to 1.27) and hemorrhagic stroke was 0.82 (95% CI: 0.48 to 1.41) [Chui CSL, 2022 ].

Wan EYF et al. was a self-controlled case series study conducted in Hong Kong. The study evaluated the incidence of 30 events of special interest after vaccination with CoronaVac between February 2021 and  January 2022.  The study included 622,317 vaccinated individuals aged 60 years old and above. The results showed that the incidence rate after CoronaVac was 0.00 (0.00–0.02) for Guillain-Barré syndrome, IR 0.03 (95% CI, 0.01–0.06) for myocarditis, IR 0.16  (95% CI, 0.12–0.22) for hemorrhagic disease, IR 0.19 (95% CI, 0.14–0.25) for Bell’s Palsy, IR 1.43 (95% CI, 1.28–1.60) for thromboembolism, IR 0.00 (95% CI, 0.00–0.02) for thrombocytopenia, IR 0.03 (95% CI, 0.01–0.06) for rhabdomyolysis and IR 0.25 (95% CI, 0.09–0.54) for anaphylaxis. [Wan EYF, 2022 ]

Wong CKH was a self controlled case series study conducted in China. The study included data from 2,288,239 vaccinated individuals: 1,321,753 with at least one dose of BNT162b2 and 966,486 with at least one dose of CoronaVac. This study used data from individuals who received COVID-19 vaccination between 23 February and 30 September 2021 from a population-based electronic health database in Hong Kong, linked to vaccination records. Following the second dose of COVID-19 vaccination, there was no increase in the risks of  anti-thyroid drug initiation. Incidence rate ratio of anti-thyroid drug initiation was 0.879 (95% CI, 0.693–1.116). Incidence rate ratio of Levothyroxine initiation was 0.768 (95% CI, 0.613-0.962). [Wong CKH, 2022 ]

Wang M et al was a comparative cohort study conducted in China. The study included 1,219 couples undergoing in vitro fertilization: 275 in the vaccinated group and 944 in the non vaccinated group. This study collected and analyzed the data on in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) to investigate the possible impacts of CoronaVac vaccination on male fertility, gamete/embryo development, and assisted reproductive technology outcomes. No statistically significant differences were exhibited between the matched cohorts regarding embryo developmental parameters, including fertilization rate, cleavage rate, high-quality embryo rate, blastocyst formation rate, and available blastocyst rate, as well as clinical outcomes, such as implantation rate, biochemical pregnancy rate, and clinical pregnancy rate.[Wang M, 2022 ]

Li x et al was a cohort study conducted in China. The study included 332,707 participants vaccinated with 2 doses of  CoronaVac vaccine, 388,881 participants with 2 doses of Pfizer vaccine and 1,892,783 unvaccinated participants. In this study, territory-wide longitudinal electronic medical records of Hong Kong Hospital Authority users (≥16 years) were linked with COVID19 vaccination records between February 23, 2021 and June 30, 2021. Cumulative incidences for all autoimmune conditions were below 9 per 100,000 persons, for both vaccines and both doses. [Li X, 2022 ]

Martins-Filho et al. conducted an observational, retrospective study based on secondary data to describe the adverse events following immunization (AEFI) related to the first 145,000 doses between January 19th and April 30th 2021 in Aracaju (Brazil). 145,133 doses of COVID-19 vaccine were administered: 85,587 were CoronaVac and 59,546 were Oxford–AstraZeneca. A total of 474 AEFIs (32.7 events/10,000 doses) from 254 individuals were reported and analyzed, and all of them were classified as non-serious. There was an association between the use of the CoronaVac vaccine and headache (OR = 2.1; 95% CI, 1.4–3.2), pain at the injection site (OR = 9.6; 95% CI, 3.9–23.8), lethargy (OR = 5.2; 95% CI, 1.8–14.8), fatigue (OR = 10.1; 95% CI: 2.4–42.3), diarrhea (OR = 4.4; 95% CI, 1.5–12.5) and cold-like symptoms (OR = 8.0; 95% CI, 1.9–34.0). However, the proportion of individuals reporting fever was higher among those who received the Oxford–AstraZeneca vaccine (OR = 3.1; 95% CI, 1.5–6.4). OR = Odds Ratio. [Martins-Filho, Paulo Ricardo, 2022 ]

Ye X et al. was a self-controlled case series conducted in China that included 32,490 heart failure patients. The study was based on data from the Hong Kong Hospital Authority, and evaluated the risk of hospitalization for heart failure after vaccination. The incidence Rate Ratio (IRR) for hospitalization for heart failure 14-27 days after vaccination was 0.91 (95% CI, 0.63–1.32) after the first dose, 0.79 (95% CI, 0.46–1.35) after the second dose and 1.71 (95% CI, 0.44–6.62) after the booster dose. [Ye X, 2022 ]


Non-comparative studies
Toniassoa SCC et al. was a non-comparative study conducted in Brazil, which included 7523 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 ].

Abanoub Riad, 2021 was a cross-sectional study conducted in Turkey. This study included 780 health workers, of whom 62.5% experienced at least one adverse event after the Sinovac COVID-19 vaccine [Abanoub Riad, 2021 ].

Kaya F et al. was a prospective study conducted in Turkey that included 322 participants vaccinated with two doses of Sinovac vaccine. The frequency ratio of those who declared having had serious adverse reactions after vaccination was 33.2%. The three most common serious systemic adverse reactions were headache, sleep state/fatigue, nausea, and vomiting [Kaya F, 2021 ].

García-Grimshaw M et al. conducted a non-comparative study in Mexico that reported the incidence of Guillain-Barré syndrome (GBS) following COVID-19 vaccination. The study informed the adverse events of 81,842,426 first or second doses of seven COVID-19 vaccines (Coronavac, Moderna, Pfizer, AstraZeneca, Sputnik V, CanSino, and Janssen), with 14,532,954 doses corresponding to the CoronaVac vaccine. 97 cases of GBS were identified through passive epidemiological surveillance, 10 of them related to the CoronaVac vaccination, with an unadjusted incidence of 0.69 (95% CI, 0.37-1.27) per million doses administered [García-Grimshaw M, 2022 ].

Toledo-Salinas et al. conducted a nationwide observational study among recipients of 61,414,803 doses of seven different COVID-19 vaccines, between December 2020 - October 2021 in Mexico, to identify the observed incidence of anaphylaxis in recipients of different anti-SARS-CoV-2 vaccines. Unadjusted incidence of anaphylaxis per million doses administered was 0.21 (95% CI 0.06–0.77) for Coronavac. [Toledo-Salinas C, 2022 ]

Apiwattanakul M et al was a retrospective study conducted in Thailand that included 221 patients diagnosed with immunization stress-related responses (stroke like symptoms) of whom 211 received CoronaVac. Between March 1st and July 31st 2021, medical records of 221 patients diagnosed with stroke-like symptoms following immunization were collected and analyzed. Most patients (68.9%) developed symptoms on the left side of the body and 99.5% of the patients receiving CoronaVac had a good outcome (modified Rankin scores ≤ 2, indicating slight or no disability). [Apiwattanakul M, 2022 ]

Monitoring

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

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

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

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

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

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