Sinopharm/WIBP COVID-19 vaccine
Sinopharm; China National Biotec group Co; Wuhan Institute of Biological Products
WIBP-CorV
Authorization
World Health Organization Emergency Use Listing Procedure
Not authorized.
Expression of interest under assessment [latest check of WHO EUL official website on January 12th 2023].
European Commission (based upon the recommendation of the European Medicines Agency)
Not authorized.
China's National Medical Products Administration
Authorization on February 27th 2021 [National Medical Products Administration, 2021 ].
Conditional marketing authorization for individuals aged 18 years and older.
Regulatory Authorities of Regional Reference in the Americas
National Administration of Drugs, Foods and Medical Devices (ANMAT, Argentina)
Not authorized.
Brazilian Health Regulatory Agency
Not authorized.
Health Canada
Not authorized.
Public Health Institute (Chile)
Not authorized.
National Institute of Food and Drug Monitoring (Colombia)
Not authorized.
Center for the State Control of Drug Quality (Cuba)
Not authorized.
U.S. Food and Drug Administration (FDA)
Not authorized.
Federal Commission for the Protection against Sanitary Risk (Mexico)
Not authorized.
Authorization in jurisdictions in Latin America and the Caribbean
Paraguay
Authorization in other jurisdictions
Philippines
Other countries might have also issued an authorization.
Manufacturing
General characteristics
The coronavirus inactivated vaccine is produced by inoculating the SARS-CoV-2 strain WIV04 in Vero cells, which are then cultured, harvested, inactivated, purified, concentrated, inactivated secondarily, purified again and finally aluminum hydroxide adjuvant is added. After inoculation with the vaccine, the body produces an immune response, which is expected to prevent the development of COVID-19 [Xia S, 2020 ].
The production process of the vaccine began with the isolation of a COVID-19 strain, named 2019-nCoV WIV04, from a patient from Jinyintan Hospital in late December 2019. The novel coronavirus strain showed to had good biological characteristics and therefore, could be used for vaccine production [Xia S, 2020 ].
The developing processes of the vaccine continue with the culturing of the virus in high glucose solution. After 72-96 hours of virus culture, the virus is then harvested, followed by β-propiolactone-inactivation at 2-8 °C for 48 hours. The inactivated virus is then clarified by microfiltration and centrifugation with different particle sizes. Then, is concentrated by using an ultrafiltration membrane. After, a second β-propiolactone-inactivation procedure is carried out, followed by gel-chromatography, ion-exchange chromatography, sterile filtration, formulation with buffer, and Aluminum hydroxide (Alum), filling, packaging, and labeling [Xia S, 2020 ].
Ingredients
The vaccine contains the following ingredients:
Active ingredient
6.5 U of inactivated SARS-CoV-2 antigen
Adjuvant
0.225 mg of aluminum hydroxide
Excipients
1.4 mg disodium hydrogen phosphate
0.1373 mg sodium dihydrogen phosphate
4.25 mg sodium chloride
Risk considerations
Inactivated vaccines have been successfully employed for more than 60 years. These vaccines are made from highly purified viruses that have been made noninfectious. The effectiveness of the vaccine depends primarily on the age and immunocompetence of the vaccine recipient and the degree of similarity between the viruses in the vaccine and those in circulation. Inactivated vaccines require the use of adjuvants which may cause undesirable reactions in vaccinated individuals. Most common reactions are, but not limited to: temporal fever, headache, diarrhea, cutaneous rush, nausea & vomiting, muscular pain and dizziness [Wang H., 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 Sinopharm/WIBP COVID-19 vaccine is administered as a series of two doses (0.5 mL each) with an interval of 3 to 4 weeks [FDA Philippines, 2021 ].
The pharmaceutical form is a suspension for intramuscular injection provided in a monodose vial of 0.5 mL.
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 [NMPA, 2022 ]
A booster dose should be given 6 months after the primary series using a protein subunit vaccine (Anhui Zhifei vaccine) or a viral vector-based one (CanSino vaccine).
Heterologous COVID-19 vaccine schedules [NMPA, 2022 ]
A heterologous booster schedule with protein subunit-based or viral vector- based vaccines is recommended.
Indications and contraindications
Indications
The Sinopharm/WIBP COVID-19 vaccine is indicated for individuals 18 years of age and over [NMPA, 2021 ].
Contraindications
The Sinopharm/WIBP COVID-19 vaccine is contraindicated in individuals with a known history of a severe allergic reaction to any component of Sinopharm/WIBP COVID-19 vaccine [NMPA, 2021 ]
(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 of Sinopharm/WIBP COVID-19 vaccine.
Precautions
Allergic reactions [NMPA, 2021 ]
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.
Pregnancy
The available data on Sinopharm/WIBP COVID-19 vaccine is insufficient to assess vaccine efficacy in pregnancy since no clinical trials have included pregnant women [NMPA, 2021 ].
Breastfeeding
The available data on Sinopharm/WIBP COVID-19 vaccine for breastfeeding women is insufficient to assess if there is any associated risk.
Children and adolescents [NMPA, 2021 ]
There are limited data on the efficacy or safety of persons below 18 years of age for this vaccine. Until more data are available, vaccination of individuals in this age range is not routinely recommended.
Older persons [NMPA, 2021 ].
Vaccination is recommended for older persons without an upper age limit
Persons with previous SARS-CoV-2 infection [NMPA, 2021 ]
Vaccination may be offered regardless of a person’s history of symptomatic or asymptomatic SARS-CoV-2 infection.
Persons with current acute COVID-19
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 [PAHO, 2020 ].
Other precautions [Ministerio de Salud Argentina, 2021 ].
As with other intramuscular injections, the vaccine should be given with caution in individuals with bleeding disorders or other conditions that increase the risk of bleeding, such as anticoagulant therapy, thrombocytopenia and hemophilia.
Vaccination should be postponed in individuals suffering from acute severe febrile illness, or acute infection.
Co-administration with other vaccines
There should be a minimum interval of 14 days between the administration of this vaccine with any other vaccine in the immunization schedule until data of co-administration are available.
Storage and logistics
Storage
Sinopharm/WIBP COVID-19 vaccine must be stored refrigerated between 2°C to 8°C [35° to 46°F] [FDA Philippines, 2021 ].
Unopened vaccine vials can be stored refrigerated between 2°C to 8°C [35° to 46°F] for up to 6 months [FDA Philippines, 2021 ].
The vials should be protected from the light and they should not be frozen or undergo refrigeration.
Administration logistics
Inspect the vial before use. Sinopharm/WIBP COVID-19 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.
The vial should not be shaken roughly.
Storage after first puncture
After the first puncture of the vial, preferably use immediately.
Record the date and time the vial should be discarded.
To improve traceability, the name and batch number of the administered product should be clearly recorded.
Administration
1. Using aseptic technique, clean the vial stopper with a single-use antiseptic swab.
2. Use a 3 mL reuse prevention syringe (RUP) or a 5 mL RUP syringe, and a 21G or narrower needle.
3. Gently invert the vial to mix, and withdraw the 0.5 mL dose. If the amount of vaccine remaining in the vial cannot provide a full 0.5 mL dose, discard the vial and the remaining volume.
4. Administer the vaccine intramuscularly, preferably into the deltoid muscle. Do not administer the vaccine intravascularly, subcutaneously, or intradermally.
Disposal
Due to the high risk that discarded vials of COVID-19 vaccines may be recovered, it is essential that they are guaranteed to be safely disposed of at the site of use; or study the possibility of applying reverse logistics, if the safe treatment and disposal of vaccine residues cannot be guaranteed, so that they are transferred to the place established for that purpose. Otherwise, consider the possibility that the discarded vaccine vials are shredded, if there is a safe way to do so [WHO, 2021 ].
Clinical studies - general characteristics
The following randomized clinical trials have reported vaccine efficacy and/or safety data:
Phase 1/2:
The WIBP2020001SQ trial (ChiCTR2000031809 [Henan Provincial Center for Disease Control and Prevention, 2020 ]) was conducted in China and initiated in April 2020. In phase 1, 96 participants were assigned to 1 of 3 dose groups (2.5, 5, and 10 μg/dose) and one group placebo (n = 24 in each group), received 3 intramuscular injections on days 0, 28, and 56. In phase 2, 224 adults were randomized to 5 μg/dose in 2 schedule groups (injections on days 0 and 14 [n = 84] versus placebo [n = 28], and days 0 and 21 [n = 84] vs placebo [n = 28]) [Xia S, 2020 ], [Guo W, 2021 ].
For the children and adolescent subgroups, 240 participated in phase 1 and 576 participants in phase 2 were randomly assigned to the vaccine or the control in three cohorts (3-5, 6-12, and 13-17 years) and in three groups depending on the dose (2.5, 5.0, and 10.0 μg/dose) they received 3 intramuscular injections on days 0, 28 and 56 [Xia S, 2022 ].
Phase 3:
The trial conducted by Al Kaabi et al. (NCT04510207, [China National Biotec Group Company Limited, 2020 ]) was designed in China and conducted in several countries. It included 40,382 participants aged 18 years or older with no history of SARS-CoV-2 infection. The participants were randomized in a 1:1:1 ratio to receive one of the two inactivated SARS-CoV-2 vaccines (Sinopharm/WIBP 5 ug/dose or Sinopharm/BIBP 4ug/dose) or aluminum hydroxide as a control group, administered 28 days apart [Al Kaabi N, 2021 ].
Vaccine efficacy and effectiveness
Efficacy of preclinical studies on the vaccine
An experiment on rats, half male and half female, were reported in the protocol of this vaccine that accompanies the publication of two phase 1/2 trials [Xia S, 2020 ]. 30 rats were randomly divided to assess immunization and determination of antibody response. The inactivated vaccine was administered to a first group in low dose (1 dose / rat) and to a second group in high dose (3 doses / rat), each dose contained 0.5 mL of vaccine. Antibody tests showed that the inactivated vaccine could induce neutralization of antibodies and the specific IgG antibody in rats. After two vaccinations, all animals in the low and high dose groups produced neutralizing antibodies, and the GMT of the neutralizing antibody in the low and high dose groups was 505 and 1 047 respectively [Shengli Xia, 2020 ].
Immunogenicity, was also tested in guinea pigs. 5 guinea pigs in each group, were inoculated subcutaneously with 3 doses (200 WU/dose) of vaccines on days 0, 7, and 14 and blood samples were collected on the same days. The results demonstrated a similar number to those obtained in mice and rats. The neutralizing antibody titer increased significantly with more vaccinations. Three vaccinations on days 7, 14, and 21 showed a good immune enhancing effect [Shengli Xia, 2020 ].
Similar results showed experiments in rabbits, that neutralizing antibody titer increased significantly when more vaccinations were provided. Vaccines can stimulate higher production of neutralizing antibodies when the interval between injections was prolonged [Shengli Xia, 2020 ].
Vaccinations in rhesus monkeys were performed on days 0 and 14, by intravascular injections, in doses of 200WU, 1000UW and adjuvant as control. There were two monkeys in the control group and three monkeys in the intervention groups. Blood samples were collected on days 0, 7, 14 and 21. The results showed that the vaccine had good immunogenicity and could stimulate a high production of neutralizing and binding antibodies in rhesus monkeys [Shengli Xia, 2020 ].
Efficacy of the vaccine in clinical trials
Main immunogenicity outcomes
Immunogenicity was evaluated in the phase 1/2 randomized trial WIBP2020001SQ [Xia S, 2020 ]. The trial included healthy adults, aged 18 to 59 years, without history of SARS-CoV or SARS-CoV-2 infection, that were randomly assigned in a 1:1 ratio to receive 3 vaccine dose groups (low, medium, and high doses with 2.5, 5, and 10 µg antigen protein content per dose, respectively, corresponding to 100, 200, and 400 vaccine units/dose). Neutralizing-antibody titers in the low, medium, and high-dose groups at day 14 after 3 injections were 316, 206, and 297, respectively. In participants receiving vaccine on days 0 and 14 and on days 0 and 21, mean titer were 121 and 247, respectively.
Key messages
Sinopharm/WIBP COVID-19 vaccine reduces the risk of contracting COVID-19
Sinopharm/WIBP COVID-19 vaccine reduces the risk of contracting severe COVID-19
Main efficacy outcomes of the Sinopharm/WIBP COVID-19 vaccine
Contracting COVID-19 (measured at least 14 days after the second injection)
The relative risk of contracting COVID-19 in the group that received Sinopharm/WIBP COVID-19 vaccine versus the group that received control vaccine was 0.36 (95% CI 0.25 to 0.51). This means Sinopharm/WIBP COVID-19 vaccine reduced the risk of contracting COVID-19 by 64%, compared with control vaccine.
Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19. Comparison: Sinopharm/WIBP COVID-19 vaccine versus control vaccine
In the trial identified in this review, 116 people not receiving Sinopharm/WIBP COVID-19 vaccine out of 13471 presented this outcome (86 per 10000) versus 42 out of 13470 in the group that did receive it (31 per 10000). In other words, 55 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.55%, or that the intervention reduced the risk of contracting COVID-19 by 0.55 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 182. Which means that 182 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 Sinopharm/WIBP COVID-19 vaccine versus the group that received control vaccine was 0.2 (95% CI 0.01 to 4.17). This means Sinopharm/WIBP COVID-19 vaccine reduced the risk of contracting severe COVID-19 by 80%, compared with control vaccine.
Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting severe COVID-19. Comparison: Sinopharm/WIBP COVID-19 vaccine versus control vaccine
In the trial identified in this review, 2 people not receiving Sinopharm/WIBP COVID-19 vaccine out of 13471 presented this outcome (1 per 10000) versus 0 out of 13470 in the group that did receive it (0 per 10000). In other words,1 less to 3 more people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.01%, or that the intervention reduced the risk of contracting severe COVID-19 by 0.01 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 10000. Which means that 10000 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.
Contracting symptomatic COVID-19 (measured at least 14 days after the second injection)
The relative risk of contracting symptomatic COVID-19 after the second dose (<14 days) in the group that received Sinopharm/WIBP COVID-19 vaccine versus the group that received control vaccine was 0.27 (95% CI 0.18 to 0.42). This means Sinopharm/WIBP COVID-19 vaccine reduced the risk of contracting symptomatic COVID-19 after the second dose (<14 days) by 73%, compared with control vaccine.
Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting symptomatic COVID-19 after the second dose (<14 days). Comparison: Sinopharm/WIBP COVID-19 vaccine versus control vaccine
In the trial identified in this review, 95 people not receiving the Sinopharm/WIBP COVID-19 vaccine out of 12737 presented this outcome (75 per 10000) versus 95 out of 12737 in the group that did receive it (21 per 10000). In other words, 54 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.54%, or that the intervention reduced the risk of Sinopharm/WIBP COVID-19 vaccine by 0.54 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 185. This means that 185 people need to receive the vaccine for one of them to not contracting symptomatic COVID-19 after the second dose (<14 days).
Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.
Contracting COVID-19 (Female) (measured at least 14 days after the second injection)
The relative risk of contracting COVID-19 (Female) in the group that received Sinopharm/WIBP COVID-19 vaccine versus the group that received control vaccine was 0.23 (95% CI 0.07 to 0.83). This means Sinopharm/WIBP COVID-19 vaccine reduced the risk of contracting COVID-19 (Female) by 77%, compared with control vaccine.
Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (Female). Comparison: Sinopharm/WIBP COVID-19 vaccine versus control vaccine
In the trial identified in this review, 12 people not receiving Sinopharm/WIBP COVID-19 vaccine out of 1903 presented this outcome (63 per 10000) versus 3 out of 2037 in the group that did receive it (15 per 10000). In other words,59 less to 11 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.48%, or that the intervention reduced the risk of Sinopharm/WIBP COVID-19 vaccine by 0.48 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 208. Which means that 208 people need to receive the vaccine for one of them to not contracting COVID-19 (Female).
Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.
Contracting COVID-19 (Males) (measured at least 14 days after the second injection)
The relative risk of contracting COVID-19 (Males) in the group that received Sinopharm/WIBP COVID-19 vaccine versus the group that received control vaccine was 0.28 (95% CI 0.18 to 0.44). This means Sinopharm/WIBP COVID-19 vaccine reduced the risk of contracting COVID-19 (Males) by 72%, compared with control vaccine.
Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (Males). Comparison: Sinopharm/WIBP COVID-19 vaccine versus control vaccine
In the trial identified in this review, 83 people not receiving Sinopharm/WIBP COVID-19 vaccine out of 10805 presented this outcome (77 per 10000) versus 23 out of 10706 in the group that did receive it (22 per 10000). In other words,63 less to 43 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.55%, or that the intervention reduced the risk of Sinopharm/WIBP COVID-19 vaccine by 0.55 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 182. Which means that 182 people need to receive the vaccine for one of them to not contracting COVID-19 (Males).
Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.
Contracting COVID-19 (≥60y) (measured at least 14 days after the second injection)
No incident cases of COVID-19 occurred in participants of 60 years or more in the phase 3, randomized trial, thus efficacy was not calculated [Al Kaabi N, 2021 ].
Applying the GRADE approach [Al Kaabi N, 2021 ], we assessed the certainty of the evidence for this outcome as high.
Efficacy and effectiveness of the vaccine in subgroups
Sex
Randomized trials
Efficacy profile of the Sinopharm/WIBP COVID-19 vaccine was not evaluated across sex groups.
Edad
Randomized trials
The efficacy profile of the Sinopharm / WIBP vaccine against COVID-19 was not evaluated in all age groups.
Children and adolescents
Randomized trials
Children were excluded from the WIBP2020001SQ, therefore no data are available for this subgroup [Xia S, 2020 ].
Pregnancy
Randomized trials
Pregnant females were excluded from the WIBP2020001SQ, therefore no data are available for this subgroup [Xia S, 2020 ].
Breastfeeding
Randomized trials
Breastfeeding females were excluded from the WIBP2020001SQ, therefore no data are available for this subgroup [Xia S, 2020 ].
Immunocompromised persons
Randomized trials
Immunocompromised participants were excluded from the WIBP2020001SQ, therefore no data are available for this subgroup [Xia S, 2020 ].
Vaccine effectiveness (other comparative studies)
Contracting COVID-19
No studies reported or assessed this outcome
Contracting severe COVID-19
No studies reported or assessed this outcome
Transmission
No studies reported or assessed this outcome
Efficacy and effectiveness against SARS-CoV-2 variants
Immunogenicity outcomes
Currently, there are no studies that have assessed the vaccine immunogenicity outcomes against SARS-CoV-2 variants
Effectiveness outcomes
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 efficacy of the Sinovac and Sinopharm vaccines (BIBP and WIBP) against COVID-19 infection for 14 days or more after receiving the second dose. The results showed that the 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% [Li XN, 2021 ].
Min Kang et al. was a comparative cohort study in China, which included 10,813 healthy adults. The study evaluated the efficacy of the inactivated Sinovac, Sinopharm (BIBP and WIBP) and Biokangtai vaccine against COVID-19 infection for 14 days or more after receiving the second dose. The results showed an effectiveness against symptomatic COVID-19 infection of 69.5% (95% CI: 42.8 to 96.3) and an efficacy against severe COVID-19 infection of 100% [Min Kang, 2021 ].
Vaccine efficacy and effectiveness for booster dose
No studies reported or assessed this outcome
Vaccine efficacy and effectiveness for heterologous schedule
Immunogenicity outcomes
One randomized clinical trial has included heterologous vaccine schemes [Henan Provincial Center for Disease Control and Prevention, 2020 ] but their results are still not published.
Wang X et al was a cohort study conducted in China including 403 individuals between 18 and 59 years old: 275 Sinopharm/WIBP (WIBP-CorV) + Sinopharm/BIBP (BIBP-CorV) recipients, and 133 Sinopharm/BIBP + Sinopharm/BIBP recipients. The study compared the immunogenicity of both primary schedules. Sera of participants was obtained 1, 2, and 6 months after the second doses, and neutralizing antibody titers were measured. The GMT of neutralizing antibodies at 1 month was 21.33 (95% CI, 19.62–23.18) in the WIBP+BBIBP group and 22.45 (95% CI, 20.16–24.99) in the BBIBP+BBIBP group. At 2 months GMT was 16.80 (95% CI, 15.28–18.47) in the WIBP+BBIBP group and 19.28 (95% CI, 17.48–21.25) in the BBIBP+BBIBP group. At 6 months GMT was 3.56 (95% CI, 3.28–3.86) in the WIBP+BBIBP group and 5.36 (95% CI, 4.56–6.31) in the BBIBP+BBIBP. [Wang X, 2022 ].
Vaccine efficacy and effectiveness for heterologous booster schedule
Immunogenicity outcomes
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 ]
Safety of the vaccine
Safety of the vaccine in preclinical studies
An experiment in specific pathogen-free male Hartley guinea pigs was reported in the protocol of this vaccine that accompanies the publication of two phase 1/2 trials [Xia S, 2020 ]. Thirty six animals were randomized to high-dose vaccine group, low-dose vaccine group, negative control group, and positive control group. Vaccines were injected intramuscularly on days 1, 3, and 5 (0.1-1 ug/dose) and then injected intravenously on days 19 or 26 (0.2-2ug/dose). Regarding safety, the vaccine did not cause active systemic anaphylaxis [Shengli Xia, 2020 ].
Twenty rats were randomly divided into two groups; control group and vaccine test group, there were 5 male and 5 female rats in each group. Each rat in negative control group received 2 mL of sodium chloride injection intramuscularly, while each rat in vaccine test group received 2 mL/4 doses of inactivated vaccine (Vero cell). Acute toxic reaction symptoms were observed for four hours after injection among all animals and also during 14 days after inoculation. Results showed rats did not demonstrate abnormal reactions. The maximum tolerance dose (MTD) per animals was greater than 4 doses for each rat [Xia S, 2020 ].
150 rats, half male and half female, were randomly divided into 7 groups. There were 120 rats in the main experimental group used for toxicological study. All animals were given intramuscular injection once a week for 2 consecutive weeks (a total of 3 times) of vaccine or placebo. The inactivated vaccine (Vero cells) was administered in 0.5 mL of vaccine dose. The negative control group received 1.5 mL/rat of sodium chloride injection, and the adjuvant control group received 1.5 mL/rat of control adjuvant. Clinical observation and measurements were performed on each animal. During the experiment, no animals died and no abnormal reactions related to vaccines were observed. Compared with the animals from negative control group, there were no significant differences in body weight, food intake, body temperature, ophthalmology examination and clinical pathology [Xia S, 2020 ].
The inactivated vaccine was injected into Macaca Fascicularis by 1 dose and 4 doses each time. The injections were given weekly or biweekly for four consecutive weeks (a total of four times). The animals had no obvious systemic toxic reaction during the period between vaccinations and the end of two-week recovery period. During the period between vaccinations and the end of two-week recovery period, there were irritative effects related to aluminum adjuvants on injection sites. Immune toxicity was not observed [Xia S, 2020 ].
Safety of the vaccine in clinical trials
Key messages
Sinopharm/WIBP COVID-19 vaccine did not increase the risk of any adverse events.
Sinopharm/WIBP COVID-19 vaccine did not increase the risk of serious adverse events.
Main safety outcomes of Sinopharm/WIBP COVID-19 vaccine
Any adverse event (mean follow up: 3.4 months)
The relative risk of any adverse event in the group that received Sinopharm/WIBP COVID-19 vaccine versus the group that received control vaccine was 0.96 (95% CI 0.93 to 0.98). This means Sinopharm/WIBP COVID-19 vaccine reduced the risk of any adverse event by 4%, compared with control vaccine.
Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event . Comparison: Sinopharm/WIBP COVID-19 vaccine versus control vaccine
In the trial identified in this review, 6505 people not receiving Sinopharm/WIBP COVID-19 vaccine out of 13453 presented this outcome (4835 per 10000) versus 6237 out of 13464 in the group that did receive it (4632 per 10000). In other words,318 less to 85 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 2.03%, or that the intervention reduced the risk of Sinopharm/WIBP COVID-19 vaccine by 2.03 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 49. Which means that 49 people need to receive the vaccine for one of them to not suffering any adverse event .
Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.
Local adverse events (at least 7 days after any injection)
The relative risk of local adverse events in the group that received Sinopharm/WIBP COVID-19 vaccine versus the group that received control vaccine was 0.88 (95% CI 0.85 to 0.92). This means Sinopharm/WIBP COVID-19 vaccine reduced the risk of local adverse events by 12%, compared with control vaccine.
Figure - Forest plot of risk ratio meta-analysis. Outcome: local adverse events. Comparison: Sinopharm/WIBP COVID-19 vaccine versus control vaccine
In the trial identified in this review, 3906 people not receiving Sinopharm/WIBP COVID-19 vaccine out of 13453 presented this outcome (2903 per 10000) versus 3450 out of 13464 in the group that did receive it (2562 per 10000). In other words,439 less to 239 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 3.41%, or that the intervention reduced the risk of Sinopharm/WIBP COVID-19 vaccine by 3.41 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 29. Which means that 29 people need to receive the vaccine for one of them to not suffering local adverse events.
Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.
Systemic adverse events (at least 7 days after any injection)
The relative risk of systemic adverse events in the group that received Sinopharm/WIBP COVID-19 vaccine versus the group that received control vaccine was 0.99 (95% CI 0.95 to 1.03). This means Sinopharm/WIBP COVID-19 vaccine reduced the risk of systemic adverse events by 1%, compared with control vaccine.
Figure - Forest plot of risk ratio meta-analysis. Outcome: systemic adverse events. Comparison: Sinopharm/WIBP COVID-19 vaccine versus control vaccine
In the trial identified in this review, 3743 people not receiving Sinopharm/WIBP COVID-19 vaccine out of 13453 presented this outcome (2782 per 10000) versus 3695 out of 13464 in the group that did receive it (2744 per 10000). In other words,142 less to 70 more people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.38%, or that the intervention reduced the risk of Sinopharm/WIBP COVID-19 vaccine by 0.38 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 263. Which means that 263 people need to receive the vaccine for one of them to not contract systemic adverse events.
Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.
Serious adverse events (mean follow up: 4.1 months)
The relative risk of serious adverse events in the group that received Sinopharm/WIBP COVID-19 vaccine versus the group that received control vaccine was 0.82 (95% CI 0.59 to 1.14). This means Sinopharm/WIBP COVID-19 vaccine reduced the risk of serious adverse events by 18%, compared with control vaccine.
Figure - Forest plot of risk ratio meta-analysis. Outcome: serious adverse events. Comparison: Sinopharm/WIBP COVID-19 vaccine versus control vaccine
In the trial identified in this review, 78 people not receiving Sinopharm/WIBP COVID-19 vaccine out of 13453 presented this outcome (58 per 10000) versus 64 out of 13464 in the group that did receive it (48 per 10000). In other words,24 less to 8 more people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.1%, or that the intervention reduced the risk of Sinopharm/WIBP COVID-19 vaccine by 0.1 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNT is 1000. Which means that 1000 people need to receive the vaccine for one of them to not contract serious adverse events.
Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.
Safety of the vaccine in subgroups
Sex
Randomized trials
Safety profile of the Sinopharm/WIBP vaccine was not evaluated across sex groups.
Age groups
Randomized trials
Safety profile of the Sinopharm/WIBP vaccine was not evaluated across sex groups.
Children and adolescents
Randomized trials
WIBP2020001SQ was a clinical trial conducted in healthy children between 3 and 17 years old and aimed to evaluate the safety and immunogenicity of the Sinopharm WIBP vaccine. 240 children participated in phase 1, and 576 in phase 2 of the trial, separated into 3 cohorts and in vaccine doses of 2.5, 5.0, and 10.0 ug per dose receiving 3 doses at 0, 28, and 56 days. The most common adverse events were mild (grade 1) pain at the injection site, followed by fever (grade 1 or 2), which was reported by 19 (7.5%) of 252 participants in all three doses [Xia S, 2022 ].
Pregnancy
Randomized trials
Pregnant females were excluded from the WIBP2020001SQ, so no data are available for this subgroup [Xia S, 2020 ].
Breastfeeding
Randomized trials
Breastfeeding females were excluded from the WIBP2020001SQ, so no data are available for this subgroup [Xia S, 2020 ].
Immunocompromised persons
Randomized trials
Immunocompromised participants were excluded from the WIBP2020001SQ, so no data are available for this subgroup [Xia S, 2020 ].
Safety of the vaccine post-authorization
Monitoring
WHO indicates that after a vaccine is approved for use, regulators conduct robust monitoring of efficacy, as well as monitoring of safety and risk minimization (pharmacovigilance) activities. They need to continually monitor the safety of the vaccine to ensure that the benefits of the vaccine continue to outweigh the risks. [WHO, 2022 ]
Regarding safety surveillance and monitoring, serious adverse events, anaphylaxis and other severe allergic reactions, Bell's palsy, cases of multisystem inflammatory syndrome, cases of COVID-19 after vaccination resulting in hospitalization or death should be identified and recorded.
Regarding the effectiveness of the vaccine, the following should be monitored:
− Efficacy of the vaccine over time and whether protection can be prolonged with booster doses.
− Studies to investigate whether this vaccine reduces the transmission and viral spread of SARS-CoV-2.
− Evaluation and notification of vaccine failures and information on viral sequences.
Regarding the subgroups of interest
− Prospective studies on the safety of the COVID-19 vaccine in pregnant and lactating females.
− Occasional controlled trials on the safety and security of vaccination in children under 18 years of age.
− Safety data from vaccination in immunosuppressed people, including patients living with HIV and autoimmune diseases.
To review more information on the topic [WHO, 2022 ],[World Health Organization, 2021 ], [Organización Mundial de la Salud, 2022 ]
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