Sinopharm/BIBP COVID-19 vaccine

Extended version of the vaccine

Sinopharm/BIBP COVID-19 vaccine

Authorization

World Health Organization Emergency Use Listing Procedure
Listed for emergency use
Status of assessment: finalized May 7, 2021 [WHO, 2021 ]
EUL/WHO Authorization: Authorized for emergency use in individuals 18-59 years of age [WHO, 2021 ].
SAGE/WHO Recommendation: Individuals aged 18 years and above [World Health Organization, 2021 ]

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

China's National Medical Products Administration
Authorized [National Medical Products Administration of China, 2020 ].
31 December 2020
Conditional Marketing Authorization in individuals 18 years of age and older.

Regulatory Authorities of Regional Reference in the Americas

National Administration of Drugs, Foods and Medical Devices (ANMAT, Argentina)
Authorized for emergency use: 21 February, 2021 [Fundación Femeba, 2021 ]

Brazilian Health Regulatory Agency (ANVISA, Brazil)
Not authorized

Health Canada
Not authorized

Public Health Institute (ISP, Chile)
Not authorized

National Institute of Food and Drug Monitoring (INVIMA, Colombia)
Not authorized

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

U.S. Food and Drug Administration
Not authorized

Federal Commission for the Protection against Sanitary Risk (COFEPRIS, Mexico)
Not authorized

Authorization in other jurisdictions in the Americas
Bolivia
Dominica
Guyana
Paraguay
Peru
Venezuela
Authorization in other jurisdictions
Angola
Bahrain
Bangladesh
Belarus
Belize
Brunei
Cambodia
Cameroon
Chad
China
Congo
Egypt
Equatorial Guinea
Gabon
Gambia
Georgia
Hungary
Indonesia
Iran
Iraq
Jordan
Kyrgyzstan
Laos
Lebanon
Malaysia
Maldives
Mauritania
Mauritius
Mongolia
Montenegro
Morocco
Mozambique
Namibia
Nepal
Niger
North Macedonia
Pakistan
Philippines
Senegal
Serbia
Seychelles
Sierra Leone
Solomon Islands
Somalia
Sri Lanka
Thailand
Trinidad and Tobago
Tunisia
United Arab Emirates
Vietnam
Zimbabwe

Manufacturing

Manufacturer
Beijing Institute of Biological Products Co. Ltd.; China. Manufacturer of the inactivated vaccine against COVID-19.
Other manufacturers
G42 Healthcare; Dubai, United Arab Emirates. Production and filling of Sinopharm/BIBP COVID-19 vaccine in the UAE. The vaccine will be called Hayat-Vax when manufactured in the UAE, but is the same inactivated vaccine from the Beijing Institute of Biological Product (BiBP) [Arabian Business, 2021 ].

General characteristics

Sinopharm/BIBP COVID-19 vaccine is an inactivated vaccine that consists of virus particles that have been grown in culture and then were inactivated to lose disease-producing capacity, while still stimulating an immune response. Three SARS-CoV-2 strains were isolated from the bronchoalveolar lavage samples or throat swabs of hospitalized patients from a COVID-19 outbreak to develop preclinical in vitro neutralization and challenge models for an inactivated SARS-CoV-2 vaccine candidate. The three strains were 19nCoV-CDC-Tan-HB02 (HB02), 19nCoV-CDC-Tan-Strain03 (CQ01) and 19nCoV-CDC-Tan-Strain04 (QD01) [Wang H., 2020 ].

HBO2 strain showed optimal replication and generated the highest virus yields in Vero cells among the three viral strains. Therefore the HB02 strain was selected for the development of the inactivated SARS-CoV-2 vaccine (BBIBP-CorV) [Wang H., 2020 ].

Dosage form and ingredients
The pharmaceutical form is a suspension for intramuscular injection that is provided in a monodose vial of 0.5 ml.

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. 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 require the use of adjuvants which may cause undesirable reactions in vaccinated individuals [Wang H., 2020 ].

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

Dosification and schedule

Dose-finding studies
[Xia, Shengli, 2021 ] was a dose-finding, randomized, phase 1/2 trial sponsored by Sinopharm. It was registered with the trial registry number ChiCTR2000032459.
The trial included healthy participants ≥18 years.
The sample size was 192 (6 cohorts of 32). The mean age of the participants was 53.7 in the whole study. Participants were 47% male, 53% female; 50% aged 18-59 years, 50% aged ≥60 years.
Participants were randomly assigned in a 3:1 ratio to receive Sinopharm COVID-19 vaccine (2µg, 4µg or 8µg) or placebo.
For vaccine recipients in the group aged 18-59 years, 19 (79%) of 24 in the 2 µg group, 21 (87%) of 24 in the 4 µg group, and 23 (96%) of 24 in the 8 µg group seroconverted by day 14. Seroconversion rates reached 100% in all three cohorts on day 28. For vaccine recipients in the group aged 60 years and older, eight (4%) of 23 in the 2 µg group and 11 (46%) of 24 in each of the 4 µg and 8 µg groups seroconverted by day 14. 21 (91%) of 23 in the 2 µg group, 22 (92%) of 24 in the 4 µg group, and 22 (96%) of 23 in the 8 µg group seroconverted by day 28. The neutralizing antibodies in all placebo recipients were negative throughout the trials [Xia, Shengli, 2021 ].

There is no data available on the interchangeability of the Sinopharm/BIBP COVID-19 vaccine with other COVID-19 vaccines to complete the vaccination series.
There is no evidence yet about the effects of the coadministration of Sinopharm/BIBP COVID-19 vaccine with other vaccines included in routine vaccination programs

Indications and contraindications

Indications
Sinopharm/BIBP COVID-19 vaccine is indicated in individuals aged 18 years and above [World Health Organization, 2021 ].
Contraindications
The vaccine is contraindicated in individuals with a known history of a severe allergic reaction to any component of the vaccine.
The second dose of the vaccine should NOT BE GIVEN to those who have experienced anaphylaxis to the first dose.
Exacerbation of chronic diseases, which imply compromise of the general state [Ministerio de Salud Argentina, 2021 ].
The vaccine is contraindicated in individuals with a known history of a severe allergic reaction to any component of vaccines [Ministerio de Salud Argentina, 2021 ].
Uncontrolled epilepsy or other progressive neurological disorder [Ministerio de Salud Argentina, 2021 ].

Precautions
Severe allergic reaction (e.g. anaphylaxis) to a previous dose of any vaccine (not including Sinopharm/BIBP COVID-19 vaccine).
In general, persons with an immediate non-anaphylactic allergic reaction to the first dose should not receive additional doses, unless recommended after review by a health professional with specialist expertise.
As a small number of anaphylactic reactions have also been reported in vaccines without a history of anaphylaxis, it is recommended that Sinopharm/BIBP COVID-19 vaccine should be administered only in settings where anaphylaxis can be treated.
Severe allergic reaction (e.g. anaphylaxis) to an injectable medication.
Vaccination should be postponed in individuals suffering from acute severe febrile illness, or acute infection [Ministerio de Salud de Perú, 2021 ].
Reactions related to stress or anxiety, such as syncope or hyperventilation may occur in association with vaccination as a psychogenic response to the needle injection. It is important that precautions are in place to avoid injury from fainting.
As with other intramuscular injections, the vaccine should be given with caution in individuals with bleeding disorders or other conditions that increase the risk of bleeding, such as anticoagulant therapy, thrombocytopenia, and hemophilia [Ministerio de Salud de Perú, 2021 ].
The available data on Sinopharm/BIBP COVID-19 vaccine on pregnant females are insufficient to assess vaccine efficacy in pregnancy since no clinical trial evaluating vaccines to prevent COVID-19 has included pregnant females. The vaccine should only be given to pregnant females if the risks outweigh the benefit.
The available data on Sinopharm/BIBP COVID-19 vaccine on lactating females are insufficient to assess whether the vaccine is excreted in human milk or if there is any associated risk.
The available data on Sinopharm/BIBP COVID-19 vaccine on children are insufficient to assess vaccine efficacy since no clinical trial evaluating vaccines to prevent COVID-19 has included children.
There should be a minimum interval of 14 days between the administration of this vaccine with any other vaccine in the immunization schedule until data on co-administration with other vaccines are available.
Vaccination may be offered regardless of a person‘s history of symptomatic or asymptomatic SARS-CoV-2 infection.
Although there are currently no medical contraindications on the vaccinating of a person with COVID-19, it is recommended to defer all vaccinations until complete recovery [PAHO, 2020 ].
Although there are currently no contraindications on the vaccinating of a person who has had contact with a COVID-19 case, it is recommended to defer vaccination until the quarantine has been completed (14 days after the last exposure) [PAHO, 2020 ].

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

Storage and logistics

Storage
Sinopharm/BIBP COVID-19 vaccine is stored and transported as a refrigerated suspension between 2°C to 8°C (36°F to 46°F) [WHO, 2021 ].
The shelf life of Sinopharm/BIBP COVID-19 vaccine of up to 24 months stored between 2 ° C and 8 ° C (36 ° F to 46 ° F) [WHO, 2021 ]
Do not apply dry ice to the package or the vials as a method of refrigeration

Protect the vials from light.
Do not freeze

Logistic at the time of administration
Inspect the vial before use. SINOPHARM vaccine is an opalescent, injectable suspension with possible precipitate formation that must be resuspended by inverting the vial several times to mix [Ministerio de Salud Argentina, 2021 ].
The vial should be discarded if particles or differences are observed in the described appearance of the vaccine.
Do not shake the vial roughly.

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

Randomized trials
Al Kaabi N et al [Al Kaabi N, 2021 ] was a phase 3, randomized, double-blind, placebo-controlled, sponsored by China National Biotec Group Company Limited and conducted in China. It was registered with clinical trial number NCT04510207 [China National Biotec Group Company Limited, 2020 ] and ChiCTR2000034780 [China National Biotec Group Co.Ltd , 2020 ]. The trial included healthy people aged 18 years and more, who were negative for serum-specific IgM/IgG antibodies against SARS-CoV-2. The sample size was 40382. The mean age of the participants was 36 years and the proportion of females was 15.6%. Participants were each randomly assigned to receive two doses of 4 µg of Sinopharm/BIBP, 5 µg of Sinopharm/WIBP vaccine or placebo in a 1:1:1 ratio. Therefore, 13471 participants received Sinopharm/BIBP COVID-19 vaccine and 13453 participants received placebo.

Xia S et al [Xia, Shengli, 2021 ] was a dose-escalation, randomized, double-blind, placebo-controlled, phase 1/2 trial sponsored by Center for Disease Control and Prevention, Liangyuan District, Shangqiu City, Henan Province, China and conducted in China. It was registered with clinical trial number ChiCTR2000032459).
The trial included healthy people aged 18-80 years, who were negative for serum-specific IgM/IgG antibodies against SARS-CoV-2.
The sample size was 192. The mean age of the participants was 54 years and the proportion of females was 50%.
Participants were each randomly assigned to receive two doses of 2 µg, 4 µg, or 8 µg of vaccine or placebo in a 3:1 ratio. Therefore, 144 participants received vaccine and 48 participants received placebo.


Ongoing randomized trials
Redouane A et al is a phase 3 randomized trial (registered with the ChiCTR2000039000 [China National Biotec Group Co.Ltd , 2020 ]) sponsored by China National Biotec Group Co.Ltd that is being conducted in Morocco. It was first registered in October 2020 and has enrolled 600 adults 18 years of age or older that received vaccine or placebo in a 1:1 ratio. It is expected to run until a date not yet reported.

ECEHeVac is an ongoing randomized, open, multicenter trial (registered with the number NCT04988048 [Ministry of Public Health, Argentina, 2021 ]) sponsored by the Ministry of Public Health, Argentina that is being conducted in Argentina. It was first registered in August 2021 and plans to enroll 1760 adults 18 year of age or older that will receive different vaccines to evaluate the immunogenicity and reactogenicity of the heterologous vaccination schedules made up of the combination of vaccines available in Argentina (Sputnik-V, AstraZeneca, Sinopharm and Moderna); and to compare the immunogenicity and reactogenicity of heterologous and homologous vaccination schedules. It is expected to run until February 2022.

Cov-Peru is an ongoing phase 3 trial (registered with the number NCT04612972 [Universidad Peruana Cayetano Heredia, 2020 ]) sponsored by Universidad Peruana Cayetano Heredia that is being conducted in Perú. It was first registered in November 2020 and plans to enroll 6000 healthy adults ≥ 18 years of age that will receive the inactivated SARS CoV 2 vaccine (Vero cell). It is expected to run until September 2021.

CNBG2020003SQ is an ongoing randomized, phase 3 trial (registered with the number NCT04510207 [China National Biotec Group Company Limited, 2020 ]) sponsored by China National Biotec Group Company Limited that is being conducted in Bahrain, Egypt, Jordan and the United Arab Emirates. It was first registered in August, 2020 and plans to enroll 45000 healthy individuals aged 18 years old and above. It will evaluate the efficacy, safety and immunogenicity of inactivated sars-cov-2 vaccines (vero cell). It is expected to run until September, 2021.

Eshaghi A et al is an ongoing phase III, randomized, double blind, trial (registered with the number IRCT20201214049709N3 [REF_ERR]) sponsored by Razi Vaccine and Serum Research Institute that is being conducted in Iran. It was first registered in August 2021 and plans to enroll 41128 adults 18 year of age or older that will receive different vaccines the study will compare the safety and efficacy of recombinant spike protein COVID-19 vaccine developed by RAZI institute (Razi Cov Pars) and the Sinopharm vaccine. It is expected to run until a date not yet reported.

Farahani R et al is an ongoing randomized, double blind, controlled trial with parallel design (registered with the number IRCT20210206050259N3 [REF_ERR]) sponsored by Organization of Defensive Innovation and Research that is being conducted in Iran. It was first registered in August 2021 and plans to enroll 41128 adults 18 year of age and older that will receive different vaccines. The study will compare the safety, immunogenicity and efficacy of Fakhravac and Sinopharm SARS-CoV-2 vaccines. It is expected to run until a date not yet reported.
BIBP2020003AR is an ongoing randomized, phase 3 trial (registered with the number NCT04560881 [Laboratorio Elea Phoenix S.A., 2020 ]) sponsored by Laboratorio Elea Phoenix S.A. that is being conducted in Argentina. It was first registered in September, 2020 and plans to enroll 3000 healthy people aged between 18 and 85 years. The objective is to evaluate the efficacy, immunogenicity and safety of the inactivated vaccine. It is expected to run until December, 2021.

Al Kaabi N et al. is an ongoing phase 3 trial (registered with the number ChiCTR2000034780 [China National Biotec Group Co.Ltd , 2020 ]) sponsored by China National Biotec Group Co.Ltd, which is being conducted in China. It was first registered in July, 2020 and plans to enroll 4500 healthy adults ≥ 18 years of age. The objective is to evaluate the protective efficacy of inactivated SARS-CoV-2 Vaccine (Vero Cell) after full course of immunization in preventing diseases caused by the SARS-CoV-2. It is expected to run until July, 2021.

Other studies providing efficacy or safety data
Abu-Hammad et al was a safety monitoring non-comparative study conducted in Jordan. The study enrolled 409 healthcare personnel (nurses, dentists or doctors) participants that received AstraZeneca Vaxzevria (AZ), PfizerBioNTeck (PB), and SinoPharm (SP) vaccines. Based on data from a distributed a questionnaire among physicians, dentists and nurses who received a COVID-19 vaccine to explore the side effects (SE) [Abu-Hammad O., 2021 ].
Almufty HB et al was a safety monitoring non-comparative study conducted in Iraq. The study enrolled 1,012 healthy adults participants that received AstraZeneca Vaxzevria (AZ), PfizerBioNTeck (PB), and SinoPharm (SP) vaccines. Based on data from a distributed questionnaire among Iraqi citizen [Almufty HB, 2021 ].

Other ongoing registered studies
NJGLVAC-001 is an ongoing prospective cohort study (registered with the number NCT04729374 [The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, 2021 ]) sponsored by the Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, that is being conducted in China. It was first registered in January, 2021 and plans to enroll 200 adults 18 to 59 years of age. The objective is to analyze the vaccine´s immune response. It is expected to run until December, 2023.

AssiutU21 is an ongoing prospective cohort study (registered with the number NCT04706143 [Assiut University, 2021 ]) sponsored by Assiut University, that is being conducted in Egypt. It was first registered in January, 2021 and plans to enroll 100 adults 25 to 65 years of age. It will evaluate the immune responses in adults, up to 8 weeks after vaccination with a single or double dose of different vaccines, including: inactivated (Sinopharm), mRNA (Pfizer/ BioNTech) and viral vector (Oxford/AZ- ChAdOx1 nCoV-19) vaccines. It is expected to run until August, 2021.

Anis M et al is an ongoing observational, prospective study (registered with the number NCT04946565 [Cairo University, 2021 ]) sponsored by Cairo University that is being conducted in Egypt. It was first registered in July 2021 and plans to enroll 100 male adults between 18 to 50 year of age that will receive the inactivated vaccine. The study will assess the impact of sinopharm covid-19 vaccination on male fertility of the Egyptian population. It is expected to run until August 2022.

Methods used to assess efficacy and effectiveness

Al Kaabi N trial [Al Kaabi N, 2021 ]
Primary efficacy endpoint
Number of participants with a first occurrence of COVID-19 starting 14 days after second untill 6 motnth after the second dose evaluated with a positive PCR test or with clinical or radiographic evidence of SARS-CoV-2 infection
Secondary efficacy endpoint
The incidence of severe cases of SARS-CoV-2 pneumonia and deaths accompanied by COVID-19 after two-doses of vaccination from 14 day after the second dose to 6 month after the second dose.

Methods used to assess safety

Primary safety endpoints
Number of participants with adverse events or medically attended adverse events leading to withdrawal.
Number of participants with solicited local and systemic adverse reactions.
Number of participants with unsolicited adverse events.
Number of Participants with Serious adverse events.

Efficacy and effectiveness of the vaccine

Efficacy of the vaccine in preclinical studies

To assess the immunogenicity of the vaccine, BALB / c mice were injected with different vaccine schedules (2, 4 or 8 µg / dose). In the one-dose immunization group, mice were administered intraperitoneally with a high (8 µg / dose), medium (4 µg / dose), or low (2 µg / dose) dose of vaccine on day 0, then, on days 7, 14, 21 and 28 post-inoculation, the levels of neutralizing antibodies were evaluated. The results showed that the seroconversion rate in the high, medium and low dose groups reached 100% at day 7 after immunization, and the effect of immunization was time-dependent [Wang H., 2020 ].
In the two-dose immunization group, two immunization programs were assessed at days 0/7, days 0/14, and days 0/21, respectively. The seropositivity of the high, medium and low-dose groups from all three immunization programs reached 100% at 7 days after the second immunization. The immunogenicity of a three-dose immunization program, in which the mice were intraperitoneally administered a high (8 µg/dose), middle (4 µg/dose), or low (2 µg/dose) dose of vaccine at days 0, 7, and 14, showed that seroconversion rate in all three groups reached 100% at day 7 after the first immunization [Wang H., 2020 ].

Immunogenicity of the vaccine was tested in different animal models: rabbits, guinea pigs, rats, and mice. The animals were immunized with high (8 µg/dose), middle (4 µg/dose), or low (2 µg/dose) doses of vaccine in the different immunization programs. The seroconversion rate reached 100% at 21 days after immunization in all animal models in all the immunization programs tested. [Wang H., 2020 ]
Immunogenicity was also tested in primates. One group of macaques was selected to be immunized twice, on days 0 and 14, while another group received physiological saline intramuscularly to act as control. The experimental groups were injected intramuscularly with a low dose (2 µg / dose) or a high dose (8 µg / dose) of the vaccine. Subsequently, on day 24 (10 days after the second immunization), all macaques were challenged intratracheally with 106 TCID50 of SARS-CoV-2. Body temperature measurements were performed in both the vaccinated and placebo groups. The temperatures of both groups fluctuated within the normal range 7 days after the exposure to the virus. Furthermore, the biochemical parameters after vaccination remained constant. [Wang H., 2020 ]

Efficacy of the vaccine in clinical trials

Main immunogenicity outcomes

Xia et al was a a dose-escalation, randomized trial. The trial included healthy people aged 18-80 years, who were negative for serum-specific IgM/IgG antibodies against SARS-CoV-2. The sample size was 192. The mean age of the participants was 54 years and the proportion of females was 50%.
Participants were randomly assigned to receive placebo or vaccine. In phase 1, on days 0 and 28, the intervention group received Sinopharm/BBIBP COVID-19 vaccine containing 2 µg, 4 µg, or 8 µg total protein, and the control group received placebo.
Neutralizing antibody mean titres were higher at day 42 in the group aged 18-59 years: 87·7 for the 2 µg group; 211·2 for the 4 µg group; and 228·7 for the 8 µg group. In the elderly group of participants (>60 years), mean titres were 80·7 in the 2 µg group; 131·5 in the 4 µg group; and 170·87 in the 8 µg group [Xia, Shengli, 2021 ].

Key messages

Sinopharm/BIBP COVID-19 vaccine reduces the risk of contracting COVID-19

Sinopharm/BIBP COVID-19 vaccine reduces the risk of contracting severe COVID-19

Main efficacy outcomes of Sinopharm/BIBP COVID-19 vaccine

Contracting COVID-19 (at least 14 days following 2nd dose)

The relative risk of contracting COVID-19 in the group that received Sinopharm/BIBP COVID-19 vaccine versus the group that received placebo vaccine was 0.27 (95% CI 0.18 to 0.4). This means Sinopharm/BIBP COVID-19 vaccine reduced the risk of contracting COVID-19 by 73%, compared with placebo vaccine.

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

In the trial identified in this review, 116 people not receiving Sinopharm/BIBP COVID-19 vaccine out of 12722 presented this outcome (9 per 1000) versus 31 out of 12713 in the group that did receive it (2 per 1000). In other words, 7 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 0.7%, or that the intervention reduced the risk of contracting COVID-19 by 0.7 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 NNTB is 143. Which means that 143 people need to receive the vaccine for one of them to not contract COVID-19.

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

Contracting severe COVID-19 (at least 14 days following 2nd dose)

The relative risk of contracting severe COVID-19 in the group that received Sinopharm/BIBP COVID-19 vaccine versus the group that received placebo vaccine was 0.2 (95% CI 0.01 to 4.17). This means Sinopharm/BIBP COVID-19 vaccine reduce the risk of contracting severe COVID-19 by 80%, compared with placebo vaccine.

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

In the trial identified in this review, 2 people not receiving Sinopharm/BIBP COVID-19 vaccine out of 12737 presented this outcome (16 per 100000) versus 0 out of 12726 in the group that did receive it (3 per 100000). In other words, 13 less people per 100000 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 0.013%, or that the intervention reduced the risk of contracting severe COVID-19 by 0.013 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 NNTB is 7692. Which means that 7692 people need to receive the vaccine for one of them to not contract severe COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as low. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: the information available is based on a short term follow-up; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Mortality

The existing evidence does not allow to assess the impact of Sinopharm/BIBP COVID-19 vaccine on the risk of death attributable to COVID-19. 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 Moderna COVID-19 vaccine would require trials with a higher statistical power.


Efficacy of the vaccine in subgroups

Contracting COVID-19 (Female) (at least 14 days following 2nd dose)

The relative risk of contracting covid-19 in women in the group that received Sinopharm/BIBP COVID-19 vaccine versus the group that received placebo vaccine was 0.24 (95% CI 0.07 to 0.86). This means Sinopharm/BIBP COVID-19 vaccine reduce the risk of contracting covid-19 in women by 76%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting covid-19 in women . Comparison: Sinopharm/BIBP COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 12 people not receiving Sinopharm/BIBP COVID-19 vaccine out of 1932 presented this outcome (6 per 1000) versus 3 out of 1976 in the group that did receive it (1 per 1000). In other words, 5 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.5%, or that the intervention reduced the risk of contracting covid-19 in women by 0.5 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 200. Which means that 200 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as low. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: the information available is based on a short term follow-up; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Contracting COVID-19 (Males) (at least 14 days following 2nd dose)

The relative risk of contracting covid-19 in males in the group that received Sinopharm/BIBP COVID-19 vaccine versus the group that received placebo vaccine was 0.22 (95% CI 0.13 to 0.36). This means Sinopharm/BIBP COVID-19 vaccine reduce the risk of contracting covid-19 in males by 78%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting covid-19 in males. Comparison: Sinopharm/BIBP COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 83 people not receiving Sinopharm/BIBP COVID-19 vaccine out of 10805 presented this outcome (8 per 1000) versus 18 out of 10706 in the group that did receive it (2 per 1000). In other words, 6 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 0.6%, or that the intervention reduced the risk of contracting covid-19 in males by 0.6 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 167. Which means that 167 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 low. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: the information available is based on a short term follow-up; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Contracting COVID-19 (≥60y) (at least 14 days following 2nd dose)

There was 0 event out of 198 participants in the control group of the trials and no events in the intervention group (201 participants).

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 ].

Summary of findings (iSoF) Table

Efficacy and effectiveness of the vaccine on subgroups

Sex

Randomized trials
Similar efficacy rates were observed for men and women in the phase 3, randomized trial [Al Kaabi N, 2021 ].
The relative risk of contracting covid-19 in women in the group that received Sinopharm/BIBP COVID-19 vaccine versus the group that received placebo vaccine was 0.24 (95% CI 0.07 to 0.86). This means Sinopharm/BIBP COVID-19 vaccine reduce the risk of contracting covid-19 in women by 76%, compared with placebo vaccine [Al Kaabi N, 2021 ].
The relative risk of contracting covid-19 in males in the group that received Sinopharm/BIBP COVID-19 vaccine versus the group that received placebo vaccine was 0.22 (95% CI 0.13 to 0.36). This means Sinopharm/BIBP COVID-19 vaccine reduce the risk of contracting covid-19 in males by 78%, compared with placebo vaccine [Al Kaabi N, 2021 ].
Age

Randomized trials
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 ].
Non-comparative studies
AssiutU21 is an ongoing prospective cohort study (registered with the number NCT04706143 [Assiut University, 2021 ]), that will evaluate the immune responses in adults aged 25 to 65 years, of different vaccines including; inactivated (Sinopharm), m Biontech) and viral vector (Oxford / AZ- ChAdOx1 nCoV-19) vaccines.

Children and adolescents

Randomized trials
Children were excluded from the Xia S et al, so no data are available for this subgroup [Xia, Shengli, 2021 ].
Pregnancy

Randomized trials
Pregnant females were excluded from the Xia S et al, so no data are available for this subgroup [Xia, Shengli, 2021 ].
Breast-feeding

Randomized trials
Breastfeeding females were excluded from the Xia S et al, so no data are available for this subgroup [Xia, Shengli, 2021 ].
Immunocompromised persons

Randomized trials
Immunocompromised participants were excluded from the Xia S et al, so no data are available for this subgroup [Xia, Shengli, 2021 ].

Other data from vaccine efficacy and effectiveness

Duration of protection

Randomized trials
The exact duration of protection provided by the vaccine is unknown, as it is still being determined by ongoing clinical trials.
SARS-CoV-2 variants

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

Other comparative studies
Neutralization activity was assessed in 24 serum samples from participants in two clinical trials, 12 of whom had been vaccinated with Sinopharm/BBIBP COVID-19 vaccine. Neutralizing activity was measured in these serum samples against live SARS-CoV-2 strains GDPCC (501Y.V2). SARS-CoV-2 strains HB02 (wild type) and BJ01 (D614G) were tested as the control.
The serum samples preserved neutralization of the 501Y.V2 variant, with slightly reduced geometric mean titres (GMTs) compared with their titres against the wild type or D614G strains. Findings suggest that the 501Y.V2 variant does not escape the immunity induced by vaccines targeting the whole virus (BBIBP-CorV) [Huang B, 2021 ].
Booster dose

Randomized trials

Safety of the vaccine

Safety of the vaccine in preclinical studies

Vaccine was tested in Sprague-Dawley rats to evaluate the acute toxicity of the inactivated vaccine. In this study, 20 rats were divided into two groups and intramuscularly injected with 3 doses (8 µg/dose) of vaccine and physiological saline as the control. After inoculation, all rats were continuously observed for 14 days and euthanized at day 15 to assess systematic anatomy and for general observation. No cases of death or impending death or obvious clinical signs were observed in any of the groups over the 14 days after vaccine inoculation [Wang H., 2020 ].
Systemic anaphylaxis was subsequently evaluated by intramuscular and intravenous injections in guinea pigs. Thirty-six male guinea pigs were divided into 4 groups, 2 control groups and 2 intervention groups. The results showed no abnormal reactions during the inoculation and follow-up period, by clinical observation and measurement of the body weights of the guinea pigs. No allergic reaction symptoms were found in the negative control group or experimental group [Wang H., 2020 ].
The long-term toxicity of the vaccine was further evaluated in cynomolgus monkeys. Forty cynomolgus monkeys were divided into 4 groups and intramuscularly injected with a control solution or 2, 4, or 8 µg of vaccine in a volume of 0.5 ml. No cases of death or significant abnormalities in clinical physiological and pathological indicators were observed. The animals showed only local irritation characterized by mild to severe granulomatous inflammation due to injection, but this reaction was absent at 2 weeks after injection. The no observed adverse effect level was found to be 8 µg/dose in this trial No allergic reaction symptoms were found in the negative control group or experimental group [Wang H., 2020 ].

Safety of the vaccine in clinical trials

Main safety outcomes of Sinopharm/BIBP COVID-19 vaccine

Any adverse event (at least 7 days after any injection)

The relative risk of any adverse event in the group that received Sinopharm/BIBP COVID-19 vaccine versus the group that received placebo vaccine was 0.91 (95% CI 0.89 to 0.94). No statistically significant differences between groups were found for any adverse events.

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

In the trial identified in this review, 6250 people not receiving Sinopharm/BIBP COVID-19 vaccine out of 6250 presented this outcome (465 per 1000) versus 5623 out of 13471 in the group that did receive it (418 per 1000). In other words, 47 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 4.7%, or that the intervention reduced the risk of any adverse event by 4.7 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 NNTB is 21. Which means that 21 people need to receive the vaccine for one of them to experienced 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 event (at least 7 days after any injection)

The relative risk of local adverse event in the group that received Sinopharm/BIBP COVID-19 vaccine versus the group that received placebo vaccine was 0.71 (95% CI 0.68 to 0.74). No statistically significant differences between groups were found for any adverse events.

Figure - Forest plot of risk ratio meta-analysis. Outcome: local adverse event. Comparison: Sinopharm/BIBP COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 3906 people not receiving Sinopharm/BIBP COVID-19 vaccine out of 13453 presented this outcome (290 per 1000) versus 2786 out of 13471 in the group that did receive it (207 per 1000). In other words, 83 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 8.3%, or that the intervention reduced the risk of local adverse event by 8.3 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 NNTB is 12. Which means that 12 people need to receive the vaccine for one of them to experienced local adverse event.

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

Systemic adverse event (at least 7 days after any injection)

The relative risk of systemic adverse event in the group that received Sinopharm/BIBP COVID-19 vaccine versus the group that received placebo vaccine was 1.02 (95% CI 0.98 to 1.06). This means Sinopharm/BIBP COVID-19 vaccine increase the risk of systemic adverse event by 2%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: systemic adverse event. Comparison: Sinopharm/BIBP COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 3743 people not receiving Sinopharm/BIBP COVID-19 vaccine out of 13453 presented this outcome (278 per 1000) versus 3810 out of 13471 in the group that did receive it (283 per 1000). In other words, 5 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 0.5%, or that the intervention increased the risk of systemic adverse event by 0.5 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTH is 200. Which means that 200 people need to receive the vaccine for one of them to experienced systemic 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 event (SAEs) (at least 7 days after any injection)

The relative risk of serious adverse event (saes) in the group that received Sinopharm/BIBP COVID-19 vaccine versus the group that received placebo vaccine was 0.76 (95% CI 0.54 to 1.06). No statistically significant differences between groups were found for serious adverse events.

Figure - Forest plot of risk ratio meta-analysis. Outcome: serious adverse event (saes). Comparison: Sinopharm/BIBP COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 78 people not receiving Sinopharm/BIBP COVID-19 vaccine out of 13453 presented this outcome (6 per 1000) versus 59 out of 13471 in the group that did receive it (5 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 event (saes) 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 NNTB is 1000. Which means that 1000 people need to receive the vaccine for one of them to not contract COVID-19.

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

Summary of findings table (iSoF)

Safety of the vaccine in subgroups

Sex

Randomized trials
Safety profile of the Sinopharm/BIBP COVID-19 vaccine was not evaluated across sex groups.

Age

Randomized trials
For the vaccine recipients in the group aged 60 years and older (n=72), pain at the injection site was the most frequent adverse reaction (one [4%] in the 2 µg group, four [17%] in the 4 µg group, and four [17%] in the 8 µg group), an additional injection site adverse reaction was induration (two [3%] of 72) [Xia, Shengli, 2021 ].
The most common systemic adverse reactions reported in the >60 age group (n=72) were fever (one [1%]) and fatigue (one [1%]), reported in the 8 µg cohort; and headache (one [1%]), diarrhea (one [1%]), and joint pain (one [1%]) reported in the 4 µg cohort. All adverse reactions were mild or moderate in severity. No serious adverse event was reported within 28 days post vaccination for all cohorts [Xia, Shengli, 2021 ].
Children and adolescents

Randomized trials
Children and adolescents were excluded from the Xia S et al, so no data are available for this subgroup [Xia, Shengli, 2021 ].
Pregnancy

Randomized trials
Pregnant females were excluded from the Xia et al, so no data are available for this subgroup [Xia, Shengli, 2021 ].
Breast-feeding

Randomized trials
Breastfeeding females were excluded from the Xia et al, so no data are available for this subgroup [Xia, Shengli, 2021 ].
Immunocompromised persons

Randomized trials
Immunocompromised participants were excluded from the Xia et al, so no data are available for this subgroup [Xia, Shengli, 2021 ].

Safety of the vaccine post-authorization

Post-authorization studies

Comparative studies
None available

Non-comparative studies
Abu-Hammad, 2021 reported a cross sectional study conducted in Jordan. A total of 409 health workers participated in the study to report adverse events of AstraZeneca (AZ), PfizerBioNTeck (PB), and SinoPharm (SP) vaccines. Approximately 18% of participants reported no adverse events after the first dose and second dose. No serious SE were reported. The most common adverse event from the Sinopharm vaccine was pain at the injection site [Abu-Hammad O., 2021 ].
Almufty HB, 2021 reported a cross sectional study conducted in Iraq. 1012 healthy adults were included in this study that reported side effects of Sinopharm, AstraZeneca-Oxford and Pfizer- BioNTech vaccines. Results showed that younger participants (less than 50 years old) were most likely to have symptoms after vaccination;p value=0.003. Additionally, female participants with history of COVID-19 infection and with comorbid diseases were statistically significant risk factors for having adverse reactions post-vaccination. Regarding severity of symptoms, only 139 out of 850 symptomatic participants faced severe to critical side effects and were related with AstraZeneca-Oxford vaccine [Almufty HB, 2021 ].

Case reports and case series
None available

Spontaneous report data

Disclaimer: Reporting suspected adverse reactions after authorization of the medicinal product is important because it allows continuous monitoring of the benefit/risk balance of the vaccines. However, they do not indicate a causal association between the vaccine and the observed effects. Furthermore, this information should not be used to estimate the frequency of adverse events in people receiving the vaccine or to make comparisons between different vaccines. The information emerging about possible adverse effects needs to be carefully evaluated in order to first establish if the adverse effect might have been caused by the vaccine.

To date, in Argentina, 127/210 (60.4%) local and systemic mild to moderate adverse events have been reported related to Sinopharm/BIBP vaccine against COVID-19. No serious adverse events related to the vaccine [Ministerio de Salud Argentina, 2021 ] have been reported.

Monitoring

WHO recommends the following research and post-authorization monitoring activities [World Health Organization, 2021 ]:
Safety surveillance and monitoring
- Serious adverse events, anaphylaxis and other serious allergic reactions, Bell‘s palsy, cases of multisystem inflammatory syndrome following vaccination, cases of COVID-19 following vaccination that result in hospitalization or death.
Vaccine effectiveness
− vaccine effectiveness over time and whether protection can be prolonged by booster doses.
− studies to investigate whether this vaccine reduces SARS-CoV-2 transmission and viral shedding;
− assessment and reporting of vaccination failures and virus sequence information.
Subgroups
− prospective studies on the safety of COVID-19 vaccine in pregnant and lactating females.
− randomized controlled trials on efficacy and safety of vaccination in children below the age of 18 years.
− safety data on vaccination in immunocompromised persons, including persons living with HIV and persons with autoimmune disease.
Vaccination logistics
− immunogenicity and safety studies with co-administration of other vaccines, including influenza and pneumococcal vaccines, to adults and older persons.
− safety, immunogenicity, and impact of a delayed second dose, as currently implemented by certain countries.
− stability of the vaccine under alternative cold-chain distribution and storage conditions.
− effectiveness of the proposed strategies for the prevention and management of anaphylactic reactions.
− interchangeability studies within and across COVID-19 vaccine platforms.

References

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