Bharat Biotech COVID-19 vaccine

Extended version of the vaccine

Bharat Biotech COVID-19 vaccine

Authorization

World Health Organization Emergency Use Listing Procedure

Listed for emergency use on 3 November 2021 [WHO, 2021 ].
EUL/WHO Authorization: Authorized for emergency use in individuals 18 years of age and over [WHO, 2021 ].
SAGE/WHO Recommendation: Authorized for emergency use in individuals 18 years of age and over [WHO, 2021 ].

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

Central Drugs Standard Control Organization (CDSCO, India)
Authorized on 3 January 2021 [Ministry of Health and Family Welfare. Government of India, 2021 ].
Conditional marketing authorization for individuals 18 years of age and over.

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)
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 (FDA)
Not authorized.

Federal Commission for the Protection against Sanitary Risk (COFEPRIS, Mexico)
Authorized for emergency use on 6 April 2021 [COFREPRIS, 2021 ].

Authorization in other jurisdictions in the Americas
Guatemala
Guyana
Paraguay
Venezuela

Authorization in other jurisdictions
Bahrain
Botswana
Iran
Mauritius
Nepal
Philippines
Trinidad and Tobago
Vietnam
Zimbabwe

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

Manufacturing

Manufacturer
Bharat Biotech, India: Bharat Biotech COVID-19 vaccine from India was developed in collaboration with the Indian Council for Medical Research (ICMR) and the National Institute of Virology (NIV). The indigenous inactivated vaccine is developed and manufactured by Bharat Biotech.

Other manufacturers
Indian Immunologicals Ltd (IIL), located in India, will start the production of the vaccine by July/August 2021, using the same technology of Bharat Biotech.

Ocugen Inc, USA, partnered with Bharat Biotech to co-develop the COVID-19 vaccine candidate for the U.S. market.

Precisa Medicamentos pharmaceutical, Brazil, signed an agreement with Bharat Biotech for the supply of its COVID-19 vaccine and for it to be manufactured locally in Brazil.

Haffkine Biopharma Corporation, India, received permission from the Union government to manufacture the vaccine.

General characteristics

The Bharat Biotech COVID-19 vaccine (BBV152) is a whole virion inactivated SARS-CoV-2 antigen adsorbed to alum and formulated with a toll-like receptor (TLR) 7/8 agonist Imidazo quinolin gallamide (IMDG) and the preservative 2-phenoxyethanol [WHO, 2021 ].

The Bharat Biotech COVID-19 vaccine is given in 2 doses, separated by 4 weeks. Inactivated vaccines have been used for diseases such as seasonal influenza, polio, and hepatitis A. Inactivated vaccines cannot replicate and therefore cannot infect individuals. IMDG and alum are adjuvants added to enhance immunogenicity. IMDG is a novel adjuvant which has not been used in any previous vaccine [WHO, 2021 ].

Studies generally demonstrate that TLR 7/8 agonists enhance Th1 responses and inhibit Th2 responses which is considered beneficial for COVID-19 vaccines. In addition, CD8 T-cell responses may be increased when using TLR 7/8 agonists as adjuvants [Ganneru B, 2021 ].

 

Dosage form and ingredients

The pharmaceutical form is a suspension for intramuscular injection that is provided as a monodose vial of 0.5 mL or, as a multidose vial of 5 doses (2,5 mL), 10 doses (5 mL) and 20 doses (10 mL) [Central Drugs Standard Control Organization of the Government of India, 2021 ], [WHO, 2021 ].

The vaccine contains the following ingredients:

Active ingredient

6µg of whole-virion inactivated SARS-CoV-2 antigen (Strain: NIV-2020-770).

Excipients

250 µg of aluminum hydroxide gel.
15 µg of TLR 7/8 (imidazoquinolinone)
2.5 mg of 2-phenoxyethanol.
0.5 mL of phosphate buffer saline.

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 ].

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 ]. This condition would be probably caused by a response from type 2 (Th2) helper T cells. Although the cellular response can be elicited by many vaccines, protection against subsequent coronavirus infections is largely mediated for humoral immunity. The 'cytokine storm' induced by excess T cells has been shown to accentuate the pathogenesis of COVID-19 [Qiang Gao, 2020 ].

Dosing and schedule

Dose-finding studies

The BBIL/BBV152-A/2020 trial assessed 380 healthy participants aged 12 to 65 years that received two vaccination schedules, 3 μg with Algel-IMDG or 6 μg with Algel-IMDG. Vaccines were administered intramuscularly at a volume of 0.5 mL per dose in a two-dose regimen on day 0 and day 28. Findings showed that seroconversion rates were 98.4% (95% CI 95.3 to 99.7) in the 3 µg with Algel-IMDG group and 96.6% (95% CI 92.8 to– 98.8) in the 6 µg with Algel-IMDG group, at day 56. Both doses of the vaccine-induced significant neutralizing antibody responses to live SARS-CoV-2 [Ella R, 2021 ].

There is no evidence yet about the effects of the coadministration of Bharat Biotech COVID-19 vaccine with other vaccines included in routine vaccination programs.

Indications and contraindications

Indications

The Bharat Biotech COVID-19 vaccine is indicated in adult individuals 18 years of age and over [WHO, 2021 ].

Contrandications

The vaccine is contraindicated in individuals with a known history of a severe allergic reaction to any component of vaccines [Central Drugs Standard Control Organization of the Government of India, 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 Bharat Biotech COVID-19 vaccine.

Precautions

Severe allergic reaction (e.g., anaphylaxis) to a previous dose of any vaccine (not including Bharat Biotech COVID-19 vaccine).

Severe allergic reaction (e.g., anaphylaxis) to an injectable medication

Vaccination should be postponed in individuals suffering from acute severe febrile illness, or acute infection.

As with other intramuscular injections, the vaccine should be given with caution in individuals with bleeding disorders or other conditions that increase the risk of bleeding, such as anticoagulant therapy, thrombocytopenia and hemophilia [Ministerio de Salud Pública y Bienestar Social, 2021 ].

Bharat Biotech COVID-19 vaccine may interact with chloroquine and corticosteroids impairing the immune antibody response [Central Drugs Standard Control Organization of the Government of India, 2021 ].

There should be a minimum interval of 14 days between the administration of this vaccine with any other vaccine in the immunization schedule until data on co-administration with other vaccines are available.

Vaccination may be offered regardless of a person’s history of symptomatic or asymptomatic SARS-CoV-2 infection.

Although there are currently no medical contraindications to vaccinate a person with COVID-19, it is recommended to defer all vaccinations until complete recovery [PAHO, 2020 ].

Although there are currently no contraindications to vaccinate 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.

Clinical studies - general characteristics

Randomized trials 

Ella R et al. was a phase 1/2 randomized trial (registered with the number NCT04471519 [Bharat Biotech International Limited, 2020 ]), sponsored by Bharat Biotech International Limited that was conducted in India. In the phase 1 trial, the aim was to evaluate the safety, reactogenicity, tolerability, and immunogenicity the vaccine. It was first registered in July 2020 and enrolled 375 participants of 18 to 55 years of age that were randomized in a 4:1 ratio to receive either one of three vaccine formulations or a control vaccine. Results were published in a scientific journal on January 2021 [Ella R, 2021 ].

The phase 2 of the trial [Ella R, 2021 ] randomized 380 participants of 12 to 65 years of age in a 1:1 ratio to receive one of two vaccine schedules. The interim results of the trial were published in a scientific journal on March, 2021 [Ella R, 2021 ].

Ella R et al. was a phase 3 randomized trial sponsored by Bharat Biotech International Limited and conducted India between November 2020 and December 2022. It was registered with trial registry number NCT04641481.
The trial included healthy adults (age 18–98 years).
The sample size was 24,419. The mean age of the participants was 40 years and the proportion of women was 33%.
Participants were randomly assigned in a 1:1 ratio to receive BBV152 or placebo. The intervention was administered as two intramuscular 6 µg Algel-IMDG doses of BBV152 or placebo on days 0 and 28 [Raches Ella MBBS, MS, 2021 ], [Ella R, 2021 ].

Ongoing randomized trials

Ella R et al. is an ongoing phase 3 trial (registered with the number NCT04641481 [Bharat Biotech International Limited, 2020 ]) sponsored by Bharat Biotech that is being conducted in India. It was first registered on November 16, 2020 and plans to enroll 25,800 adults from 18 years of age and over, that will receive the vaccine or placebo, in a 1:1 ratio. It is expected to run until December, 2022.

Preliminary results were announced through press release in March 2021 [Bharat Biotech, 2021 ].

Other studies providing efficacy or safety data

The following non-comparative studies have reported efficacy or safety data:

Srivastava et al. [Srivastava RK, 2021 ];

Singh et al. [AWADHESH KUMAR SINGH, 2021 ];

Parai et al. [Parai D, 2021 ];

Tyagi et al. [Tyagi K, 2021 ];

Arora et al. [Arora P, 2021 ];

Khawaja et al. [Khawaja T, 2021 ].

Methods used to assess efficacy

In the Ella R et al. (phase 3) [Raches Ella MBBS, MS, 2021 ], the primary endpoint was specified in preventing a first occurrence of symptomatic COVID-19 (any severity) with onset at least 14 days after the second dose among participants who were SARS-CoV-2 negative by PCR and serology at baseline, had no major protocol deviations, and followed-up for at least two weeks after the second dose. End points were judged by an independent adjudication committee that was unaware of group assignment.

COVID-19 cases were defined as participants with at least two of the following symptoms: fever (temperature ≥ 38°C), chills, myalgia, headache, sore throat, or new olfactory or taste disorder, or had at least one respiratory sign or symptom (including cough, shortness of breath, or clinical or radiographic evidence of pneumonia) and at least one SARS-CoV-2 PCR-positive nasopharyngeal swab. COVID-19 cases were followed daily to assess symptom severity until symptoms resolved. In PCR-positive participants who consented, an additional NP swab for genotyping and a blood sample for evaluating correlates of protection were collected [Raches Ella MBBS, MS, 2021 ].

Safety evaluation methods

Safety assessments included: Medically Attended Adverse Events, Adverse Events of Special Interest, Solicited Local and Systemic Adverse Reactions, Unsolicited Adverse Events, Immediate Adverse events, and Serious Adverse Events

End points were judged by an independent adjudication committee that was unaware of group assignment.

Efficacy and effectiveness of the vaccine

Efficacy of preclinical studies on the vaccine

Immunogenicity of the vaccine has been evaluated in mice, rats and rabbits [Ganneru B, 2021 ], Syrian hamsters [Mohandas S, 2021 ] and non-human primates [Yadav PD, 2021 ].

Ganneru et al assessed immunogenicity of the vaccine at two antigen concentrations (3μg and 6μg), with two different adjuvants, in mice, rats and rabbits. All formulations generated significantly high antigen-binding and neutralizing antibody titers, at both concentrations, in all three species. The formulation containing TLR7/8 agonist adjuvant-induced Th1 biased antibody responses with elevated IgG2a/IgG1 ratio and increased levels of SARS-CoV-2 specific IFN-γ+ CD4+ T lymphocyte response [Ganneru B, 2021 ].

Mohandas et al assessed immunogenicity of different vaccination regimes in Syrian hamsters (BBV152A, BBV152B, and BBV152C). All the regimes induced significant titers of SARS-CoV-2-specific IgG and neutralizing antibodies. Post-SARS-CoV-2 infection, vaccinated hamsters did not show any histopathological changes in the lungs. Of the three candidates, BBV152A showed the better response.

Yadav et al assessed immunogenicity of three different vaccine schedules, at day 0 and 14, in 20 rhesus macaques. A protective response was observed with increasing SARS-CoV-2 specific IgG and neutralizing antibody titers from 3rd week post-immunization. No evidence of pneumonia was observed by histopathological examination in the vaccinated groups [Yadav PD, 2021 ].

Efficacy of the vaccine in clinical trials

Main immunogenicity outcomes

BBIL/BBV152-A/2020 trial evaluated the immunogenicity of a two-dose schedule with three different formulations of the vaccine in participants 12 to 65 years old. The vaccine induced high neutralising antibody responses that remained at 3 months after the second vaccination. The 6 µg with Algel-IMDG formulation was selected for the phase 3 efficacy trial [Ella R, 2021 ].

The phase 3 BBIL/BBV152-C/2020 trial evaluated the consistency of immune responses from three consecutive manufacturing batches. The results showed that the neutralizing antibodies of the mean antibody titers in the groups that received lots 1, 2, 3 or placebo were 130.3 (95% CI: 105.8-160.4), 121.2 (97.6-150.5), 125.4 (101.3-155.1), and 13.7 (10.7-17.4) respectively on day 56. Antibody titers were higher (194, 3 [95% CI 134.4-280.9, n = 48] in vaccinated participants who were seropositive for SARS-CoV-2 at baseline [40b42c59d7d5e26930510ba5afíritu78a6a82e36f].

Main efficacy outcomes of Bharat Biotech COVID-19 vaccine

Key messages

There is no evidence available at this moment to assess the efficacy of Bharat Biotech 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 Bharat Biotech COVID-19 vaccine, versus the group that received control vaccine was 0.23 (95% CI 0.15 to 0.35). This means Bharat Biotech COVID-19 vaccine reduced the risk of contracting COVID-19 by 77%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19. Comparison: control vaccine versus Bharat Biotech COVID-19 vaccine

In the trials identified in this review, 106 people not receiving Bharat Biotech COVID-19 vaccine out of 8502 presented this outcome (12 per 1000) versus 24 out of 8471 in the group that did receive it (3 per 1000). In other words,10 less to 8 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 77%, or that the intervention reduced the risk of contracting COVID-19 by 77 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 111. Which means that 111 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 Bharat Biotech COVID-19 vaccine, versus the group that received control vaccine was 0.07 (95% CI 0.01 to 0.51). This means Bharat Biotech COVID-19 vaccine reduced the risk of contracting severe COVID-19 by 93%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting severe COVID-19. Comparison: control vaccine versus Bharat Biotech COVID-19 vaccine

In the trials identified in this review, 15 people not receiving Bharat Biotech COVID-19 vaccine out of 8502 presented this outcome (2 per 1000) versus 1 out of 8471 in the group that did receive it (0 per 1000). In other words,2 less to 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 93%, or that the intervention reduced the risk of contracting severe COVID-19 by 93 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 500. Which means that 500 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.


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 Bharat Biotech COVID-19 vaccine, versus the group that received control vaccine was 0.34 (95% CI 0.12 to 0.92). This means Bharat Biotech COVID-19 vaccine reduced the risk of contracting COVID-19 (>60y) by 66%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (>60y). Comparison: control vaccine versus Bharat Biotech COVID-19 vaccine

In the trials identified in this review, 16 people not receiving Bharat Biotech COVID-19 vaccine out of 965 presented this outcome (17 per 1000) versus 5 out of 893 in the group that did receive it (6 per 1000). In other words,15 less to 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 66%, or that the intervention reduced the risk of contracting COVID-19 (>60y) by 66 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 91. Which means that 91 people need to receive the vaccine for one of them to not contracting COVID-19 (>60y).

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

Summary of findings (iSoF)


Efficacy and effectiveness of the vaccine in subgroups

Sex

Randomized trials

There are no phase 3 randomized trials that have yet reported outcome data. The differential efficacy of the vaccine in sex groups was not reported in the phase 1/2 trial BBIL/BBV152-A/2020 [Ella R, 2021 ].

 

Age

Randomized trials

There are no phase 3 randomized trials that have yet reported outcome data. In the phase 1/2 trial BBIL/BBV152-A/2020, the percentage of participants by age was: 12-17 years: 3.7%; 18-54 years: 92%; 55-65: 4.3%. Seroconversion rates across the three age groups were similar [Ella R, 2021 ].

 

Children and adolescents

Randomized trials

There are no phase 3 randomized trials that have yet reported outcome data. In the phase 1/2 trial BBIL/BBV152-A/2020, the percentage of participants 12 to 17 years of age was 3.7% (14 out of 380). Seroconversion rate in this age group was similar. Children <12 years were excluded [Ella R, 2021 ].

 

Pregnancy

Randomized trials

There are no phase 3 randomized trials that have yet reported outcome data. In the phase 1/2 trial BBIL/BBV152-A/2020, pregnant females were excluded, so no data are available for this subgroup [Ella R, 2021 ].

 

Breast-feeding

Randomized trials

There are no phase 3 randomized trials that have yet reported outcome data. In the phase 1/2 trial BBIL/BBV152-A/2020, breast-feeding females were excluded, so no data are available for this subgroup [Ella R, 2021 ].

 

Immunocompromised persons

Randomized trials

There are no phase 3 randomized trials that have yet reported outcome data. In the phase 1/2 trial BBIL/BBV152-A/2020, immunocompromised patients were excluded, so no data are available for this subgroup [Ella R, 2021 ].

Other data on vaccine efficacy and effectiveness

Main effectiveness outcomes of Bharat Biotech COVID-19 vaccine (Other 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

SARS-CoV-2 variants

Immunogenicity outcomes

Sapkal GN et al. was a non-comparative study (neutralizing capacity from recipients' sera) in India, in which 38 vaccine recipients were included. The study reported data from 4 weeks post-immunization. The results showed that Bharat Biotech vaccine-induced antibodies show no significant decrease in neutralization activity against the Alpha (B.1.1.7) variant. Median ratio of 50% neutralisation of sera was 0.8 compared with hCoV-19/India/2020770 against mutant hCoV-19/India/20203522 (B.1.1.7 variant) Non-parametric test for the comparison of the PRNT50 values from different groups revealed non-significant difference [Sapkal GN, 2021 ].

Yadav PD et al. conducted a non-comparative study (neutralizing capacity from recipients' sera) in India, in which they included 17 vaccine recipients. The study reported data from 28 days post-immunization. The results showed that the Bharat Biotech vaccine had shown a significant reduction in neutralization titer for the Beta variant (GMT: 187.5 (95%CI 129.3 to 271.9)) [Yadav PD, 2021 ].

Pragya D Yadav et al. conducted a comparative study (neutralizing capacity from recipients' sera) in India, which included 42 recipients of the Bharat Biotech COVID-19 vaccine. The study reported data from 16 weeks post-immunization (median). The results showed a minor reduction was observed in the neutralizing antibody titer in COVID- 19 recovered cases full Bharat Biotech vaccinated (reduction: 1.3-fold) [Pragya D Yadav, 2021 ].

Yadav PD et al. conducted a non-comparative study (neutralizing capacity from recipients' sera) in India, in which they included 17 vaccine recipients. The study reported data from 28 days post-immunization. The results showed that the vaccinees had shown a significant reduction in neutralization titer for Deta variant (GMT 61.57 (95% CI 36.3 to104.3)) [Yadav PD, 2021 ].

Randomized trials

Ella R et al. was a multicenter, phase 3, randomized clinical trial conducted in 25 hospitals in India, where 16,973 participants were recruited (8,471 vaccine group and 8,502 placebo group). The study seeks to evaluate the efficacy of Bharat's biotech vaccine in preventing the first occurrence of symptomatic COVID-19 (any severity) starting at least 14 days after the second dose. The results showed an efficacy against symptomatic infection of 65.2% (95% CI 33.1 to 83.0) [Raches Ella MBBS, MS, 2021 ].

Other studies

To date, no studies have assessed the vaccine efficacy outcomes against SARS-CoV-2 variants.

Booster dose

Immunogenicity outcomes

To date, no studies have assessed the vaccine immunogenicity outcomes on a booster regimen.

 

Heterologous vaccine regimens

Immunogenicity outcomes

To date, no studies have assessed the vaccine immunogenicity outcomes on heterologous regimen.

 

Heterologous-booster regimens

Immunogenicity outcomes

To date, no studies have assessed the vaccine immunogenicity outcomes on a heterologous-booster regimen.

Safety of the vaccine

Safety of the vaccine in preclinical studies

The safety of the vaccine has been evaluated in mice, rats and rabbits [Ganneru B, 2021 ]. Other preclinical studies did not assess safety outcomes [Mohandas S, 2021 ],[Yadav PD, 2021 ].

Ganneru et al assessed preclinical safety of either adjuvant-alone (Algel-IMDG) or three formulations of the vaccine in mice, rats and rabbits. The studies did not indicate any undesirable pathological changes and systemic toxicity, except local reactogenicity at the site of injection. Mutagenicity assay performed with Algel-IMDG at various concentrations revealed the adjuvant-alone or in combination with the adjuvanted vaccine formulation was non-mutagenic [Ganneru B, 2021 ].

Safety of the vaccine in clinical trials

Local adverse events after the 1st dose (measured at least 7 days after vaccination)

The relative risk of local adverse events after the 1st dose in the group that received Bharat Biotech COVID-19 vaccine, versus the group that received control vaccine was 1.08 (95% CI 0.94 to 1.23). This means Bharat Biotech COVID-19 vaccine increased the risk of local adverse events after the 1st dose by 8%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: local adverse events after the 1st dose. Comparison: control vaccine versus Bharat Biotech COVID-19 vaccine

In the trials identified in this review, 399 people not receiving Bharat Biotech COVID-19 vaccine out of 12874 presented this outcome (31 per 1000) versus 431 out of 12879 in the group that did receive it (33 per 1000). In other words,2 less to 7 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 8%, or that the intervention increased the risk of local adverse events after the 1st dose by 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 500. Which means that 500 people need to receive the vaccine for one of them to present local adverse events after the 1st dose.

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


Local adverse events after the 2nd dose (measured at least 7 days after vaccination)

The relative risk of local adverse events after the 2nd dose in the group that received Bharat Biotech COVID-19 vaccine, versus the group that received control vaccine was 1.07 (95% CI 0.9 to 1.26). This means Bharat Biotech COVID-19 vaccine increased the risk of local adverse events after the 2nd dose by 7%, compared with control vaccine.

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

In the trials identified in this review, 260 people not receiving Bharat Biotech COVID-19 vaccine out of 12874 presented this outcome (20 per 1000) versus 278 out of 12879 in the group that did receive it (21 per 1000). In other words, people per 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%, or that the intervention increased the risk of local adverse events after the 2nd dose by 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 1000. Which means that 1000 people need to receive the vaccine for one of them to present 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 1st dose (measured at least 7 days after vaccination)

The relative risk of systemic adverse events after the 1st dose in the group that received Bharat Biotech COVID-19 vaccine, versus the group that received control vaccine was 1.34 (95% CI 1.14 to 1.58). This means Bharat Biotech COVID-19 vaccine increased the risk of systemic adverse events after the 1st dose by 34%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: systemic adverse events after the 1st dose. Comparison: control vaccine versus Bharat Biotech COVID-19 vaccine

In the trials identified in this review, 247 people not receiving Bharat Biotech COVID-19 vaccine out of 12874 presented this outcome (19 per 1000) versus 331 out of 12879 in the group that did receive it (25 per 1000). In other words,3 more to 11 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 34%, or that the intervention increased the risk of systemic adverse events after the 1st dose by 34 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 167. Which means that 167 people need to receive the vaccine for one of them to present systemic adverse events after the 1st 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 (measured at least 7 days after vaccination)

The relative risk of systemic adverse events after the 2nd dose in the group that received Bharat Biotech COVID-19 vaccine, versus the group that received control vaccine was 1.13 (95% CI 0.93 to 1.36). This means Bharat Biotech COVID-19 vaccine increased the risk of systemic adverse events after the 2nd dose by 13%, compared with control vaccine.

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

In the trials identified in this review, 205 people not receiving Bharat Biotech COVID-19 vaccine out of 12874 presented this outcome (16 per 1000) versus 231 out of 12879 in the group that did receive it (18 per 1000). In other words,1 less to 6 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 13%, or that the intervention increased the risk of systemic adverse events after the 2nd dose by 13 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 500. Which means that 500 people need to receive the vaccine for one of them to present 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.


Any adverse event (median follow up 146 days)

The relative risk of any adverse event in the group that received Bharat Biotech COVID-19 vaccine, versus the group that received control vaccine was 1 (95% CI 0.94 to 1.07). This means Bharat Biotech COVID-19 vaccine increased the risk of any adverse event by 0%, compared with control vaccine.

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

In the trials identified in this review, 1597 people not receiving Bharat Biotech COVID-19 vaccine out of 12874 presented this outcome (124 per 1000) versus 1597 out of 12879 in the group that did receive it (124 per 1000). In other words,8 less to 8 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%, or that the intervention increased the risk of any adverse event by 0 percentage points.

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 146 days)

The relative risk of serious adverse events in the group that received Bharat Biotech COVID-19 vaccine, versus the group that received control vaccine was 0.65 (95% CI 0.43 to 0.97). This means Bharat Biotech COVID-19 vaccine reduced the risk of serious adverse events by 35%, compared with control vaccine.

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

In the trials identified in this review, 60 people not receiving Bharat Biotech COVID-19 vaccine out of 12874 presented this outcome (5 per 1000) versus 39 out of 12879 in the group that did receive it (3 per 1000). In other words,3 less to 0 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 35%, or that the intervention reduced the risk of serious adverse events by 35 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 500. Which means that 500 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.

Summary of findings (iSoF)

Safety of the vaccine in subgroups

Sex

Randomized trials

There are no phase 3 randomized trials that have yet reported outcome data. The differential safety of the vaccine in sex groups was not reported in the phase 1/2 trial BBIL/BBV152-A/2020 [Ella R, 2021 ].

 

Age

Randomized trials

There are no phase 3 randomized trials that have yet reported outcome data. Adults older than 65 years were not included in the phase 1/2 trial. Safety in the different age groups included was not reported [Ella R, 2021 ].

 

Children and adolescents

Randomized trials

There are no phase 3 randomized trials that have yet reported outcome data. In the phase 1/2 trial BBIL/BBV152-A/2020, the percentage of participants 12 to 17 years of age was 3.7% (14 out of 380). Differential safety in this age group was not reported. Children <12 years were excluded [Ella R, 2021 ].

 

Pregnancy

Randomized trials

There are no phase 3 randomized trials that have yet reported outcome data. In the phase 1/2 trial BBIL/BBV152-A/2020, pregnant females were excluded, so no data are available for this subgroup [Ella R, 2021 ].

 

Breast-feeding

Randomized trials

There are no phase 3 randomized trials that have yet reported outcome data. In the phase 1/2 trial BBIL/BBV152-A/2020, breast-feeding females were excluded, so no data are available for this subgroup [Ella R, 2021 ].

 

Immunocompromised persons

Randomized trials

There are no phase 3 randomized trials that have yet reported outcome data. In the phase 1/2 trial BBIL/BBV152-A/2020, immunocompromised patients were excluded, so no data are available for this subgroup [Ella R, 2021 ].

Safety of the vaccine post-authorization

Post-authorization studies

Comparative studies

No comparative study reported or evaluated this outcome.

Non-comparative studies 

Cherian S et al. was a non-comparative study carried out in India that included 724 participants with and without rheumatic and musculoskeletal diseases, vaccinated with at least one dose of Covashield or Covaxin vaccine. 436 (60.22%) participants had at least one adverse effect (AE). Four patients reported an arthritis flare that resolved within 5 days. No patient had severe AE or required hospitalization. All AE were self-limited. AE's do not differ between patients with autoimmune rheumatic disease (AIRD) or non-AIRD. Both the ChAdOx1 and BBV152 vaccines appear safe in patients with rheumatic and musculoskeletal diseases [Cherian S, 2021 ].

 

Monitoring

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

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

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

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

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

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