Bharat Biotech COVID-19 vaccine

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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 ].
Suspension of supply [WHO, 2022 ]

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

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 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 (ANVISA, Brazil)
Authorization suspended.

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 jurisdictions in Latin America and the Caribbean
Guyana
Paraguay
Peru
Trinidad and Tobago

Authorization in other jurisdictions
Bahrain
Botswana
Comoros
Ethiopia
Iran
Malaysia
Mauritius
Nepal
Oman
Philippines
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).

Other manufacturers
Indian Immunologicals Ltd (IIL), located in India, produces the Covaxin drug substance for supplying Bharat Biotech to accelerate production.

Haffkine Biopharmaceutical Corporation, India. Manufacturer of the vaccine.

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

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, 2022 ].

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, 2022 ].

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 ].

 

Ingredients

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

The Bharat Biotech COVID-19 vaccine is administered as a series of two doses (0.5 mL each). According to the manufacturer’s product label, the vaccine can be administered with an interval of 4 weeks [WHO, 2022 ].

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, 10 and 20 doses [WHO, 2021 ].
The preferred site of injection is the deltoid muscle of the upper arm.

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


Booster dose [WHO, 2022 ]
A booster dose is recommended for the highest and high priority-use groups (i.e. older adults, health workers, persons with comorbidities), administered 4–6 months after completion of the primary series.

Once high booster dose coverage has been achieved in the highest priority-use group, countries may also consider a booster for other lower priority-use groups.

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


Heterologous schedule [WHO, 2022 ]
WHO supports a flexible approach to using different EUL COVID-19 vaccine products for different doses (heterologous schedule), and considers a total of 2 doses of any combination of EUL COVID-19 vaccines (e.g. 1 dose of BBV152 vaccine, and 1 dose of another EUL COVID-19 vaccine) to be a complete primary series.

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


Vaccination schedule for immunocompromised persons [WHO, 2022 ]
WHO recommends and extended primary series including an additional (third) dose for immunocompromised persons aged 18 years and older, administered 1–3 months after the second dose in the standard primary series.
A booster (fourth) dose administered 3–6 months after the additional (third) dose should be considered for immunocompromised persons.

Indications and contraindications

Indications

The Bharat Biotech COVID-19 vaccine is indicated in individuals 18 of age and over [WHO, 2022 ].

Contrandications

The vaccine is contraindicated in individuals with a known history of a severe allergic reaction to any component of the Bharat Biotech COVID-19 vaccine [WHO, 2022 ]. (See the list of ingredients under 'General characteristics' in the extended version).

The second dose of the vaccine should NOT BE GIVEN to those who have experienced anaphylaxis to the first dose of Bharat Biotech COVID-19 vaccine.

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

Precautions

Allergic reactions [WHO, 2022 ].
Persons with a history of anaphylaxis to any other vaccine or injectable therapy should be observed for 30 minutes after vaccination in health care settings where anaphylaxis can be immediately treated.

Pregnancy [WHO, 2022 ].
Available data from clinical trials are still insufficient to assess vaccine safety or efficacy of the Bharat Biotech COVID-19 vaccine in pregnancy. Emerging post-introduction pharmacovigilance data have not identified any pregnancy-related safety concerns.

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

Breastfeeding [WHO, 2022 ].
WHO recommends using the Bharat Biotech COVID-19 vaccine in breastfeeding as in non-breastfeeding women. This is based on the following considerations: (a) Vaccine effectiveness is expected to be similar in breastfeeding women as in other adults, and (b) Bharat Biotech COVID-19 is not a live virus vaccine, and it is biologically and clinically unlikely to pose a risk to the breastfeeding child.
WHO does not recommend discontinuing breastfeeding after vaccination.

Children and adolescents [WHO, 2022 ].
Until EUL authorization for this age group has been granted, vaccination of individuals below 18 years of age with this vaccine is not recommended.

Older persons [WHO, 2022 ].
Vaccination is recommended for older persons, booster dose is recommended for the highest and high priority-use groups such as older adults, administered 4–6 months after completion of the primary series.

Persons living with HIV [WHO, 2022 ].

Given that the vaccine is nonreplicating, persons living with HIV who are well controlled may be vaccinated with the standard primary series of two doses. Counseling should be provided to inform the individual benefit-risk assessment.

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

Persons with current acute COVID-19 [WHO, 2022 ].

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

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

Other precautions
Vaccination should be postponed in individuals with an acute febrile illness (body temperature over 38.5ºC) until they are afebrile [WHO, 2022 ].

Co-administration with other vaccines [WHO, 2022 ].
For adults, COVID-19 vaccines may be administered concomitantly or at any time before or after other adult vaccines, including: live attenuated vaccines, inactivated, adjuvanted, or non-adjuvanted vaccines.


















Adults: Based on several co-administration studies of COVID-19 and other adult vaccines, vaccines for COVID-19 can be administered concomitantly with, or at any time before or after, other adult vaccines, including live attenuated vaccines, inactivated, vaccines with or without adjuvant [WHO, 2022 ].

When administered concomitantly, the vaccines should be injected at separate sites, preferably different extremities [WHO, 2022 ].

Storage and logistics

Storage

Bharat Biotech COVID-19 vaccine is provided as a suspension stored at 5°C/41°F (between 2°C to 8°C [35° to 46°F]).
Unopened vaccine vials can be stored refrigerated between 2°C to 8°C [35° to 46°F] for up to 9 months [WHO, 2021 ].
Protect the vials from light.
Do not freeze.

Administration logistics

Inspect the vial before administration.
The vial should be discarded if particles or differences are observed in the described appearance of the vaccine.
Gently invert the vaccine vial several times to homogenize the contents. Do not shake.

Storage after first puncture

Once the multidose vial of the vaccine is opened, it can be stored between 2°C and 8°C (36 ° F to 46 ° F) during the immunization session and discarded within 6 hours of opening (first puncture) or at the end of the session, whichever comes first [WHO, 2021 ].

The single-dose vial should be used immediately after opening.
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 BBIL/BBV152-A/2020 trial, (NCT04471519 [Bharat Biotech International Limited, 2020 ]) was conducted in India and initiated in July 2020. Phase 1 enrolled healthy adults aged 18 to 55 years who were randomly assigned to receive one of three vaccine formulations (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) or a control vaccine group. Two intramuscular doses were administered on days 0 and 14. Phase 2 included adults and adolescents (12 to 65 years) who were randomly assigned (1:1) to receive 3 μg with Algel-IMDG or 6 μg with Algel-IMDG. IMDG [Venkata V Edara, 2022 ], [Deshpande GR, 2022 ], [Vadrevu KM, 2022 ], [Ella R, 2021 ], [Ella R, 2021 ], [Bharat Biotech International Limited, 2020 ], [Krishna Mohan Vadrevu, 2022 ].

Phase 3:
The trial conducted by Ella R et al. (NCT04641481 [Bharat Biotech International Limited, 2020 ]) in India from November 2020, enrolled 24,419 adults aged 18 years and older randomized in a 1:1 ratio, who received either two 6 µg intramuscular doses of BBV152 or placebo on days 0 and 28 [Ella R, 2021 ].

Vaccine efficacy and effectiveness

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 the Bharat Biotech COVID-19 vaccine

Key messages

Bharat Biotech COVID-19 vaccine reduces the risk of contracting COVID-19

Bharat Biotech COVID-19 vaccine reduces the risk of contracting severe COVID-19

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
The differential efficacy of the vaccine in sex groups was not reported in the phase 3 trial conducted by Ella et al. [Ella R, 2021 ].
   
Age
Randomized trials
The proportion of patients >60 years of age in the phase 3 trial conducted by Ella et al. was 10.95% (1858 out of 16973 participants) [Ella R, 2021 ].
Vaccine efficacy was 67.8% (95% CI, 8% to 90%) in the ≥60 years group [Ella R, 2021 ].

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
Children and adolescents were excluded from the phase 3 trial conducted by Ella et al. [Ella R, 2021 ], therefore no data are available for this subgroup.

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
Pregnant women were excluded from the phase 3 trial conducted by Ella et al. [Ella R, 2021 ], therefore no data are available for this subgroup.

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
Breastfeeding women were excluded from the phase 3 trial conducted by Ella et al. [Ella R, 2021 ], therefore no data are available for this subgroup.

In the phase 1/2 trial BBIL/BBV152-A/2020, breastfeeding females were excluded, so no data are available for this subgroup [Ella R, 2021 ].
  
Immunocompromised persons
Randomized trials
Immunocompromised persons were excluded from the phase 3 trial conducted by Ella et al. [Ella R, 2021 ], therefore no data are available for this subgroup.

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 ].

Vaccine effectiveness (other comparative studies)

Contracting COVID-19
Sumit Malhotra et al. was a cohort study conducted in India. The study enrolled 12,237 participants: 8,248 vaccine group; 3,989 control group. Based on data from different HCWs employed at the All India Institute of Medical Sciences (AIIMS), New Delhi, India, a public-funded, teaching and multi-speciality tertiary care institute, between April 10 and June 24, 2021, the study results showed a vaccine effectiveness of 44% (95% CI 37 to 51) against symptomatic infection, hospitalization or death and a vaccine effectiveness of 61% (95% CI 37 to 76) against hospitalization or death [Sumit Malhotra, 2022 ].

Malhotra S et al. was a retrospective cohort study conducted in India. The study included 1,917 health care workers for vaccine effectiveness assessment: 1,089 in fully vaccinated group, 356 in partially vaccinated group and 472 in unvaccinated group. The aim was to assess the incidence density of reinfection among a cohort of HCWs and estimate the effectiveness of the inactivated whole virion vaccine BBV152 against reinfection. The estimated effectiveness of BBV152 against reinfection was 86% (95% CI 77% to 92%); symptomatic reinfection, 87% (95% CI, 76%-93%); and asymptomatic reinfection, 84% (95% CI, 47%-95%) among fully vaccinated HCWs. Partial vaccination was not associated with reduced risk of reinfection [Malhotra S, 2022 ].

Contracting severe COVID-19
Sumit Malhotra et al. was a cohort study conducted in India. The study enrolled 12,237 participants: 8,248 vaccine group; 3,989 control group. Based on data from different HCWs employed at the AllIndia Institute of Medical Sciences (AIIMS), New Delhi, India, a public-funded, teaching and multi-speciality tertiary care institute, between April 10 and June 24, 2021, the study results showed a vaccine effectiveness of 44% (95% CI 37 to 51) against symptomatic infection, hospitalization or death and a vaccine effectiveness of 61% (95% CI 37 to 76) against hospitalization or death [Sumit Malhotra, 2022 ]. 
Bhatnagar T was a case-control study conducted in India. The study enrolled 3684 participants older than 45 years that were attended 11 hospitals between May and July 2021. For the primary vaccine effectiveness (VE) analysis, the proportion of fully vaccinated and unvaccinated individuals was compared among cases (test-confirmed severe COVID-19 patients, n= 1143) and controls (negative RT-PCR for SARS-CoV-2, n= 2541). The study results showed that VE in fully vaccinated individuals was 71% (95% CI 57 to 81%) against severe COVID-19 and that it was significantly higher (P = 0.027) than partial vaccination [39% (95% CI: 2-62%)]. The VE for fully vaccinated individuals with an interval of 6-8 weeks for BBV152/Covaxin was 93% (95% CI: 34-99%) [Bhatnagar T, 2022 ].

Transmission
No studies reported or assessed this outcome

Efficacy and effectiveness against SARS-CoV-2 variants

Immunogenicity outcomes
Alpha (B.1.1.7)
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 neutralisation 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 ].

BBIL/BBV152-A/2020 was a phase 2, randomized, controlled, trial in India, in which 184 vaccine recipients were included. The study reported data from 243 days post-immunization. The results showed that 6 months after a two-dose Bharat Biotech vaccination series cell-mediated immunity and neutralizing antibodies to both homologous (D614G) and heterologous strains (Alpha, Beta, Delta, and Delta plus) persisted above baseline, although the magnitude of the responses had declined. Neutralizing antibodies against homologous and heterologous SARS-CoV-2 variants increased 19- to 97-fold after a third vaccination[Krishna Mohan Vadrevu, 2022 ].

Vikkurthi et al. examined the immune memory in 97 SARS-CoV-2 unexposed individuals who had received BBV152 vaccine, up to 6 months (median, 4 months) after 2-dose vaccination. They compared the vaccine-induced responses with the immune memory in 99 individuals recovered from mild COVID-19.  The samples in the infection group were collected between October 2020 and January 2021. The samples were collected 130 or 214 days (median) post the second dose of BBV152 vaccine or the diagnosis of COVID-19, respectively. The neutralizing potential: vaccine-induced antibodies had no significant impact on the Alpha variant (1.2-fold vs ancestral). Breadth of RBD-specific B cells in their reactivity to the SARS-CoV-2 variants: The modest reduction of 1.5 to 2-fold was observed against the Alpha variant over the ancestral virus RBD-specific IgG+ B cells. BBV152-induced CD4+ T cells: were not reduced significantly against Alpha as compared with the ancestral virus spike protein (mean %, ancestral: 0.39±0.07; Alpha: 0.31±0.05). The reactivity profile of CD4+ T cells acquired from natural infection was comparable with that of the vaccine, except that the median decline was ~2-fold for Alpha (P=0.004) [Vikkurthi R, 2022 ].

Beta (B.1.351)
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 Beta variant (GMT: 187.5 (95%CI 129.3 to 271.9)) [Yadav PD, 2021 ].

BBIL/BBV152-A/2020 was a phase 2, randomized, controlled, trial in India, in which 184 vaccine recipients were included. The study reported data from 243 days post-immunization. The results showed that 6 months after a two-dose Bharat Biotech vaccination series cell-mediated immunity and neutralizing antibodies to both homologous (D614G) and heterologous strains (Alpha, Beta, Delta, and Delta plus) persisted above baseline, although the magnitude of the responses had declined. Neutralizing antibodies against homologous and heterologous SARS-CoV-2 variants increased 19- to 97-fold after a third vaccination[Krishna Mohan Vadrevu, 2022 ].

Deshpande et al. was a comparative study conducted in India, derived from the BBIL/BBV152-A/2020 trial. The study evaluated the antibody responses in sera of participants who received two doses of Covaxin collected 6 months post second dose (2 dose group, n = 51) and 28 days after receiving a booster dose (booster dose group, n = 49) and its impact against the Beta VOC. The anti-SARS CoV-2 spike (S1-RBD) and nucleocapsid (N) IgG binding antibodies levels were characterized by ELISA and the plaque reduction neutralization test (PRNT) was used to assess the neutralizing antibody (Nab) capacity against prototype B.1, Alpha, Beta, Delta and Omicron variants. The study showed a fold increase of 2.8 (95% CI 2.65 to 2.95) in anti-S1-RBD IgG GM titers between the 2 dose and booster dose groups and a fold increase of 14.7 (95% CI 26.87 to 8.04), p=0.0002 in NAbs titers against Beta variant between the two groups [Deshpande GR, 2022 ].

Vadrevu et al. conducted a report on the immunogenicity of the Covaxin booster dose against the ancestral variant and those of concern, at one year of follow-up of the BBIL/BBV152-A/2020 trial. Patients were followed up to 6 months after the second dose to assess the durability of immune responses, then participants who previously received the 6 µg dose with Algel-IMDG were randomized to receive a third (boost) dose of BBV152 or placebo. Neutralizing antibody GMTs against SARS-CoV-2 variants were assessed by PRNT on days 208 and 243 in the booster group. GMTs against the Beta variant were 549 (374–805) and 41-fold increases from day 208. [Vadrevu KM, 2022 ]

Vikkurthi et al. examined the immune memory in 97 SARS-CoV-2 unexposed individuals who had received BBV152 vaccine, up to 6 months (median, 4 months) after 2-dose vaccination. They compared the vaccine-induced responses with the immune memory in 99 individuals recovered from mild COVID-19.  The samples in the infection group were collected between October 2020 and January 2021. The samples were collected 130 or 214 days (median) post the second dose of BBV152 vaccine or the diagnosis of COVID-19, respectively. The neutralizing potential: vaccine-induced antibodies declined significantly against Beta (1.7-fold vs ancestral; P=0.03) variant. Breadth of RBD-specific B cells in their reactivity to the SARS-CoV-2 variants: The modest reduction of 1.5 to 2-fold was observed against the Beta variant over the ancestral virus RBD-specific IgG+ B cells. BBV152-induced CD4+ T cells:. A significant decline was observed in the Beta variant, the median reduction was 1.3-fold over the ancestral virus (0.25±0.04; P=0.004). The reactivity profile of CD4+ T cells acquired from natural infection was comparable with that of the vaccine, except that the median decline was ~2-fold for Beta (P=0.0003) [Vikkurthi R, 2022 ].

Delta (B.1.617.2)
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 ].

BBIL/BBV152-A/2020 was a phase 2, randomized, controlled, trial in India, in which 184 vaccine recipients were included. The study reported data from 243 days post-immunization. The results showed that 6 months after a two-dose Bharat Biotech vaccination series cell-mediated immunity and neutralizing antibodies to both homologous (D614G) and heterologous strains (Alpha, Beta, Delta, and Delta plus) persisted above baseline, although the magnitude of the responses had declined. Neutralizing antibodies against homologous and heterologous SARS-CoV-2 variants increased 19- to 97-fold after a third vaccination[Krishna Mohan Vadrevu, 2022 ].

Das et al. was a non-comparative study conducted in India, the study analyzed the immune response against wild variants, Delta and Omicron after a first dose of the Bharat vaccine. The study updated data from 94 people scheduled to receive their first dose of the Bharat vaccine for COVID-19. The results are based on blood samples collected one day before and 4 weeks after the first dose of the vaccine. The study showed increases in neutralizing test titers for all variants compared to baseline. However, this increase was insignificant or modest against the delta and omicron variants in people who had been infected before receiving the vaccine [Das, S., 2022 ].

Deshpande et al. was a comparative study conducted in India, derived from the BBIL/BBV152-A/2020 trial. The study evaluated the antibody responses in sera of participants who received two doses of Covaxin collected 6 months post second dose (2 dose group, n = 51) and 28 days after receiving a booster dose (booster dose group, n = 49) and its impact against the Delta VOC. The anti-SARS CoV-2 spike (S1-RBD) and nucleocapsid (N) IgG binding antibodies levels were characterized by ELISA and the plaque reduction neutralization test (PRNT) was used to assess the neutralizing antibody (Nab) capacity against prototype B.1, Alpha, Beta, Delta and Omicron variants. The study showed a fold increase of 2.8 (95% CI 2.65 to 2.95) in anti-S1-RBD IgG GM titers between the 2 dose and booster dose groups and a fold increase of 16.54 (95% CI 34.08 to 8.03), p<0.0001 in NAbs titers against Delta variant between the two groups [Deshpande GR, 2022 ].

Vadrevu et al. conducted a report on the immunogenicity of the Covaxin booster dose against the ancestral variant and those of concern, at one year of follow-up of the BBIL/BBV152-A/2020 trial. Patients were followed up to 6 months after the second dose to assess the durability of immune responses, then participants who previously received the 6 µg dose with Algel-IMDG were randomized to receive a third (boost) dose of BBV152 or placebo. Neutralizing antibody GMTs against SARS-CoV-2 variants were assessed by PRNT on days 208 and 243 in the booster group. The GMTs against the Delta and Delta Plus variant were 369 (222–614) and 310 (198–483), 410- and 281-fold increases from day 208, respectively. Sera collected after 6 months after the third dose were evaluated for neutralization efficacy against Delta by PRNT50, obtaining GMT 159.9 (55.8–240.8) and a seroconversion rate of 96.8 ( 81.5–99.8) in the booster group. [Vadrevu KM, 2022 ]

Vikkurthi et al. examined the immune memory in 97 SARS-CoV-2 unexposed individuals who had received BBV152 vaccine, up to 6 months (median, 4 months) after 2-dose vaccination. They compared the vaccine-induced responses with the immune memory in 99 individuals recovered from mild COVID-19.  The samples in the infection group were collected between October 2020 and January 2021. The samples were collected 130 or 214 days (median) post the second dose of BBV152 vaccine or the diagnosis of COVID-19, respectively. The neutralizing potential: vaccine-induced antibodies declined significantly against the Delta (2-fold vs ancestral; P<0.0001). Breadth of RBD-specific B cells in their reactivity to the SARS-CoV-2 variants:  A ~2-fold reduction in vaccine-induced IgG+ B cells was observed against the Delta variant. BBV152-induced CD4+ T cells: were not reduced significantly against Delta as compared with the ancestral virus spike protein (mean %, ancestral: 0.39±0.07; Delta: 0.28±0.05) [Vikkurthi R, 2022 ].

Omicron (B.1.1.529)
BBIL/BBV152-A/2020 was a phase 2, randomized, controlled, trial in India, in which 184 vaccine recipients were included. The study reported data from 243 days post-immunization. The results showed that 6 months after a two-dose Bharat Biotech vaccination series cell-mediated immunity and neutralizing antibodies to both homologous (D614G) and heterologous strains (Alpha, Beta, Delta, and Delta plus) persisted above baseline, although the magnitude of the responses had declined. Neutralizing antibodies against homologous and heterologous SARS-CoV-2 variants increased 19- to 97-fold after a third vaccination[Krishna Mohan Vadrevu, 2022 ].

Das et al. was a non-comparative study conducted in India, the study analyzed the immune response against wild variants, Delta and Omicron after a first dose of the Bharat vaccine. The study updated data from 94 people scheduled to receive their first dose of the Bharat vaccine for COVID-19. The results are based on blood samples collected one day before and 4 weeks after the first dose of the vaccine. The study showed increases in neutralizing test titers for all variants compared to baseline. However, this increase was insignificant or modest against the delta and omicron variants in people who had been infected before receiving the vaccine [Das, S., 2022 ].

Deshpande et al. was a comparative study conducted in India, derived from the BBIL/BBV152-A/2020 trial. The study evaluated the antibody responses in sera of participants who received two doses of Covaxin collected 6 months post second dose (2 dose group, n = 51) and 28 days after receiving a booster dose (booster dose group, n = 49) and its impact against the Omicron VOC. The anti-SARS CoV-2 spike (S1-RBD) and nucleocapsid (N) IgG binding antibodies levels were characterized by ELISA and the plaque reduction neutralization test (PRNT) was used to assess the neutralizing antibody (Nab) capacity  against prototype B.1, Alpha, Beta, Delta and Omicron variants. The study showed a fold increase of 2.8 (95% CI 2.65 to 2.95) in anti-S1-RBD IgG GM titers between the 2 dose and booster dose groups and a fold increase of 18.53 (95% CI 28.92 to 11.88), p=0.0002 in NAbs titers between the two groups [Deshpande GR, 2022 ].

Vadrevu et al. conducted a report on the immunogenicity of the Covaxin booster dose against the ancestral variant and those of concern, at one year of follow-up of the BBIL/BBV152-A/2020 trial. Patients were followed up to 6 months after the second dose to assess the durability of immune responses, then participants who previously received the 6 µg dose with Algel-IMDG were randomized to receive a third (boost) dose of BBV152 or placebo. The results showed an 18.5-fold increase in neutralizing antibody titers against the Omicron variant after the booster dose of BBV15215, compared to recipients who did not receive a boost. 90% of subjects receiving the third dose of COVAXIN® showed neutralizing activity against the Omicron variant when tested 28 days after the third dose of serum. Sera collected 6 months after the third dose were evaluated for neutralization efficacy against Omicron by PRNT50, yielding GMT 25.7 (13.0–50.6) and a seroconversion rate of 93.5 ( 77.2–98.9) in the booster group. [Vadrevu KM, 2022 ]

Efficacy outcomes
Delta (B.1.617.2)
Ella R et al. was a multicenter, phase 3, randomised 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 a 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 ].

Effectiveness outcomes
Delta (B.1.617.2)
Bhatnagar T was a case-control study conducted in India. The study enrolled 3684 participants older than 45 years that were attended 11 hospitals between May and July 2021. For the primary vaccine effectiveness (VE) analysis, the proportion of fully vaccinated and unvaccinated individuals was compared among cases (test-confirmed severe COVID-19 patients, n= 1143) and controls (negative RT-PCR for Sars-CoV-2, n= 2541). The study results showed that VE against the Delta variant and sub-lineages was 66% (95% CI: 42-80%) for complete dose and 41% (95% CI: 0-70%) for vaccination with partial dose of BBV152/Covaxin (p= 0.261) [Bhatnagar T, 2022 ].

Vaccine efficacy and effectiveness for booster dose

Immunogenicity outcomes
BBIL/BBV152-A/2020 was a phase 2, randomized, controlled, trial in India, in which 184 vaccine recipients were included. The study reported data from 243 days post-immunization. The results showed that 6 months after a two-dose Bharat Biotech vaccination series cell-mediated immunity and neutralizing antibodies to both homologous (D614G) and heterologous strains (Alpha, Beta, Delta, and Delta plus) persisted above baseline, although the magnitude of the responses had declined. Neutralizing antibodies against homologous and heterologous SARS-CoV-2 variants increased 19- to 97-fold after a third vaccination [Krishna Mohan Vadrevu, 2022 ].

A new BBIL/BBV152-A/2020 study report included 13 booster vaccine recipients. Data were collected 28 days after the booster dose. The study showed that All subjects showed neutralizing activity against the Delta variant. There was however a 1.5 fold reduction compared to neutralization against the vaccine strain. In addition, 90% of subjects showed neutralizing activity against the Omicron variant. There was however a 9.4 fold reduction compared to neutralization against the vaccine strain [Venkata V Edara, 2022 ].

Deshpande et al. was a comparative study conducted in India, derived from the BBIL/BBV152-A/2020 trial. The study evaluated the antibody responses in sera of participants who received two doses of Covaxin collected 6 months post second dose (2 dose group, n = 51) and 28 days after receiving a booster dose (booster dose group, n = 49) and its impact against the Omicron VOC. The anti-SARS CoV-2 spike (S1-RBD) and nucleocapsid (N) IgG binding antibodies levels were characterized by ELISA and the plaque reduction neutralization test (PRNT) was used to assess the neutralizing antibody (Nab) capacity  against prototype B.1, Alpha, Beta, Delta and Omicron variants. The study showed a fold increase of 2.8 (95% CI2.65 to 2.95) in anti-S1-RBD IgG GM titers between the 2 dose and booster dose groups and a fold increase of 18.53 (95% CI 28.92 to 11.88), p=0.0002 in NAbs titers between the two groups [Deshpande GR, 2022 ].

Vadrevu et al. conducted a report on the immunogenicity of the Covaxin booster dose against the ancestral variant and those of concern, at one year of follow-up of the BBIL/BBV152-A/2020 trial. Patients were followed up to 6 months after the second dose to assess the durability of immune responses, then participants who previously received the 6 µg dose with Algel-IMDG were randomized to receive a third (boost) dose of BBV152 or placebo. The results showed persistence of cell-mediated and humoral immunity up to 12 months after vaccination, despite the decrease in the magnitude of antibody titers. Administration of a third dose of BBV152 increased neutralization titers against both homologous (D614G) and heterologous (Alpha, Beta, Delta, Delta Plus, and Omicron) strains with a slight increase in B-cell memory responses. Thus, the seronversion rate remains high in boosted compared with unboosted recipients, even after 6 months, after the third dose against the variants. No serious adverse events except injection site pain, itching, and redness were observed. [Vadrevu KM, 2022 ]

Vaccine efficacy and effectiveness for heterologous schedule

Currently, there are no studies that have assessed the vaccine immunogenicity outcomes on heterologous regimen.

Vaccine efficacy and effectiveness for heterologous booster schedule

Currently, there are no studies that have assessed the vaccine results for heterologous booster schedule.

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
In the phase 3 randomized trial conducted by Ella et al. the proportion of participants 60 years of age or older was 10.7% (2761 out of 25753) in the safety population. The proportion of participants >60 years that experienced adverse events was not reported in detail. However, no specific safety concerns were identified in this subgroup [Ella R, 2021 ].

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
Children and adolescents below 18 years of age were excluded from the phase 3 trial conducted by Ella et al., therefore no data are available for this subgroup [Ella R, 2021 ].

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
Pregnant women were excluded from the phase 3 trial conducted by Ella et al. therefore no data are available for this subgroup [Ella R, 2021 ].

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
Breastfeeding women were excluded from the phase 3 trial conducted by Ella et al. therefore no data are available for this subgroup [Ella R, 2021 ].

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
Immunocompromised persons were excluded from the phase 3 trial conducted by Ella et al. therefore no data are available for this subgroup [Ella R, 2021 ].

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
Joshi PC et al was a cohort study conducted in India. The study enrolled 3,235 participants: 828 vaccine group; 2,407 control group and assessed CT-Severity Score in vaccinated and non-vaccinated subjects who were diagnosed with COVID-pneumonia or were COVID suspects, based on findings in high resolution CT scans. The study results showed a CT Severity score median difference amongst non-vaccinated cases, cases with history of 1 dose and fully vaccinated cases of 7.0, 5.0, and 3.0 respectively in the 18-44 years group; 9.0, 7.0, and 7.0 respectively in the 45-59 years group and 9.0, 8.0 and 6.0 respectively in the >60 years group [Joshi PC, 2021 ].
  
Vadrevu KM et al was a cohort study conducted in 6 hospitals in India. The study included 526 children between the ages of 2 and 18 who were enrolled in three groups, depending on their age: group 1 (12 to 18 years, n= 176); group 2 (6 to 12 years old, n= 175) and group 3 (2 to 6 years old, n= 175). The objective of the study was to evaluate the safety, reactogenicity and immunogenicity of vaccination with the adult formulation of BBV152 in children, on days 0 (first dose) and 28 (second dose). The results of the study showed that there were no serious adverse events, deaths or withdrawals due to an adverse event during the period, with the exception of one case of COVID-19 in group 1. Local reactions consisted mainly of mild pain at the site of injection (35% of any group after the first dose and less than 25% after the second dose). Mild to moderate fever was reported in 5% in Group 1, 10% in Group 2, and 13% in Group 3. No cases of severe fever were reported, and total fever rates were 4% or less after the second dose [Vadrevu KM, 2022 ].

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 ].

Parida SP et al. was a non-comparative study conducted in India. The study enrolled 1826 participants and assessed the adverse events following COVID‐19 vaccine immunization at a tertiary care institution and also assessed the predictors of the adverse events following immunization. The study results showed that the major factors associated with AEFI were female sex, history of an allergicreaction, presence of comorbidities, acute infection in the past 3 months, and intake ofchronic medications [Parida SP, 2022 ].

Nasergivehchi S et al. was a cohort study conducted in Iran. The study enrolled 334 healthcare workers who had contracted COVID-19 of different intensities and were vaccinated with different types of COVID-19 vaccine (Astrazeneca 12.9%, Sinopharm 16.2%, Sputnik 62.3%,Bharat Covaxin 6.9%) at least one month following recovery from the virus, between April 2021 and September 2021. The study assessed the incidence of headache following injection, showing that 39.2% of participants reported post-vaccination headache, with highest rates reported for AstraZeneca, followed by Sputnik V [Nasergivehchi S, 2022 ].

Houshmand B et al. was a cross-sectional study conducted in Iran. The study included 1,205 respondents of a multicenter electronic questionnaire via an online platform over a 1-week period among vaccinated dental staff and dental students inquiring whether they experienced vaccine-related side-effects after vaccine administration.  The majority of respondents received AstraZeneca (51.1%) and Sputnik (37.6%). The symptoms most frequently reported after vaccination were fatigue (79%), local pain in the injection site (77.4%), malaise (73%), and body pain (71.1%). Enrollees reported more onset of reactions on 0–12 h (44.1%) and 12–24 h (29.0%) after vaccine administration [Houshmand B, 2022 ].

Monitoring

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

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

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

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

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

References

[WHO, 2021] WHO. WHO recommendation Bharat Biotech International Ltd – COVID-19 vaccine (Whole Virion Inactivated Corona Virus. 2021; WHO. WHO recommendation Bharat Biotech International Ltd – COVID-19 vaccine (Whole Virion Inactivated Corona Virus. 2021;
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