Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19: grading of evidence, evidence to recommendations tables, first issued 25 September 2023

Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 Grading of evidence Evidence to recommendations tables First issued 25 September 2023 Background These are the annexes to the Interim recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19. Annexes 1–6 contain tables that summarize the grading of recommendations, assessment, development and evaluations (GRADE). Annexes 7–9 contain the SAGE evidence-to-recommendation framework tables (ETR tables). The ETR tables are based on the DECIDE Work Package 5: Strategies for communicating evidence to inform decisions about health system and public health interventions. Evidence to a recommendation (for use by a guideline panel) (www.decide-collaboration.eu/, accessed 9 December 2021). Contents Annex 1. GRADE table: Efficacy of BECOV-2 COVID-19 vaccine in adults (18-80 years) ......................................... 2 Annex 2. GRADE table: Safety of BECOV-2 vaccine in adults (18-80 years) ............................................................... 3 Annex 3. GRADE table: Efficacy of BECOV-2 COVID-19 vaccine in adolescents (12<18 years) ............................... 4 Annex 4. GRADE table: Safety of BECOV-2 vaccine in adolescents (12<18 years) ..................................................... 5 Annex 5. GRADE table: Efficacy of BECOV-2 COVID-19 vaccine in children (5 to <12 years) ................................. 6 Annex 6. GRADE table: Safety of BECOV-2 vaccine in children (5 to <12 years) ....................................................... 7 Annex 7. SAGE evidence-to-recommendation framework: BECOV-2 vaccine’s use in adults...................................... 8 Annex 8. SAGE evidence-to-recommendation framework: BECOV-2 vaccine’s use in adolescents ........................... 18 Annex 9. SAGE evidence-to-recommendation framework: BECOV-2 vaccine’s use in children ................................ 27 Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -2- Annex 1. GRADE table: Efficacy of BECOV-2 COVID-19 vaccine in adults (18-80 years) Population: Adults (18–80 years) Intervention: Two doses of BECOV-2 vaccine Comparison: Active control (ChAdOx1-S) Outcome: COVID-19 (PCR-confirmed) What is the efficacy of two doses of BECOV-2 vaccine compared with active control (ChAdOx1-S) in preventing PCR-confirmed COVID-19 in adults (18–80 years)? Rating Adjustment to rating Q ua lit y A ss es sm en t No. of studies/starting rating 1/ RCT(1) 4 Factors decreasing confidence Limitation in study designa Not serious 0 Inconsistency Not serious 0 Indirectness Very seriousb -2 Imprecision Not serious 0 Publication bias Undetected 0 Factors increasing confidence Large effect Not applicable 0 Dose-response Not applicable 0 Antagonistic bias and confounding Not applicable 0 Final numerical rating of quality of evidence 2 Su m m ar y of F in di ng s Statement on quality of evidence Evidence supports a limited level of confidence that the true effect lies close to the estimate of the effect on the health outcome (level 2). Conclusion Vaccine efficacy in adults (18–80 years) is inferred by demonstrating a superiority in immune response between BECOV-2 vaccine and ChAdOx1-S vaccine for which efficacy against PCR-confirmed COVID-19 has been estimated. The confidence in the quality of evidence is limited due the indirectness of the data. a For the risk of bias assessments using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2), which noted no concerns for the primary efficacy outcome of neutralizing antibodies (NAb), please see www.covid-nma.com/vaccines. b No efficacy estimates were obtained. Protection of BECOV-2 vaccine is inferred by immunobridging to ChAdOx1-S vaccine (geometric mean titres (GMT) ratio 1.15 (95% CI: 1.02–1.32); with regulatory significance >0.67. Participants 18-80 years (that included about 6% of people between 60-80 years) were randomized equally to receive two doses of either vaccine. This indirect data for estimating vaccine effectiveness was considered as constituting a very serious limitation that led to downgrading of the evidence by two levels. There is no sub-group data for the elderly population from the phase 3 study but from the phase 2/3 study for the elderly cohort (45 to 80 years) the seroconversion was 88% for both the anti-RBD concentrations and the NAb titres compared to 95% and 90% for the young cohort (18 to 45 years) respectively. Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -3- Annex 2. GRADE table: Safety of BECOV-2 vaccine in adults (18-80 years) Population: Adults (18–80 years) Intervention: One or two doses of BECOV-2 vaccine Comparison: Active control (ChAdOx1-S) Outcome: Serious adverse events (SAEs) following immunization What is the risk of serious adverse events following BECOV-2 vaccination compared with active control (ChAdOx1-S) in adults (18–80 years)? Rating Adjustment to rating Q ua lit y A ss es sm en t No. of studies/starting rating 1/ RCT(1) 4 Factors decreasing confidence Limitation in study designa Serious -1 Inconsistency Not serious 0 Indirectness Not serious 0 Imprecision Very seriousb -2 Publication bias Undetected 0 Factors increasing confidence Large effect Not applicable 0 Dose-response Not applicable 0 Antagonistic bias and confounding Not applicable 0 Final numerical rating of quality of evidence 1 Su m m ar y of F in di ng s Statement on quality of evidence Evidence supports a very limited level of confidence that the true effect lies close to the estimate of the effect on the health outcome (level 1). Conclusion We have very low level of confidence in the evidence that the risk of serious adverse events following one or two doses of BECOV-2 vaccine in adults (18–80 years) is low due to the limitations in the study design, the imprecise estimate and because the trial was not adequately powered to detect rare adverse events. a For the risk of bias assessments using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2), please see www.covid-nma.com/vaccines which noted some concerns and is therefore downgraded. This was due to the following limitation that the serious adverse events (SAE) contained both clinically- and laboratory-detected events, which could be influenced by knowledge of the intervention assignment. b RR= 0.88 (95%CI 0.04–18.30); downgraded for the following two limitations: the estimate of SAE was imprecise, and the trial was not adequately powered to detect rare adverse events (i.e. fewer than about 1 in 2000). There were no SAEs in either arm for the immunogenicity cohort, but two SAE were seen for BECOV-2 for the safety cohort (neither related to the vaccine; one case of dengue fever and one femur fracture). Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -4- Annex 3. GRADE table: Efficacy of BECOV-2 COVID-19 vaccine in adolescents (12<18 years) Population: Adolescents (12<18 years) Intervention: Two doses of BECOV-2 vaccine Comparison: Active control (BECOV-2 vaccine in adults) Outcome: COVID-19 (PCR-confirmed) What is the efficacy of two doses of BECOV-2 vaccine in adolescents compared with adults? Rating Adjustment to rating Q ua lit y A ss es sm en t No. of studies/starting rating 1/ RCT(2) 4 Factors decreasing confidence Limitation in study designa Not serious 0 Inconsistency Not serious 0 Indirectness Very seriousb -2 Imprecision Seriousc -1 Publication bias Undetected 0 Factors increasing confidence Large effect Not applicable 0 Dose-response Not applicable 0 Antagonistic bias and confounding Not applicable 0 Final numerical rating of quality of evidence 1 Su m m ar y of F in di ng s Statement on quality of evidence Evidence supports a very limited level of confidence that the true effect lies close to the estimate of the effect on the health outcome (level 1). Conclusion Vaccine efficacy in adolescents (12<18 years years) is inferred by immunobridging with adults, with both populations receiving BECOV-2 vaccine. The BECOV-2 vaccine has demonstrated a superiority in immune response compared to ChAdOx1-S vaccine for which efficacy against PCR-confirmed COVID-19 has been estimated. The confidence in the quality of evidence is very limited due the indirectness of the data and the imprecise effect estimate. a For the risk of bias assessments using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2), which noted no concerns for the primary efficacy outcome of neutralizing antibodies, please see www.covid-nma.com/vaccines. b No efficacy estimates were obtained. Protection of BECOV-2 vaccine in adolescents is inferred by immunobridging to adults. Immunogenicity data for participants 12<18 years were compared to those from the adults’ phase 2 study. This indirect data for estimating vaccine effectiveness was considered as constituting a very serious limitation that led to downgrading of the evidence by two levels. c GMT ratio 0.82 (95%CI 0.59–1.13), with regulatory significance >0.67. The evidence was downgraded by one level as the effect estimate was imprecise. Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -5- Annex 4. GRADE table: Safety of BECOV-2 vaccine in adolescents (12<18 years) Population: Adolescents (12<18 years) Intervention: One or two doses of BECOV-2 vaccine Comparison: Placebo Outcome: All adverse events following immunization What is the risk of adverse events following BECOV-2 vaccination in adolescents compared with placebo? Rating Adjustment to rating Q ua lit y A ss es sm en t No. of studies/starting rating 1/ RCT(2) 4 Factors decreasing confidence Limitation in study designa Not serious 0 Inconsistency Not serious 0 Indirectness Not serious 0 Imprecision Very seriousb -2 Publication bias Undetected 0 Factors increasing confidence Large effect Not applicable 0 Dose-response Not applicable 0 Antagonistic bias and confounding Not applicable 0 Final numerical rating of quality of evidence 2 Su m m ar y of F in di ng s Statement on quality of evidence Evidence supports a limited level of confidence that the true effect lies close to the estimate of the effect on the health outcome (level 2). Conclusion We have low confidence that there is a very risk of adverse events following one or two doses of BECOV-2 vaccine in adolescents (12<18 years) is low. This is because the trial was not adequately powered to detect rare adverse events and the imprecise effect estimate. a For the risk of bias assessments using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2), which noted no concerns for adverse events, please see www.covid-nma.com/vaccines. b RR=1.00 (95%CI 0.66–1.51); downgraded for the following two limitations: the trial was not adequately powered to detect rare adverse events (i.e. fewer than about 1 in 500) and wide confidence intervals were seen for the effect estimate. There were no SAEs in either arm of the study. Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -6- Annex 5. GRADE table: Efficacy of BECOV-2 COVID-19 vaccine in children (5 to <12 years) Population: Children (5 to <12 years) Intervention: Two doses of BECOV-2 vaccine Comparison: Active control (BECOV-2 vaccine in adults) Outcome: COVID-19 (PCR-confirmed) What is the efficacy of two doses of BECOV-2 vaccine in children compared with adults? Rating Adjustment to rating Q ua lit y A ss es sm en t No. of studies/starting rating 1/ RCT(2) 4 Factors decreasing confidence Limitation in study designa Not serious 0 Inconsistency Not serious 0 Indirectness Very seriousb -2 Imprecision Seriousc -1 Publication bias Undetected 0 Factors increasing confidence Large effect Not applicable 0 Dose-response Not applicable 0 Antagonistic bias and confounding Not applicable 0 Final numerical rating of quality of evidence 1 Su m m ar y of F in di ng s Statement on quality of evidence Evidence supports a very limited level of confidence that the true effect lies close to the estimate of the effect on the health outcome (level 1). Conclusion Vaccine efficacy in children (5 to <12 years) is inferred by immunobriding with adults, with both populations receiving BECOV-2 vaccine. The BECOV-2 vaccine has demonstrated a superiority in immune response compared to ChAdOx1-S vaccine for which efficacy against PCR-confirmed COVID-19 has been estimated. The confidence in the quality of evidence is limited due the indirectness of the data. a For the risk of bias assessments using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2), which noted no concerns for the primary efficacy outcome of neutralizing antibodies, please see www.covid-nma.com/vaccines. b No efficacy estimates were obtained. Protection of BECOV-2 vaccine in children is inferred by immunobridging to adults. Immunogenicity data for participants 12<18 years were compared to those from the adult phase 2 study. This indirect data for estimating vaccine effectiveness was considered as constituting a very serious limitation that led to downgrading of the evidence by two levels. c GMT ratio 0.86 (95%CI 0.62–1.18) with regulatory significance >0.67. The evidence was downgraded by one level as the effect estimate was imprecise. Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -7- Annex 6. GRADE table: Safety of BECOV-2 vaccine in children (5 to <12 years) Population: Children (5 to <12 years) Intervention: One or two doses of BECOV-2 vaccine Comparison: Placebo Outcome: All adverse events following immunization What is the risk of adverse events following BECOV-2 vaccination in children compared with placebo? Rating Adjustment to rating Q ua lit y A ss es sm en t No. of studies/starting rating 1/ RCT(2) 4 Factors decreasing confidence Limitation in study designa Not serious 0 Inconsistency Not serious 0 Indirectness Not serious 0 Imprecision Seriousb -1 Publication bias Undetected 0 Factors increasing confidence Large effect Not applicable 0 Dose-response Not applicable 0 Antagonistic bias and confounding Not applicable 0 Final numerical rating of quality of evidence 3 Su m m ar y of F in di ng s Statement on quality of evidence Evidence supports a moderate level of confidence that the true effect lies close to the estimate of the effect on the health outcome (level 3). Conclusion We are moderately confident that there is a very low risk of adverse events following one or two doses of BECOV-2 vaccine in children (5 to <12 years). This is because the trial was not adequately powered to detect rare adverse events. a For the risk of bias assessments using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2), which noted no concerns for adverse events, please see www.covid-nma.com/vaccines. b RR=0.67 (95%CI 0.45–0.99); downgraded for the following limitation: the trial was not adequately powered to detect rare adverse events (i.e. fewer than about 1 in 500). There were no SAEs in either arm of the study. Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -8- Annex 7. SAGE evidence-to-recommendation framework: BECOV-2 vaccine’s use in adults Question: Should BECOV-2 vaccine be administered to adults to prevent PCR-confirmed COVID-19? Population: Adults (18–80 years) Intervention: Two doses of BECOV-2 vaccine Comparison(s): Active control (ChAdOx1-S) Outcome: COVID-19 (PCR-confirmed) Background: On 31 December 2019, WHO was alerted to several cases of pneumonia of unknown origin in Wuhan City, Hubei Province, China. The cause was found to be a novel coronavirus, SARS-CoV-2. The disease caused by this novel virus has been named COVID-19. The outbreak of COVID-19 was declared a public health emergency of international concern in January 2020. The disease has since spread, with an enormous impact on the health and well-being of individuals and populations worldwide. It has further caused major disruptions to various sectors of society and the economy across the globe. Vaccines are a critical tool in combating the pandemic. In the rapidly evolving field of COVID-19 vaccines, WHO has issued, to date, interim recommendations on the use of a number of COVID-19 vaccines (3). CRITERIA JUDGEMENTS RESEARCH EVIDENCE ADDITIONAL INFORMATION PR O BL EM Is the problem a public health priority? No Uncertain Yes Varies by setting The COVID-19 situation is evolving rapidly. The cumulative number of COVID-19 deaths globally has surpassed 6 million. The most recent epidemiological situation can be found on the following website: https://covid19.who.int/table. ☐ ☐ ☒ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -9- There has been collateral damage to other public health programmes. BE N EF IT S & H A R M S O F TH E O PT IO N S Benefits of the intervention Are the desirable anticipated effects large? No Uncertain Yes Varies The phase 3 immuno-bridging trial was conducted in India. Participants aged ≥18 to ≤80 years in the immunogenicity arm were randomly assigned 1:1 to receive two doses of BECOV-2 (n=319) or ChAdOx1-S (n=329), 28 days apart; participants aged ≥18 to ≤80 years (n=1500) in the safety cohort received two doses of BECOV-2 open label. The GMTs neutralization antibody titres when assessed against ancestral strain gave a GMT ratio of 1.15 (95% CI: 1.02 –1.32) and when assessed against the Delta strain gave a GMT ratio of 1.56 (95% CI: 1.27 –1.91) (1). The seroconversion for BECOV-2 was 91% compared to 88% for the ChAdOx1-S. BECOV-2 had median 120 (IQR 43–249) or average 176 IFN-γ (interferon-gamma) secreting SFU (spot forming units) per million PBMCs (peripheral blood mononuclear cells) compared to median 40 (IQR 8–103) or average 99 IFN-γ SFU per million PBMCs for ChAdOx1-S, indicating a higher response for BECOV-2 (1). ☐ ☐ ☒ ☐ Harms of the intervention Are the undesirable anticipated effects small? No Uncertain Yes Varies From the immunogenicity cohort, 68 out of 319 (21·3%) participants reported adverse events (AEs) in the BECOV-2 arm and 136 out of 320 (42·5%) participants reported AEs in the ChAdOx1-S arm. The safety profile was comparable between the two arms in terms of medically From the heterologous booster phase 3 study participants previously vaccinated with 2 doses of either ChAdOx1-S or BBV152 as a primary series, received a single dose of BECOV-2, at 6- 9 months. All reported AEs were mild to ☐ ☐ ☒ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -10- attended AEs and AEs considered related to the vaccine, and no SAEs were reported. From the safety cohort, 553 out of 1500 (36.9%) participants reported AEs. The most AEs were injection site pain, pyrexia, myalgia, headache and fatigue. All AEs reported were mild or moderate in intensity. Two SAEs were reported in the safety cohort, none were related to the vaccine. There were no AEs reported in the first 60 minutes’ post vaccination, no AESIs and no deaths reported in the study. Most of the systemic events resolved within 1 to 2 days (1). moderate in intensity and no severe AEs were reported during the study. Additionally, no SAEs or AESI were reported during weekly follow-up up to 3 months after booster dose administration in any of the participants in any of the study arms. Balance between benefits and harms Favours interventi on Favours compariso n Favours both Favours neither Unclear Immunogenicity data suggest benefit, and safety data suggest minimal harms of two doses of both BECOV-2 and ChAdOx1-S vaccines. Further studies will need to be undertaken as part of post- marketing surveillance. ☐ ☐ ☒ ☐ ☐ What is the overall quality of this Effectiveness of the intervention Please see the related GRADE tables. No included studies Very low Low Moderate High Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -11- evidence for the critical outcomes? ☐ ☐ ☒ ☐ ☐ Safety of the intervention No included studies Very low Low Moderate High ☐ ☒ ☐ ☐ ☐ V A LU ES & P R EF ER EN C ES How certain is the relative importance of the desirable and undesirable outcomes? Important uncertaint y or variability Possibly important uncertaint y or variability Probably no important uncertaint y or variabilit y No important uncertain ty or variabilit y No known undesirab le outcomes Available scientific evidence on the relative importance of the intervention, as well as the relative weights that the target population attributes to the desirable (i.e. protection conferred by the vaccine) and the undesirable outcomes (i.e. the currently reported safety signals), varies. Different population groups may have different opinions regarding the weights assigned to desirable and undesirable outcomes. ☐ ☒ ☐ ☐ ☐ Values and preferences of the target population: Are the desirable effects large relative to undesirable effects? No Probabl y No Uncerta in Probabl y Yes Yes Varies The target population probably assigns more weight to the desirable effects than the undesirable effects related to COVID-19 vaccination. Targeted studies should assess this aspect. ☐ ☐ ☐ ☒ ☐ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -12- R ES O U R C E U SE Are the resources required small? No Uncertain Yes Varies BECOV-2 vaccine can be distributed and stored using existing cold-chain infrastructure and does not require ultra-cold-chain capacity. Nevertheless, considerable resources are needed to ensure the implementation of a COVID- 19 vaccination programme. Resources required include, but are not restricted to, human resources, vaccine costs, logistics, planning and coordination, training, social mobilization and communications, and immunization safety surveillance. COVAX, the vaccine pillar of the Access to COVID-19 Tools Accelerator (ACT- Accelerator), has now shipped over 1 billion doses of COVID-19 vaccine to 144 countries and territories (4). By January 2022, additional funding of at least US$ 5.2 billion was required for the Gavi COVAX Advance Market Commitment to establish a Pandemic Vaccine Pool of a minimum of 600 million additional vaccine doses to: address uncertainties and risks in the evolution of the virus; provide bundled finance to strengthen delivery systems in recipient countries; and cover essential ancillary costs (5). ☒ ☐ ☐ ☐ No Uncertain Yes Varies Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -13- Cost- effectivenes s ☐ ☐ ☐ ☒ Formal global cost- effectiveness analyses have not been conducted, but the emerging evidence indicates that the benefits, including the impact on recovery of the global economy, are likely to outweigh the cost of COVID- 19 vaccination in general at global level. No formal cost-effectiveness analyses of BECOV-2 vaccine compared with other vaccines have been conducted. The ability to use BECOV-2 in existing cold-chain infrastructure in all country settings may allow higher population-level coverage (6). Cost-effectiveness analyses should be conducted at country level; cost- effectiveness of COVID-19 vaccination may vary by country depending on COVID-19 burden, comparator interventions assessed, analysis perspective, and local cost-effectiveness thresholds used. The global economy is estimated to be losing US$375 billion per month because of the coronavirus pandemic. G20 countries have invested approximately US$10 trillion in domestic economic stimulus to mitigate the economic consequences of e.g. reduced business activity and unemployment due to the pandemic, which is expected to amount up to US$13.8 trillion through 2024 (7). Initial estimates suggest that timely rolled out COVID-19 vaccination will provide nomic value in terms of averted morbidity and mortality costs and averted losses in gross domestic product (GDP) (8-13). EQ U IT Y What would be the impact on Increased Uncertain Reduced Varies Equity and ethical considerations are critical. SAGE has produced a Values Vaccine nationalism is seen as a threat to reducing health ☐ ☐ ☒ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -14- health inequities? Framework (14), which offers guidance on the fair allocation of COVID-19 vaccines based on 6 core ethical principles that should guide distribution. If distributed fairly, COVID- 19 vaccines may have considerable impact on reducing health inequities. inequity, in particular as high-income countries have arranged bilateral contracts with manufacturers. This has led to the establishment of the Access to COVID-19 Tools (ACT) Accelerator and within this, the COVAX facility, which aims to ensure equitable access to vaccines for its participating member states (15). A C C EP TA BI LI TY Which option is acceptable to key stakeholders (e.g. ministries of health, immunizatio n managers)? Interventi on Comparis on Both Neither Un-clear Vaccination is an important tool to combat COVID-19 and key stakeholders, in particular ministries of health and immunization managers, are generally strongly in favour of COVID-19 vaccination. Both BECOV-2 and ChAdOx1-S vaccines would be acceptable to key stakeholders. 190 economies are participating in COVAX suggesting a very high acceptability of COVID-19 vaccination in general. ☐ ☐ ☒ ☐ ☐ Which option is acceptable to target group? Interventi on Comparis on Both Neither Un-clear COVID-19 vaccine acceptability in general varies between (sub)population groups and may be correlated with the perceived risk posed by the disease. In a global survey (19 countries) of acceptance rates in the general ☐ ☐ ☒ ☐ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -15- population of any COVID-19 vaccine product, 71.5% of participants reported that they would be very or somewhat likely to take a COVID-19 vaccine. Acceptance rates ranged from almost 55% to 87% (16). Additionally, representative multi-country surveys are carried out periodically to assess the percentage of those willing to receive (or of those who have already received) COVID-19 vaccination (non- product specific). While these polls are limited to selected countries, they provide a certain degree of insight into vaccine acceptance and trends over time. (17, 18) Both BECOV-2 and ChAdOx1-S vaccines would be acceptable to target groups. FE A SI BI LI TY Is the intervention feasible to implement? No Probabl y No Uncertain Probabl y Yes Yes Varies The vaccine is assumed to be easily implementable in settings – including low- and middle-income-countries – with existing vaccine logistics and delivery infrastructure. Storage and distribution requirements of the BECOV-2 vaccine are the same as those ☐ ☐ ☐ ☐ ☒ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -16- of many other vaccines currently in use globally. BECOV-2 can be stored and transported at 2°C to 8°C within the 12 months of shelf life. The chemical and physical in-use stability of the vaccine has been demonstrated for 6 hours in vial when stored at room temperature. Its shipping and storage fit into the existing medical supply infrastructure. BALANCE OF CONSEQUENCES Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings ☐ ☐ ☐ ☒ ☐ TYPE OF RECOMMENDATI ON We recommend the intervention We suggest considering recommendation of the intervention We recommend the comparison We recommend against the intervention and the comparison ☐ ☐ Only in the context of rigorous research ☐ ☐ ☒ Only with targeted monitoring and evaluation ☒ Only in specific contexts or specific (sub)populations Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -17- RECOMMENDATI ON (TEXT) Please see the interim recommendations. IMPLEMENTATI ON CONSIDERATION S Please see the interim recommendations. MONITORING, EVALUATION AND RESEARCH PRIORITIES Please see the interim recommendations. Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -18- Annex 8. SAGE evidence-to-recommendation framework: BECOV-2 vaccine’s use in adolescents Question: Should BECOV-2 vaccine be administered to adolescents to prevent PCR-confirmed COVID-19 Population: Adolescents (12<18) Intervention: Two doses of BECOV-2 vaccine Comparison(s): Placebo Outcome: COVID-19 (PCR-confirmed) Background: On 31 December 2019, WHO was alerted to several cases of pneumonia of unknown origin in Wuhan City, Hubei Province, China. The cause was found to be a novel coronavirus, SARS-CoV-2. The disease caused by this novel virus has been named COVID-19. The outbreak of COVID-19 was declared a public health emergency of international concern in January 2020. The disease has since spread with an enormous impact on the health and well-being of individuals and populations worldwide. It has further caused major disruptions to various sectors of society and the economy across the globe. Vaccines are a critical tool in combating the pandemic. In the rapidly evolving field of COVID-19 vaccines, WHO has issued to date interim recommendations on the use of a number of COVID-19 vaccines (3). CRITERIA JUDGEMENTS RESEARCH EVIDENCE ADDITIONAL INFORMATION PR O BL EM Is the problem a public health priority? No Uncertain Yes Varies by setting The COVID-19 situation is evolving rapidly. The cumulative number of COVID- 19 deaths globally has surpassed 6 million. The most recent epidemiological situation can be found on the following website: https://covid19.who.int/table. ☐ ☐ ☒ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -19- There has been collateral damage to other public health programmes. BE N EF IT S & H A R M S O F TH E O PT IO N S Benefits of the intervention Are the desirable anticipated effects large? No Uncertain Yes Varies The NAb GMT titres were 1099 post vaccination with the ancestral strain for the 12 to <18 years compared with 1338 for adults, giving a GMT ratio of 0.82 (95%CI 0.59–1.13) (2). The seroconversion was 91% compared to 94% in adults (2). ☐ ☒ ☐ ☐ Harms of the intervention Are the undesirable anticipated effects small? No Uncertain Yes Varies 66 (28.2%) participants reported 118 AEs in the BECOV-2 arm (n=234) and 22 (28.2%) participants reported 35 AEs in the placebo arm (n=78). All the reported AEs were mild to moderate in their intensity. There were no SAEs/grade-3 AEs/ deaths/AESIs reported during the study period and all the reported AEs resolved without any sequelae (2). In India, 70 million have been given to children and adolescents (this includes 30 million that have received 2 doses), no Grade 3 or higher AEs, no SAEs and no AESIs have been reported in post- authorization surveillance. Few AEs following immunization (AEFIs) around vaccine anxiety were noted. ☐ ☐ ☒ ☐ Balance between benefits and harms Favours interventi on Favours compariso n Favours both Favours neither Unclear Efficacy data suggest benefit in those aged 12<18 years and that overall, the vaccine is well tolerated. Balancing benefits and harms of COVID-19 disease and vaccination with BECOV-2, the ☒ ☐ ☐ ☐ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -20- benefit of the intervention is larger than the potential harms What is the overall quality of this evidence for the critical outcomes? Effectiveness of the intervention Please see the related GRADE tables No included studies Very low Low Moderate High ☐ ☒ ☐ ☐ ☐ Safety of the intervention No included studies Very low Low Moderate High ☐ ☐ ☒ ☐ ☐ V A L U ES & P R EF ER E N C E S How certain is the relative importance of the desirable and undesirable outcomes? Important uncertaint y or variability Possibly important uncertaint y or variability Probably no important uncertaint y or variabilit y No important uncertain ty or variabilit y No known undesirab le outcomes Available scientific evidence on the relative importance of the intervention, as well as the relative weights that the target population attributes to the desirable (i.e. protection conferred by the vaccine) and the undesirable outcomes (i.e. the currently reported safety signals), varies. Different population groups may have different opinions regarding the weights assigned to desirable and undesirable outcomes. ☐ ☒ ☐ ☐ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -21- Values and preferences of the target population: Are the desirable effects large relative to undesirable effects? No Probably No Uncerta in Probabl y Yes Yes Varies Available scientific evidence suggests that he target population probably assigns more weight to the desirable effects than the undesirable effects related to COVID-19 vaccination. Targeted studies should assess this aspect. ☐ ☐ ☐ ☒ ☐ ☐ R ES O U R C E U SE Are the resources required small? No Uncertain Yes Varies BECOV-2 vaccine can be distributed and stored using existing cold-chain infrastructure and does not require ultra-cold-chain capacity. Nevertheless, considerable resources are needed to ensure the implementation of a COVID-19 vaccination programme. Resources required include, but are not restricted to, human resources, vaccine costs, logistics, planning and coordination, training, social mobilization and communications, and immunization safety surveillance. COVAX, the vaccine pillar of the Access to COVID-19 Tools Accelerator (ACT- Accelerator), has now shipped over 1 billion doses of COVID-19 vaccine to 144 countries and territories (4). By January 2022, additional funding of at least US$ 5.2 billion was required for the Gavi COVAX Advance Market Commitment to establish a Pandemic Vaccine Pool of a minimum of 600 million additional vaccine doses to: address uncertainties and risks in the ☒ ☐ ☐ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -22- evolution of the virus; provide bundled finance to strengthen delivery systems in recipient countries; and cover essential ancillary costs (5). Cost- effectivenes s No Uncertain Yes Varies Formal global cost- effectiveness analyses have not been conducted, but the emerging evidence indicates that the benefits, including the impact on recovery of the global economy, are likely to outweigh the cost of COVID-19 vaccination in general at global level. No formal cost-effectiveness analyses of BECOV-2 vaccine compared with other vaccines have been conducted. The BECOV-2 vaccine is expected to be less costly than other COVID-19 vaccines (see previous subcriterion). (6) The ability to use BECOV-2 in existing cold-chain infrastructure in all country settings may allow higher population-level coverage. Cost-effectiveness analyses should be conducted at country The global economy is estimated to be losing US$375 billion per month because of the coronavirus pandemic. G20 countries have invested approximately US$10 trillion in domestic economic stimulus to mitigate the economic consequences of e.g. reduced business activity and unemployment due to the pandemic, which is expected to amount up to US$13.8 trillion through 2024(7). Initial estimates suggest that timely rolled out COVID-19 vaccination will provide nomic value in terms of averted morbidity and ☐ ☐ ☐ ☒ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -23- level; cost-effectiveness of COVID-19 vaccination may vary by country depending on COVID-19 burden, comparator interventions assessed, analysis perspective, and local cost- effectiveness thresholds used. mortality costs and averted losses in gross domestic product (GDP)(8-13). EQ U IT Y What would be the impact on health inequities? Increased Uncertain Reduced Varies Equity and ethical considerations are critical. SAGE has produced a Values Framework (14), which offers guidance on the fair allocation of COVID-19 vaccines based on 6 core ethical principles that should guide distribution. If distributed fairly, COVID-19 vaccines may have considerable impact on reducing health inequities. Vaccine nationalism is seen as a threat to reducing health inequity, in particular as high-income countries have arranged bilateral contracts with manufacturers. This has led to the establishment of the Access to COVID-19 Tools (ACT) Accelerator and within this, the COVAX facility, which aims to ensure equitable access to vaccines for its participating member states(15). ☐ ☐ ☒ ☐ A C C EP TA BI LI TY Which option is acceptable Interventi on Comparis on Both Neither Un-clear Vaccination is an important tool to combat COVID-19 and key stakeholders, in particular The fact that 190 economies are participating in Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -24- to key stakeholders (e.g. ministries of health, immunizatio n managers)? ☒ ☐ ☐ ☐ ☐ ministries of health and immunization managers, are generally strongly in favour of COVID-19 vaccination. COVAX suggests a very high acceptability of COVID-19 vaccination in general, though not necessarily of this vaccine in particular. Which option is acceptable to target group? Interventi on Comparis on Both Neither Un-clear COVID-19 vaccine acceptability in general varies between (sub)population groups and may be correlated with the perceived risk posed by the disease. In a global survey (19 countries) of acceptance rates in the general population of any COVID-19 vaccine product, 71.5% of participants reported that they would be very or somewhat likely to take a COVID-19 vaccine. Acceptance rates ranged from almost 55% to 87%. (16) Additionally, representative multi-country surveys are carried out periodically to assess the percentage of those willing to receive (or of those who have already received) COVID-19 vaccination (non-product specific). While these polls are limited to selected countries, they provide a certain degree of ☒ ☐ ☐ ☐ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -25- insight into vaccine acceptance and trends over time. (17, 18) Single-dose administration of this product may be favourable to some target groups. FE A SI BI LI TY Is the intervention feasible to implement? No Probabl y No Uncertain Probabl y Yes Yes Varies The vaccine is assumed to be easily implementable in settings – including low- and middle- income-countries – with existing vaccine logistics and delivery infrastructure. Storage and distribution requirements of the BECOV-2 vaccine are the same as those of many other vaccines currently in use globally. BECOV-2 can be stored and transported at 2°C to 8°C within the 12 months of shelf life. The chemical and physical in-use stability of the vaccine has been demonstrated for 6 hours in vial when stored at room temperature. Its shipping and storage fit into the existing medical supply infrastructure (19). ☐ ☐ ☐ ☐ ☒ ☐ BALANCE OF CONSEQUENCES Undesirable consequences clearly outweigh desirable Undesirable consequences probably outweigh desirable The balance between desirable and undesirable consequences is Desirable consequences probably outweigh undesirable Desirable consequences clearly outweigh undesirable Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -26- consequences in most settings consequences in most settings closely balanced or uncertain consequences in most settings consequences in most settings ☐ ☐ ☐ ☒ ☐ TYPE OF RECOMMENDATI ON We recommend the intervention We suggest considering recommendation of the intervention We recommend the comparison We recommend against the intervention and the comparison ☐ ☐ Only in the context of rigorous research ☐ ☐ ☒ Only with targeted monitoring and evaluation ☒ Only in specific contexts or specific (sub)populations RECOMMENDATI ON (TEXT) Please see the interim recommendations. IMPLEMENTATI ON CONSIDERATION S Please see the interim recommendations. MONITORING, EVALUATION AND RESEARCH PRIORITIES Please see the interim recommendations. Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -27- Annex 9. SAGE evidence-to-recommendation framework: BECOV-2 vaccine’s use in children Question: Should BECOV-2 vaccine be administered to children to prevent PCR-confirmed COVID-19 Population: Children (5 to <12 years) Intervention: Two doses of BECOV-2 vaccine Comparison(s): Placebo Outcome: COVID-19 (PCR-confirmed) Background: On 31 December 2019, WHO was alerted to several cases of pneumonia of unknown origin in Wuhan City, Hubei Province, China. The cause was found to be a novel coronavirus, SARS-CoV-2. The disease caused by this novel virus has been named COVID-19. The outbreak of COVID-19 was declared a public health emergency of international concern in January 2020. The disease has since spread with an enormous impact on the health and well-being of individuals and populations worldwide. It has further caused major disruptions to various sectors of society and the economy across the globe. Vaccines are a critical tool in combating the pandemic. In the rapidly evolving field of COVID-19 vaccines, WHO has issued to date interim recommendations on the use of a number of COVID-19 vaccines (3). CRITERIA JUDGEMENTS RESEARCH EVIDENCE ADDITIONAL INFORMATION PR O BL EM Is the problem a public health priority? No Uncertain Yes Varies by setting The COVID-19 situation is evolving rapidly. The cumulative number of COVID- 19 deaths globally has surpassed 6 million. The most recent epidemiological situation can be found on the following website: https://covid19.who.int/table. ☐ ☐ ☒ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -28- There has been collateral damage to other public health programmes. BE N EF IT S & H A R M S O F TH E O PT IO N S Benefits of the intervention Are the desirable anticipated effects large? No Uncertain Yes Varies The NAb GMT titres were 1148 post vaccination with the ancestral strain for the 5 to <12 years compared with 1338 for adults, giving a GMT ratio of 0.86 (95%CI 0.62–1.18) (2). The seroconversion was 96% compared to 94% in adults (2). ☐ ☐ ☒ ☐ Harms of the intervention Are the undesirable anticipated effects small? No Uncertain Yes Varies 52 (22.2%) participants reported 95 AEs in the BECOV-2 arm (n=234) and 26 (33.3%) participants reported 45 events AEs in the placebo arm (n=78). All the reported AEs were mild to moderate in their intensity. There were no SAEs/grade-3 AEs/ deaths/AESIs reported during the study period and all the reported AEs resolved without any sequelae (2). In India, 70 million have been given to children and adolescents (this includes 30 million that have received 2 doses), no Grade 3 or higher AEs, no SAEs and no AESIs have been reported in post- authorization surveillance. Few AEs following immunization (AEFIs) around vaccine anxiety were noted. ☐ ☐ ☒ ☐ Balance between benefits and harms Favours interventi on Favours compariso n Favours both Favours neither Unclear Efficacy data suggest benefit in those aged 5 to <12 years and that overall, the vaccine is well tolerated. Balancing benefits and harms of COVID-19 disease and vaccination with BECOV-2, the ☒ ☐ ☐ ☐ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -29- benefit of the intervention is larger than the potential harms What is the overall quality of this evidence for the critical outcomes? Effectiveness of the intervention Please see the related GRADE tables No included studies Very low Low Moderate High ☐ ☒ ☐ ☐ ☐ Safety of the intervention No included studies Very low Low Moderate High ☐ ☐ ☐ ☒ ☐ V A L U ES & P R EF ER E N C E S How certain is the relative importance of the desirable and undesirable outcomes? Important uncertaint y or variability Possibly important uncertaint y or variability Probably no important uncertaint y or variabilit y No important uncertain ty or variabilit y No known undesirab le outcomes Available scientific evidence on the relative importance of the intervention, as well as the relative weights that the target population attributes to the desirable (i.e. protection conferred by the vaccine) and the undesirable outcomes (i.e. the currently reported safety signals), varies. Different population groups may have different opinions regarding the weights assigned to desirable and undesirable outcomes. ☐ ☒ ☐ ☐ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -30- Values and preferences of the target population: Are the desirable effects large relative to undesirable effects? No Probably No Uncerta in Probabl y Yes Yes Varies Available scientific evidence suggests that he target population probably assigns more weight to the desirable effects than the undesirable effects related to COVID-19 vaccination. Targeted studies should assess this aspect. ☐ ☐ ☐ ☒ ☐ ☐ R ES O U R C E U SE Are the resources required small? No Uncertain Yes Varies BECOV-2 vaccine can be distributed and stored using existing cold-chain infrastructure and does not require ultra-cold-chain capacity. Nevertheless, considerable resources are needed to ensure the implementation of a COVID-19 vaccination programme. Resources required include, but are not restricted to, human resources, vaccine costs, logistics, planning and coordination, training, social mobilization and communications, and immunization safety surveillance. COVAX, the vaccine pillar of the Access to COVID-19 Tools Accelerator (ACT- Accelerator), has now shipped over 1 billion doses of COVID-19 vaccine to 144 countries and territories (4). By January 2022, additional funding of at least US$ 5.2 billion was required for the Gavi COVAX Advance Market Commitment to establish a Pandemic Vaccine Pool of a minimum of 600 million additional vaccine doses to: address uncertainties and risks in the ☒ ☐ ☐ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -31- evolution of the virus; provide bundled finance to strengthen delivery systems in recipient countries; and cover essential ancillary costs (5). Cost- effectivenes s No Uncertain Yes Varies Formal global cost- effectiveness analyses have not been conducted, but the emerging evidence indicates that the benefits, including the impact on recovery of the global economy, are likely to outweigh the cost of COVID-19 vaccination in general at global level. No formal cost-effectiveness analyses of BECOV-2 vaccine compared with other vaccines have been conducted. The BECOV-2 vaccine is expected to be less costly than other COVID-19 vaccines (see previous subcriterion). (6) The ability to use BECOV-2 in existing cold-chain infrastructure in all country settings may allow higher population-level coverage. Cost-effectiveness analyses should be conducted at country The global economy is estimated to be losing US$375 billion per month because of the coronavirus pandemic. G20 countries have invested approximately US$10 trillion in domestic economic stimulus to mitigate the economic consequences of e.g. reduced business activity and unemployment due to the pandemic, which is expected to amount up to US$13.8 trillion through 2024(7). Initial estimates suggest that timely rolled out COVID-19 vaccination will provide nomic value in terms of averted morbidity and ☐ ☐ ☐ ☒ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -32- level; cost-effectiveness of COVID-19 vaccination may vary by country depending on COVID-19 burden, comparator interventions assessed, analysis perspective, and local cost- effectiveness thresholds used. mortality costs and averted losses in gross domestic product (GDP)(8-13). EQ U IT Y What would be the impact on health inequities? Increased Uncertain Reduced Varies Equity and ethical considerations are critical. SAGE has produced a Values Framework (14), which offers guidance on the fair allocation of COVID-19 vaccines based on 6 core ethical principles that should guide distribution. If distributed fairly, COVID-19 vaccines may have considerable impact on reducing health inequities. Vaccine nationalism is seen as a threat to reducing health inequity, in particular as high-income countries have arranged bilateral contracts with manufacturers. This has led to the establishment of the Access to COVID-19 Tools (ACT) Accelerator and within this, the COVAX facility, which aims to ensure equitable access to vaccines for its participating member states(15). ☐ ☐ ☒ ☐ A C C EP TA BI LI TY Which option is acceptable Interventi on Comparis on Both Neither Un-clear Vaccination is an important tool to combat COVID-19 and key stakeholders, in particular The fact that 190 economies are participating in Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -33- to key stakeholders (e.g. ministries of health, immunizatio n managers)? ☒ ☐ ☐ ☐ ☐ ministries of health and immunization managers, are generally strongly in favour of COVID-19 vaccination. COVAX suggests a very high acceptability of COVID-19 vaccination in general, though not necessarily of this vaccine in particular. Which option is acceptable to target group? Interventi on Comparis on Both Neither Un-clear COVID-19 vaccine acceptability in general varies between (sub)population groups and may be correlated with the perceived risk posed by the disease. In a global survey (19 countries) of acceptance rates in the general population of any COVID-19 vaccine product, 71.5% of participants reported that they would be very or somewhat likely to take a COVID-19 vaccine. Acceptance rates ranged from almost 55% to 87%. (16) Additionally, representative multi-country surveys are carried out periodically to assess the percentage of those willing to receive (or of those who have already received) COVID-19 vaccination (non-product specific). While these polls are limited to selected countries, they provide a certain degree of ☒ ☐ ☐ ☐ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -34- insight into vaccine acceptance and trends over time. (17, 18) Single-dose administration of this product may be favourable to some target groups. FE A SI BI LI TY Is the intervention feasible to implement? No Probabl y No Uncertain Probabl y Yes Yes Varies The vaccine is assumed to be easily implementable in settings – including low- and middle- income-countries – with existing vaccine logistics and delivery infrastructure. Storage and distribution requirements of the BECOV-2 vaccine are the same as those of many other vaccines currently in use globally. BECOV-2 can be stored and transported at 2°C to 8°C within the 12 months of shelf life. The chemical and physical in-use stability of the vaccine has been demonstrated for 6 hours in vial when stored at room temperature. Its shipping and storage fit into the existing medical supply infrastructure (19). ☐ ☐ ☐ ☐ ☒ ☐ BALANCE OF CONSEQUENCES Undesirable consequences clearly outweigh desirable Undesirable consequences probably outweigh desirable The balance between desirable and undesirable consequences is Desirable consequences probably outweigh undesirable Desirable consequences clearly outweigh undesirable Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -35- consequences in most settings consequences in most settings closely balanced or uncertain consequences in most settings consequences in most settings ☐ ☐ ☐ ☒ ☐ TYPE OF RECOMMENDATI ON We recommend the intervention We suggest considering recommendation of the intervention We recommend the comparison We recommend against the intervention and the comparison ☐ ☐ Only in the context of rigorous research ☐ ☐ ☒ Only with targeted monitoring and evaluation ☒ Only in specific contexts or specific (sub)populations RECOMMENDATI ON (TEXT) Please see the interim recommendations. IMPLEMENTATI ON CONSIDERATION S Please see the interim recommendations. MONITORING, EVALUATION AND RESEARCH PRIORITIES Please see the interim recommendations. ☐ ☐ ☐ ☒ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -36- EQ U IT Y What would be the impact on health inequities? Increased Uncertain Reduced Varies Equity and ethical considerations are critical. SAGE has produced a Values Framework (14), which offers guidance on the fair allocation of COVID-19 vaccines based on 6 core ethical principles that should guide distribution. If distributed fairly, COVID-19 vaccines may have considerable impact on reducing health inequities. Vaccine nationalism is seen as a threat to reducing health inequity, in particular as high-income countries have arranged bilateral contracts with manufacturers. This has led to the establishment of the Access to COVID-19 Tools (ACT) Accelerator and within this, the COVAX facility, which aims to ensure equitable access to vaccines for its participating member states (15). ☐ ☐ ☒ ☐ A C C EP TA BI LI TY Which option is acceptable to key stakeholders (e.g. ministries of health, immunizatio n managers)? Interventi on Comparis on Both Neither Un-clear Vaccination is an important tool to combat COVID-19 and key stakeholders, in particular ministries of health and immunization managers, are generally strongly in favour of COVID-19 vaccination. The fact that 190 economies are participating in COVAX suggests a very high acceptability of COVID-19 vaccination in general, though not necessarily of this vaccine in particular. ☒ ☐ ☐ ☐ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -37- Which option is acceptable to target group? Interventi on Comparis on Both Neither Un-clear COVID-19 vaccine acceptability in general varies between (sub)population groups and may be correlated with the perceived risk posed by the disease. In a global survey (19 countries) of acceptance rates in the general population of any COVID-19 vaccine product, 71.5% of participants reported that they would be very or somewhat likely to take a COVID-19 vaccine. Acceptance rates ranged from almost 55% to 87%. (16) Additionally, representative multi-country surveys are carried out periodically to assess the percentage of those willing to receive (or of those who have already received) COVID-19 vaccination (non-product specific). While these polls are limited to selected countries, they provide a certain degree of insight into vaccine acceptance and trends over time(17, 18). ☐ ☒ ☐ ☐ ☐ FE A SI BI LI T Y Is the intervention feasible to implement? No Probably No Uncertain Probably Yes Yes Varies The vaccine is assumed to be easily implementable in settings – including low- and middle- income-countries – with existing vaccine logistics and delivery infrastructure. ☐ ☐ ☐ ☐ ☒ ☐ Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -38- Storage and distribution requirements of the BECOV-2 vaccine are the same as those of many other vaccines currently in use globally. BECOV-2 can be stored and transported at 2°C to 8°C within the 12 months of shelf life. The chemical and physical in-use stability of the vaccine has been demonstrated for 6 hours in vial when stored at room temperature. Its shipping and storage fit into the existing medical supply infrastructure. BALANCE OF CONSEQUENCES Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings ☐ ☐ ☒ ☐ ☐ TYPE OF RECOMMENDATI ON We recommend the intervention We suggest considering recommendation of the intervention We recommend the comparison We recommend against the intervention and the comparison ☐ ☐ Only in the context of rigorous research ☐ ☐ ☒ Only with targeted monitoring and evaluation Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -39- ☒ Only in specific contexts or specific (sub)populations RECOMMENDATI ON (TEXT) Please see the interim recommendations. IMPLEMENTATI ON CONSIDERATION S Please see the interim recommendations. MONITORING, EVALUATION AND RESEARCH PRIORITIES Please see the interim recommendations. Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -40- References 1. Thuluva S, Paradkar V, Turaga K, Gunneri S, Yerroju V, Mogulla R et al. Immunogenic superiority and safety of Biological E’s CORBEVAX™ vaccine compared to COVISHIELD™ (ChAdOx1 nCoV-19) vaccine studied in a phase III, single blind, multicenter, randomized clinical trial. medRxiv. 2022:2022.03.20.22271891. doi: 10.1101/2022.03.20.22271891. 2. Thuluva S, Paradkar V, Gunneri S, Yerroju V, Mogulla R, Suneetha PV et al. Safety, tolerability and immunogenicity of Biological E’s CORBEVAX™ vaccine in children and adolescents: A Prospective, Randomised, Double-blind, Placebo controlled, Phase-2/3 Study. medRxiv. 2022:2022.04.20.22274076. doi: 10.1101/2022.04.20.22274076. 3. WHO. COVID-19 vaccines technical documents. (https://www.who.int/groups/strategic-advisory-group- of-experts-on-immunization/covid-19-materials, accessed 8 June 2021). 4. COVID-19 Vaccine Market Dashboard (https://www.unicef.org/supply/covid-19-vaccine-market- dashboard, accessed 20 January 2022). 5. World leaders launch call for renewed support for vaccination in 2022 as part of the global fight against COVID-19. (https://www.gavi.org/news/media-room/world-leaders-launch-call-renewed-support- vaccination-2022-part-global-fight, access, accessed 22 January 2022). 6. Wouters OJ, Shadlen KC, Salcher-Konrad M, Pollard AJ, Larson HJ, Teerawattananon Y et al. Challenges in ensuring global access to COVID-19 vaccines: production, affordability, allocation, and deployment. Lancet. 2021. 7. IFM Blog. A Disrupted Global Recovery. January 2022 (https://blogs.imf.org/2022/01/25/a-disrupted- global-recovery/, accessed June 2022). 8. ACT Accelerator: An economic investment case & financing requirements. (www.who.int/docs/default- source/coronaviruse/act-accelerator/economic-investment-case-final- v2.pdf?sfvrsn=91d67ff6_4&download=true, accessed 13 December 2020)2020. 9. Reddy KP, Fitzmaurice KP, Scott JA, Harling G, Lessells RJ, Panella C et al. Clinical outcomes and cost- effectiveness of COVID-19 vaccination in South Africa. Nature Communications. 2021;12:6238. doi: 10.1038/s41467-021-26557-5. 10. Pearson CAB, Bozzani F, Procter SR, Davies NG, Huda M, Jensen HT et al. COVID-19 vaccination in Sindh Province, Pakistan: A modelling study of health impact and cost-effectiveness. PLOS Medicine. 2021;18:e1003815. doi: 10.1371/journal.pmed.1003815. 11. Sandmann FG, Davies NG, Vassall A, Edmunds WJ, Jit M, Sun FY et al. The potential health and economic value of SARS-CoV-2 vaccination alongside physical distancing in the UK: a transmission model-based future scenario analysis and economic evaluation. The Lancet Infectious Diseases. 2021;21:962-74. doi: 10.1016/S1473-3099(21)00079-7. 12. Liu Y, Sandmann FG, Barnard RC, Pearson CAB, Pastore R, Pebody R et al. Optimising health and economic impacts of COVID-19 vaccine prioritisation strategies in the WHO European Region: a mathematical modelling study. The Lancet Regional Health - Europe. 2022;12:100267. doi: https://doi.org/10.1016/j.lanepe.2021.100267. 13. Li R, Liu H, Fairley CK, Zou Z, Xie L, Li X et al. Cost-effectiveness analysis of BNT162b2 COVID-19 booster vaccination in the United States. International Journal of Infectious Diseases. 2022;119:87-94. doi: 10.1016/j.ijid.2022.03.029. 14. WHO. WHO SAGE values framework for the allocation and prioritization of COVID-19 vaccination, 14 September 2020. Geneva: World Health Organization; 2020 (https://www.who.int/publications/i/item/who- sage-values-framework-for-the-allocation-and-prioritization-of-covid-19-vaccination, accessed 28 May 2021). 15. ACT Accelarator and COVAX facility. www.who.int/initiatives/act-accelerator2020 (https://www.who.int/initiatives/act-accelerator. 16. Lazarus JV, Ratzan SC, Palayew A, Gostin LO, Larson HJ, Rabin K et al. A global survey of potential acceptance of a COVID-19 vaccine. NatMed. 2020. 17. YouGov COVID-19 Public Monitor.(https://yougov.co.uk/topics/international/articles- reports/2021/01/12/covid-19-willingness-be-vaccinated, accessed 22 April 2021)2021. 18. Global Attitudes on COVID-19 vaccine. Ipsos survey. ( www.ipsos.com/en/global-attitudes-covid-19- vaccine-december-2020 , accessed 22 April 2021)2021. 19. MHRA. Summary of Product Characteristics for COVID-19 Vaccine Valneva. London: Medicines and Healthcare products Regulatory Agency; 2022 (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/106916 9/COVID-19_Vaccine_Valneva_SmPC_-_final.pdf. Annexes to the recommendations for use of the Biological E Limited’s Corbevax (BECOV-2) vaccine against COVID-19 -41- © World Health Organization 2023. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO licence. WHO reference number: WHO/2019-nCoV/vaccines/SAGE_recommendation/BECOV-2/annexes/2023.1