Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 Grading of evidence Evidence to recommendation tables First issuance: 3 February 2021 (included in the background document) Updated 15 June 2021 Updated: 19 November 2021 Updated: 23 February 2022 Background These are the annexes to the Interim recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19. Annexes 1–8 contain tables that summarize the grading of recommendations, assessment, development and evaluations (GRADE). Annexes 9–12 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 15 February 2022). Contents Annex 1. GRADE table: Efficacy of mRNA-1273 vaccine in adults .............................................................................. 2 Annex 2. GRADE table: Safety of mRNA-1273 vaccine in adults ................................................................................. 3 Annex 3. GRADE table: Efficacy of mRNA-1273 vaccine in older adults..................................................................... 4 Annex 4. GRADE table: Safety of mRNA-1273 vaccine in older adults ........................................................................ 5 Annex 5. GRADE table: Efficacy of mRNA-1273 vaccine in individuals with underlying conditions .......................... 6 Annex 6. GRADE table: Safety of mRNA-1273 vaccine in individuals with underlying conditions ............................. 7 Annex 7. GRADE table: Efficacy of mRNA-1273 vaccine in children (12–17 years) ................................................... 8 Annex 8. GRADE table: Safety of mRNA-1273 vaccine in children (12–17 years) ....................................................... 9 Annex 9. SAGE evidence-to-recommendation framework: mRNA-1273 vaccine use in adults .................................. 10 Annex 10. SAGE evidence-to-recommendation framework: mRNA-1273 vaccine use in older adults ....................... 19 Annex 11. SAGE evidence-to-recommendation framework: mRNA-1273 vaccine use in individuals with comorbidities ................................................................................................................................................................. 28 Annex 12. SAGE evidence-to-recommendation framework: mRNA-1273 mRNA-1273 vaccine use in children (12–17 years) ............................................................................................................................................................................. 40 Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 2 Annex 1. GRADE table: Efficacy of mRNA-1273 vaccine in adults Population: Adults (aged 18–64 years) Intervention: Two doses of mRNA-1273 vaccine Comparison: Placebo/active control Outcome: COVID-19 (PCR-confirmed) What is the efficacy of two doses of mRNA-1273 vaccine compared with placebo/active control in preventing PCR-confirmed COVID-19 in adults (aged 18–64 years)? Rating Adjustment to rating Q ua lit y A ss es sm en t No. of studies/starting ratinga 1/ RCT (1) 4 Factors decreasing confidence Limitation in study designb Not serious 0 Inconsistency Not serious 0 Indirectness Not serious 0 Imprecision Not serious 0 Publication bias Not serious 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 4 Su m m ar y of F in di ng s Statement on quality of evidence Evidence supports a high level of confidence that the true effect lies close to the estimate of the effect on the health outcome (level 4). Conclusion We are very confident that 2 doses of mRNA-1273 vaccine are efficacious in preventing PCR- confirmed COVID-19 in adults (18–64 years) up to approx. 2 months following immunization in the context of wild-type and pre-Omicron variants of concern. a High vaccine effectiveness of mRNA-1273 against severe disease and death has been confirmed in post-introduction observational studies, including in settings where Omicron is present. b 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. Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 3 Annex 2. GRADE table: Safety of mRNA-1273 vaccine in adults Population: Adults (aged 18–64 years) Intervention: Two doses of mRNA-1273 vaccine Comparison: Placebo/active control Outcome: Serious adverse events following immunization What is the risk of serious adverse events following mRNA-1273 vaccination compared with placebo/active control in adults (aged 18–64 years)? Rating Adjustment to rating Q ua lit y A ss es sm en t No. of studies/starting rating 2/ RCT (1, 2)a 4 Factors decreasing confidence Limitation in study designb Not serious 0 Inconsistency Not serious 0 Indirectness Not serious 0 Imprecision Not serious 0 Publication bias Not serious 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 4 Su m m ar y of F in di ng s Statement on quality of evidence Evidence supports a high level of confidence that the true effect lies close to the estimate of the effect on the health outcome (level 4). Conclusion We are confident that the risk of serious adverse events following one or two doses of mRNA-1273 vaccine in adults (aged 18–64 years) is low. A very rare, but significantly elevated risk of myocarditis and pericarditis has been reported after mRNA COVID-19 vaccine use. These cases occurred more often in younger men (aged 16–24 years) and after the second dose of the vaccine, typically within a few days after vaccination. a Post-licensure data have identified a very rare but increased risk of myocarditis and pericarditis, mainly in male individuals (aged 18–24 years) who received COVID-19 mRNA vaccines. b 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. Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 4 Annex 3. GRADE table: Efficacy of mRNA-1273 vaccine in older adults Population: Older adults (aged ≥65 years) Intervention: Two doses of mRNA-1273 vaccine Comparison: Placebo/active control Outcome: COVID-19 (PCR-confirmed) What is the efficacy of two doses of mRNA-1273 vaccine compared with placebo/active control in preventing PCR-confirmed COVID-19 in older adults (aged ≥65 years)? Rating Adjustment to rating Q ua lit y A ss es sm en t No. of studies/starting rating 1/ RCT (1) a 4 Factors decreasing confidence Limitation in study designb Not serious 0 Inconsistency Not serious 0 Indirectness Not serious 0 Imprecision Not serious 0 Publication bias Not serious 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 4 Su m m ar y of F in di ng s Statement on quality of evidence Evidence supports a high level of confidence that the true effect lies close to the estimate of the effect on the health outcome (level 4). Conclusion We are confident that 2 doses of mRNA-1273 vaccine are efficacious in preventing PCR- confirmed COVID-19 in older adults (aged ≥65 years) up to approx. 2 months following immunization in the context of wild-type and pre- Omicron variants of concern. a Observational studies have confirmed the high vaccine effectiveness against COVID-19 and especially against hospitalization and severe disease in older adults. b 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. Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 5 Annex 4. GRADE table: Safety of mRNA-1273 vaccine in older adults Population: Older adults (aged ≥65 years) Intervention: Two doses of mRNA-1273 vaccine Comparison: Placebo/active control Outcome: Serious adverse events following immunization What is the risk of serious adverse events following mRNA-1273 vaccination compared with placebo/active control in older adults (aged ≥65 years)? Rating Adjustment to rating Q ua lit y A ss es sm en t No. of studies/starting rating 2/ RCT (1, 2)a 4 Factors decreasing confidence Limitation in study designb Not serious 0 Inconsistency Not serious 0 Indirectness Not serious 0 Imprecision Not serious 0 Publication bias Not serious 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 4 Su m m ar y of Fi nd in gs Statement on quality of evidence Evidence supports a high level of confidence that the true effect lies close to the estimate of the effect on the health outcome (level 4). Conclusion We are confident that the risk of serious adverse events following one or two doses of mRNA-1273 vaccine in older adults (aged ≥65 years) is low. a Observational data supports the low risk of serious adverse events in older adults following mRNA-1273 vaccine. b 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. Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 6 Annex 5. GRADE table: Efficacy of mRNA-1273 vaccine in individuals with underlying conditions Population: Individuals with comorbidities or health states that increase risk for severe COVID-19 Intervention: Two doses of mRNA-1273 vaccine Comparison: Placebo/active control Outcome: COVID-19 (PCR-confirmed) What is the efficacy of two doses of mRNA-1273 vaccine compared with placebo/active control in preventing PCR-confirmed COVID-19 in individuals with comorbidities or health states that increase risk for severe COVID-19? Rating Adjustment to rating Q ua lit y A ss es sm en t No. of studies/starting ratinga 1/ RCT (1) 4 Factors decreasing confidence Limitation in study designb Not serious , 0 Inconsistency Not serious 0 Indirectness Seriousc,d -1 Imprecision Not serious 0 Publication bias Not serious 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 2 doses of mRNA- 1273 vaccine are efficacious in preventing PCR- confirmed COVID-19 in individuals with comorbidities or health states that increase risk for severe COVID-19, as included in the clinical trial up to approx. 2 months following immunization in the context of wild-type and pre-Omicron variants of concerns. Data suggest that individuals with moderately to severely compromised immune systems; or people living with organ or stem cell transplants, blood cancer, certain autoimmune disease and treatment with specific immunosuppressive medications, may not mount the same level of immunity following a regular 2- dose vaccination schedule compared to people who are not immunocompromised. a High vaccine effectiveness in specific subpopulations of mRNA-1273 has been confirmed in post-introduction observational studies. b 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. c Underlying comorbidities included diabetes, chronic lung disease, severe obesity, significant cardiovascular disease, liver disease, or infection with HIV. Around 46% of the trial population were either obese or affected by comorbidities. SAGE will continue to review any emerging data and adjust its quality assessment as required. d Trial excluded pregnant and breastfeeding women, and persons who were immunocompromised. Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 7 Annex 6. GRADE table: Safety of mRNA-1273 vaccine in individuals with underlying conditions Population: Individuals with comorbidities or health states that increase risk for severe COVID-19 Intervention: Two doses of mRNA-1273 vaccine Comparison: Placebo/active control Outcome: Serious adverse events following immunization What is the risk of serious adverse events following mRNA-1273 vaccination compared with placebo/active control in individuals with comorbidities or health states that increase risk for severe COVID-19? Rating Adjustment to rating Q ua lit y A ss es sm en t No. of studies/starting rating 1/ RCT 4 Factors decreasing confidence Limitation in study designa Not serious 0 Inconsistency Not serious 0 Indirectness Not seriousb 0 Imprecision Seriousc -1 Publication bias Not serious 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 have moderate confidence in the quality of evidence that the risk of serious adverse events in individuals with comorbidities or health states that increase risk for severe COVID-19 following one or two doses of mRNA-1273 vaccine is low. 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. b The phase 3 trial excluded pregnant and breastfeeding women, and persons who were immunocompromised. Additional studies in pregnant and lactating women with regard to the COVID-19 mRNA vaccines (BNT162b2 or mRNA-1273) were conducted and data generated demonstrating a good safety profile in these populations. c Missing safety data in certain subpopulations and data in immunocompromised individuals were considered as limitations that led to downgrading of the evidence. Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 8 Annex 7. GRADE table: Efficacy of mRNA-1273 vaccine in children (12–17 years) Population: Children (aged 12–17 years) Intervention: Two doses of mRNA-1273 vaccine Comparison: Placebo/active control Outcome: COVID-19 (PCR-confirmed) What is the efficacy of two doses of mRNA-1273 vaccine compared with placebo/active control in preventing PCR-confirmed COVID-19 in children (aged 12–17 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 Not serious 0 Imprecision Not serious 0 Publication bias Not serious 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 4 Su m m ar y of F in di ng s Statement on quality of evidence Evidence supports a high level of confidence that the true effect lies close to the estimate of the effect on the health outcome (level 4). Conclusion We are confident that 2 doses of mRNA-1273 vaccine are efficacious in preventing PCR- confirmed COVID-19 in children (aged 12–17 years) up to approx. 2 months following immunization in the context of wild-type and pre-Omicron variants of concerns. 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. Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 9 Annex 8. GRADE table: Safety of mRNA-1273 vaccine in children (12–17 years) Population: Children (aged 12–17 years) Intervention: Two doses of mRNA-1273 vaccine Comparison: Placebo/active control Outcome: Serious adverse events following immunization What is the risk of serious adverse events following mRNA-1273 vaccination compared with placebo/active control in children (aged 12–17 years)? Rating Adjustment to rating Q ua lit y A ss es sm en t No. of studies/starting rating 1/ RCT (3) 4 Factors decreasing confidence Limitation in study designa Serious b -1 Inconsistency Not serious 0 Indirectness Not serious 0 Imprecision Not seriousc 0 Publication bias Not serious 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 moderate level of confidence that the true effect lies close to the estimate of the effect on the health outcome (level 3). Conclusion We have moderate confidence in the quality of evidence that the risk of serious adverse events in children (aged 12–17 years) following 1 or 2 doses of mRNA-1273 vaccine is low. A very rare, but significantly elevated risk of myocarditis/pericarditis has been reported recently after mRNA COVID-19 vaccine use. These cases occurred more often in male than in female adolescents and after the second dose of the vaccine, typically within few days after vaccination. 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. b Downgraded for limitations in follow-up time of clinical trial, which may not allow detection of adverse events occurring several months after vaccination. Not adequately powered to detect rare adverse events. These may emerge only when large populations have been vaccinated. c The clinical trials had no estimates around safety outcomes as the number of serious adverse events occurring during the observation period. No serious adverse events related to mRNA-1273 or placebo were noted. Post-licensure surveillance and observational safety data support the very low risk of serious adverse events following immunization. Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 10 Annex 9. SAGE evidence-to-recommendation framework: mRNA-1273 vaccine use in adults Question: Should mRNA-1273 vaccine be administered to adults to prevent COVID-19? Population: Adults (aged 18–64 years) Intervention: Two doses of mRNA-1273 vaccine Comparison(s): Active control/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 (4). CRITERIA JUDGEMENTS RESEARCH EVIDENCE ADDITIONAL INFORMATION PR O B LE M 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 5 million. The most recent epidemiological situation can be found on the following website: https://covid19.who.int/table. There has been collateral damage to other public health programmes. ☐ ☐ ☒ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 11 B EN 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 Primary efficacy analysis shows that mRNA-1273 vaccine is 93% efficacious (95%CI: 91–95%) in individuals aged 18–64 years against COVID-19 beginning 14 days after the second dose (1). Based on data identified through a living systematic review of COVID- 19 vaccine effectiveness studies, high vaccine effectiveness (VE) against symptomatic disease up to 4 months following receipt of 2 doses was demonstrated following large-scale roll-out of mRNA-1273, including in the context of variants (5). In the period 4–6 months after vaccination with 2 doses of mRNA- 1273, immunity wanes and VE against symptomatic infection declines (6), while VE against severe disease is largely maintained 6 months and more following vaccination (7). Enhanced VE of an mRNA-1273 booster dose compared to a 2-dose schedule was demonstrated (8-10). In the context of the Omicron variant, early data suggest that VE after 2 doses is significantly lower against infection and symptomatic disease compared to Delta (6). Based on a currently limited number of studies, VE against hospitalization appears to be substantially higher than that against symptomatic disease, but nonetheless lower than against Delta (7). Phase 1 trial data show seroconversion of all participants by day 15, independent of dosage used. The study showed immunogenicity of the mRNA-1273 vaccine, binding antibody IgG concentrations and SARS- CoV-2 neutralizing titres in sera increased with dose level (25, 100 and 250 μg) and after a second dose. Further, 2 doses of either 25 or 100 μg of mRNA-1273 vaccine elicited robust CD4+ T-cell response. CD8+ T-cell responses were elicited at low levels after the second dose in the 100 μg group (2). A phase 2a trial showed that the immune response as assessed by binding antibody IgG and neutralizing antibodies after 2 doses were comparable in the two groups assessed (50-μg and 100-μg) (13). Various heterologous primary and prime-boost schedules using mRNA- 1273 as a booster dose have demonstrated to be safe, immunogenic and effective. WHO has summarized the available evidence and issued interim recommendations for heterologous COVID-19 vaccine schedules (14). ☐ ☐ ☒ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 12 Mitigating effects of a third booster dose were observed in settings where Omicron was circulating. Preliminary data suggest a decrease in risk of symptomatic infection as well as hospital admission following the receipt of a third dose of mRNA-1273 (5, 11, 12). Harms of the intervention Are the undesirable anticipated effects small? No Uncertain Yes Varies Data from over 30 000 participants demonstrate that mRNA-1273 vaccine was well tolerated across all populations. Solicited systemic adverse events occurred more often in the mRNA-1273 group than in the placebo group after both the first dose (8320/15168 (54.9%) vs. 6399/15155 (42.2%)), and the second dose (11652/14677 (79.4%) vs. 5323/14566 (36.5%)), with severity increasing after the second dose (1, 15). Both solicited injection-site and systemic adverse events were more common among younger participants (aged 18–64 years) than among older participants (aged ≥65 years). The frequency of grade 3 adverse events in the placebo group (202/15166 (1.3%)) was similar to that in the vaccine group (234/15185 (1.5%)), as were the frequencies of medically attended adverse events (1465/15166 (9.7%) vs. 1372/15185 (9.0%)), and serious adverse events (89/15166 vs. 93/15185 (0.6% in both groups)). ☐ ☐ ☒ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 13 Cases of myocarditis and pericarditis, although rare, occurred more often in younger men (adolescents or young adults) and after the second dose, typically within a few days after vaccination with the COVID-19 mRNA vaccines (16). An extended interval between dose 1 and dose 2 decreases the risk of myocarditis, while increasing vaccine effectiveness (17). Balance between benefits and harms Favours intervention Favours comparison Favours both Favours neither Unclear Two doses of mRNA-1273 confer high VE. Observational data confirm the beneficial effects of 2 doses of mRNA-1273, in particular in the context of non-Omicron variants and in the <6 months following primary immunization. VE against hospitalization and severe disease is maintained following 6 months post primary immunization. An additional third dose of mRNA- 1273 decreases the risk of symptomatic infection and hospitalization, in particular in the context of Omicron. Safety data suggest minimal harms. Further data are needed as part of post- marketing surveillance. ☒ ☐ ☐ ☐ ☐ 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 Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 14 ☐ ☐ ☐ ☐ ☒ VA LU ES & P R EF ER EN C ES How certain is the relative importance of the desirable and undesirable outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability No known undesirabl e outcomes Available scientific evidence varies on the relative importance of the intervention, as well as the relative weights that the target population attributes to the desirable outcomes (i.e. protection conferred by the vaccine) and the undesirable outcomes (i.e. the currently reported safety signals). 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 Probably No Uncertain Probably Yes Yes Varies Available scientific evidence suggests that the target population assigns more weight to the desirable effects than to 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 Considerable resources are needed to ensure the implementation of a COVID-19 vaccination programme, especially given the urgency of vaccination roll-out worldwide. This necessitates additional surge resources in many settings to accelerate implementation with adequate infection prevention and control procedures in the context of COVID-19. Resources required include, but are not restricted to, human resources, vaccine costs, logistics, 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 (18). By January 2022, additional funding of at least US$ 5.2 billion was required for the ☒ ☐ ☐ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 15 planning and coordination, training, social mobilization and communications, and immunization safety surveillance. 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 (19). Cost– effectiveness No Uncertain Yes Varies Formal global cost–effectiveness analyses have not been conducted, but emerging evidence indicates that the benefits, including the impact on recovery of the global economy, are likely to outweigh the costs of COVID-19 vaccination in general at global level. Formal cost–effectiveness analyses of mRNA-1273, compared with other vaccines, have been conducted in some settings. The ability to use mRNA- 1273 in existing cold-chain infrastructure in all country settings may allow higher population-level coverage. 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 reduced business activity and unemployment due to the pandemic. Initial estimates suggest that COVID-19 vaccination will provide substantial economic value in terms of averted morbidity and mortality costs and averted losses in gross domestic product (20-26). ☐ ☐ ☐ ☒ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 16 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 (27), which offers guidance on the fair allocation of COVID-19 vaccines based on six core ethical principles that should guide distribution. If distributed fairly, COVID-19 vaccines may have considerable impact on reducing health inequities. The temperature storage requirements of the current formulation of the mRNA-1273 vaccine raise equity concerns, both within countries and globally. The required cold-chain capacity is not currently available in many low- and middle-income countries, and in some regions of high-income countries, particularly in hard-to- reach or otherwise already disadvantaged communities. If other vaccines with less demanding storage requirements are not made available, or if vaccines that are feasible and available to deliver are less efficacious or less safe, health inequities will result and existing health inequities may be exacerbated. Vaccine nationalism is seen as a threat to reducing health inequity, particularly 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 (28). ☒ ☐ ☐ ☐ A C C EP T A B IL IT Y Which option is acceptable to key stakeholders Intervention Comparison Both Neither Unclear As vaccination is an important tool to combat COVID-19, it is assumed that key stakeholders, in particular ministries of health and The fact that 190 economies are participating in COVAX suggests a very high Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 17 (e.g. ministries of health, immunization managers)? ☒ ☐ ☐ ☐ ☐ immunization managers, are strongly in favour of it. acceptability of COVID-19 vaccination in general. Which option is acceptable to target group? Intervention Comparison Both Neither Unclear 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 receive a COVID-19 vaccine. Acceptance rates ranged from almost 55% to 87% (29). 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 (30, 31). ☒ ☐ ☐ ☐ ☐ FE A SI B IL IT Y Is the intervention feasible to implement? No Probably No Uncertain Probably Yes Yes Varies The temperature storage requirements of the current formulation of the mRNA-1273 vaccine raise feasibility concerns. The required cold-chain capacity is not currently available in many low- and middle-income countries, and in some regions of high-income ☐ ☐ ☐ ☐ ☐ ☒ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 18 countries, particularly in hard-to- reach or otherwise already disadvantaged communities. Administration of the vaccine to novel target groups currently not reached by national immunization programmes may pose a challenge in certain settings. 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 RECOMMENDATION 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 RECOMMENDATION (TEXT) Please see the interim recommendations. IMPLEMENTATION CONSIDERATIONS Please see the interim recommendations. MONITORING, EVALUATION AND RESEARCH PRIORITIES Please see the interim recommendations. Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 19 Annex 10. SAGE evidence-to-recommendation framework: mRNA-1273 vaccine use in older adults Question: Should mRNA-1273 vaccine be administered to older adults to prevent COVID-19? Population: Older adults (aged ≥65 years) Intervention: Two doses of mRNA-1273 vaccine Comparison(s): Active control/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 (4). CRITERIA JUDGEMENTS RESEARCH EVIDENCE ADDITIONAL INFORMATION PR O B LE M 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 5 million. The most recent epidemiological situation can be found on the following website: https://covid19.who.int/table. There has been collateral damage to other public health programmes. ☐ ☐ ☒ ☐ B EN E FI TS & H A R No Uncertain Yes Varies Of the trial participants, approximately 24% were aged ≥65 years. Phase 1 trial data showed seroconversion of all participants by day Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 20 Benefits of the intervention Are the desirable anticipated effects large? ☐ ☐ ☒ ☐ Primary efficacy analysis shows that mRNA-1273 is 86% efficacious (95%CI: 61–95%) in individuals aged ≥65 years (1, 15). Based on data identified through a living systematic review of COVID- 19 vaccine effectiveness studies, high vaccine effectiveness (VE) against symptomatic disease up to 4 months following receipt of 2 doses was demonstrated following large-scale roll-out of mRNA-1273, including in the context of variants (5). In the period 4–6 months after vaccination with 2 doses of mRNA- 1273, immunity wanes and VE against symptomatic infection declines (6), while VE against severe disease is largely maintained 6 months and more following vaccination (7). Enhanced VE of an mRNA-1273 booster dose compared to a 2- dose schedule was demonstrated (8-10). In the context of the Omicron variant, early data suggest that VE after 2 doses of mRNA-1273 is significantly lower against infection and symptomatic disease compared to Delta (6). Based on a currently limited number of studies, VE against hospitalization appears to be substantially higher than that against symptomatic disease, but nonetheless lower than against Delta (7). Mitigating effects of a third dose were observed in settings where 15, independent of dosage used. The study showed immunogenicity of the mRNA-1273 vaccine, binding antibody IgG concentrations and SARS-CoV-2 neutralizing titres in sera increased with dose level (25, 100 and 250 μg) and after a second dose. Further, 2 doses of either 25 or 100 μg of mRNA-1273 vaccine elicited robust CD4+ T- cell response. CD8+ T- cell responses were elicited at low levels after the second dose in the 100 μg group (2). A phase 2a trial showed that the immune response, as assessed by binding antibody IgG and neutralizing antibodies after 2 doses, were comparable in the two groups assessed (50-μg and 100-μg) (13). Various heterologous primary and prime-boost schedules using mRNA- 1273 as a booster dose have demonstrated to be safe, immunogenic and effective. WHO has summarized the available evidence and issued interim Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 21 Omicron was circulating. Preliminary data suggest a decrease in risk of symptomatic infection as well as in hospital admission following receipt of a third dose of mRNA-1273 (5, 11, 12). recommendations for heterologous COVID-19 vaccine schedules (14). Harms of the intervention Are the undesirable anticipated effects small? No Uncertain Yes Varies Data from over 30 000 participants demonstrate that mRNA-1273 vaccine was well tolerated across all populations. Solicited systemic adverse events occurred more often in the mRNA-1273 group than in the placebo group after both the first dose (8320/15168 (54.9%) vs. 6399/15155 (42.2%)), and the second dose (11652/14677 (79.4%) vs. 5323/14566 (36.5%)), with severity increasing after the second dose (1, 15). Both solicited injection-site and systemic adverse events were more common among younger participants (aged 18–64 years) than among older participants (aged ≥65 years). In those aged ≥65 years, the frequency of grade 3 adverse events in the placebo group (70/3750 (1.9%)) was similar to that in the vaccine group (78/3770 (2.1%)), as were the frequencies of medically attended adverse events (414/3750 (11.0%) vs. 381/10.1 (10.1%)), and serious adverse events (43/3750 (1%) vs. 39/3770 (1.1%)). In older adults (aged ≥ 65 years), solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, chills, headache, myalgia, and pain at the injection site. Such adverse events were dose-dependent and were more common after the second vaccine dose (32). ☐ ☐ ☒ ☐ Balance between Favours interventio n Favours compariso n Favours both Favours neither Unclear Two doses of mRNA-1273 vaccine in adults aged ≥65 years confer high VE. Observational data Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 22 benefits and harms ☒ ☐ ☐ ☐ ☐ confirm the beneficial effects of 2 doses of mRNA-1273, particularly in the context of non-Omicron variants and in the <6 months following primary series immunization. VE against hospitalization and severe disease is maintained following 6 months post primary series immunization. An additional third dose of mRNA- 1273 decreases the risk of symptomatic infection and hospitalization, particularly in the context of Omicron. Safety data suggest minimal harms. Further data are needed as part of post- marketing surveillance. 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 ☐ ☐ ☐ ☒ ☐ VA LU ES & PR EF ER EN C ES How certain is the relative importance of the desirable and undesirable outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability No known undesirable outcomes The majority of severe disease occurs in older (aged ≥65 years) individuals. Available scientific evidence suggests that the target population probably considers the desirable effects, i.e. the potential protection conferred by the vaccine, more important than the undesirable effects, i.e. the currently reported safety signals related to COVID-19 vaccination. ☐ ☒ ☐ ☐ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 23 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 Probably No Uncertain Probably Yes Yes Varies Available scientific evidence suggests that 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. ☐ ☐ ☐ ☒ ☐ ☐ R ES O U R C E U SE Are the resources required small? No Uncertain Yes Varies Considerable resources are needed to ensure the implementation of a COVID-19 vaccination programme, especially given the urgency of vaccination roll-out worldwide. This necessitates additional surge resources in many settings to accelerate implementation with adequate infection prevention and control procedures in the context of COVID-19. 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 (18). 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 ☒ ☐ ☐ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 24 countries; and cover essential ancillary costs (19). Cost– effectiveness 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 costs of COVID-19 vaccination in general at global level. Formal cost–effectiveness analyses of mRNA-1273 vaccine compared with other vaccines have been conducted in some settings. The ability to use mRNA- 1273 in existing cold-chain infrastructure in all country settings may allow higher population-level coverage. 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 reduced business activity and unemployment due to the pandemic. Initial estimates suggest that COVID-19 vaccination will provide substantial economic value in terms of averted morbidity and mortality costs and averted losses in gross domestic product (20-26). ☐ ☐ ☐ ☒ 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 (33), which offers guidance on the fair allocation of COVID-19 vaccines based on six core ethical principles that should guide distribution. If Vaccine nationalism is seen as a threat to reducing health inequity, particularly as high- income countries have arranged bilateral contracts with ☒ ☐ ☐ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 25 distributed fairly, COVID-19 vaccines may have considerable impact on reducing health inequities. Storage and distribution of mRNA- 1273 vaccines lies at -20°C. Once thawed, it can be kept in a refrigerator for up to 30 days. This requirement is not shared by many other vaccine platforms. This cold-chain capacity is not currently available in many low- and middle-income-countries, and in some regions of high-income countries, particularly in hard-to- reach or otherwise already disadvantaged communities. If other vaccines with less demanding storage requirements are not made available, or if vaccines that are feasible and available to deliver are less efficacious or less safe, health inequities will result and existing health inequities may be exacerbated. manufacturers. This has led to the establishment of ACT-Accelerator, and within this, the COVAX facility, which aims to ensure equitable access to vaccines for its participating member states (28). A C C EP TA B IL IT Y Which option is acceptable to key stakeholders (e.g. ministries of health, immunization managers)? Interventio n Comparison Both Neither Unclear As vaccination is an important tool to combat COVID-19, it is assumed that key stakeholders, in particular ministries of health and immunization managers are 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. ☒ ☐ ☐ ☐ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 26 Which option is acceptable to target group? Intervention Comparison Both Neither Unclear 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 receive a COVID-19 vaccine. Acceptance rates ranged from almost 55% to 87% (29). 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 (30, 31). ☒ ☐ ☐ ☐ ☐ FE A SI B IL IT Y Is the intervention feasible to implement? No Probably No Uncertain Probably Yes Yes Varies The temperature storage requirements of the current formulation of the mRNA-1273 vaccine raise feasibility concerns. The required cold-chain capacity is not currently available in many low- and middle-income countries, and in some regions of high-income countries, particularly in hard-to- reach or otherwise already disadvantaged communities. Administration of the vaccine to novel target groups currently not reached by national immunization ☐ ☐ ☐ ☐ ☐ ☒ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 27 programmes may pose a challenge in certain settings. 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 RECOMMENDATION 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 RECOMMENDATION (TEXT) Please see the interim recommendations. IMPLEMENTATION CONSIDERATIONS Please see the interim recommendations. MONITORING, EVALUATION AND RESEARCH PRIORITIES Please see the interim recommendations. Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 28 Annex 11. SAGE evidence-to-recommendation framework: mRNA-1273 vaccine use in individuals with comorbidities a Comorbidities included were cardiovascular disease, hypertension, obesity and type 2 diabetes. Comorbidities for which there were too few data to evaluate were asthma, cancer, chronic kidney disease, chronic obstructive pulmonary disorder (COPD), HIV infection, immunocompromised, liver disease, and neurological conditions. Question: Should mRNA-1273 vaccine be administered to individuals with comorbiditiesa or health states that increase risk for severe COVID-19 to prevent COVID-19? Population: Individuals with comorbidities or health states that increase risk for severe COVID-19 Intervention: Two doses of mRNA-1273 vaccine Comparison(s): Active control/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 (4). CRITERIA JUDGEMENTS RESEARCH EVIDENCE ADDITIONAL INFORMATION PR O B LE M 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 5 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 Moderna mRNA-1273 vaccine against COVID-19 29 There has been collateral damage to other public health programmes. Individuals with certain comorbidities are particularly affected by COVID-19 and bear a higher risk of severe COVID-19 outcomes and death. Identified risk factors include comorbidities such as hypertension, chronic cardiac disease, non-asthmatic chronic pulmonary disease, chronic kidney disease, liver disease, and obesity (particularly a body mass index (BMI) >40). People with multiple comorbidities are at a higher risk of COVID-19-related adverse outcomes. Although the relative risk may be high for some conditions, the absolute risk for younger adults with comorbidities is typically lower than for healthy older adults (i.e. aged >75 years). Pregnant women with COVID-19 are at higher risk of developing severe disease, with increased risk of intensive care unit admission and invasive ventilation, compared with non-pregnant women of reproductive age. COVID-19 in pregnancy is also associated with an increased risk of preterm birth, and of neonates requiring neonatal intensive care. It may also be associated with an increased risk of maternal mortality. B EN E FI TS & H A R No Uncertain Yes Varies At least one protocol-defined high- risk condition for severe COVID-19 was present in 22.3% of Various heterologous primary and prime-boost schedules using mRNA- Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 30 Benefits of the intervention Are the desirable anticipated effects large? ☐ ☐ ☐ ☐ participants, and 4% of participants had two or more high risk conditions. Approximately 41.4% of the study population was considered at risk for progression to severe COVID- 19 due to underlying comorbidities such as diabetes, chronic lung disease, severe obesity, significant cardiovascular disease, liver disease, or infection with HIV and/or aged ≥65 years (1, 2). Primary efficacy analysis shows that mRNA-1273 vaccine is 94.4% efficacious (95%CI: 76.9–98.7%) beginning 14 days after the second dose in individuals aged 18–64 years at risk of severe COVID-19 due to underlying conditions. Efficacy (%) in individuals aged ≥65 years with or without underlying conditions shows that mRNA-1273 vaccine is 86.4% efficacious (95%CI: 61.4–95.2%). Point estimates were provided by subgroup of risk factor (chronic lung disease, cardiac disease, severe obesity, diabetes, liver disease and HIV). Vaccine efficacy was consistent across subgroups and comparable with the efficacy observed for the overall study population, though interpretation of the results is limited by small numbers of participants and cases. Recent data suggest that vaccine effectiveness and immunogenicity are lower in immunocompromised persons (ICPs) compared to persons without 1273 as a booster dose have demonstrated to be safe, immunogenic and effective. WHO has summarized the available evidence and issued interim recommendations for heterologous COVID-19 vaccine schedules (14). Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 31 immunocompromising conditions (34). Emerging evidence suggests that an additional (third) dose included in an extended primary series enhances immune responses in some ICPs (35). Data from small studies have demonstrated that COVID-19 mRNA vaccines are immunogenic in pregnant women and that vaccine-elicited antibodies are transported to infant cord blood and breast milk, suggesting possible neonatal as well as maternal protection (36, 37). Based on data identified through a living systematic review of COVID- 19 vaccine effectiveness studies, high vaccine effectiveness (VE) against symptomatic disease up to 4 months following receipt of 2 doses has been demonstrated following large-scale roll-out of mRNA-1273, including in the context of variants (5). In the period 4–6 months after vaccination with 2 doses of mRNA- 1273, immunity wanes and VE against symptomatic infection declines (6), while VE against severe disease is largely maintained 6 months and more following vaccination (7). Enhanced VE of an mRNA-1273 booster dose compared to a 2-dose schedule has been demonstrated (8-10). In the context of the Omicron variant, early data suggest that VE after 2 doses is significantly lower Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 32 against infection and symptomatic disease compared to Delta (6). Based on a currently limited number of studies, VE against hospitalization appears to be substantially higher than that against symptomatic disease, but nonetheless lower than against Delta (7). Mitigating effects of a third dose were observed in settings where Omicron was circulating. Preliminary data suggest a decrease in risk of symptomatic infection as well as hospital admission following receipt of a third dose of mRNA-1273 (5, 11, 12). Harms of the intervention Are the undesirable anticipated effects small? No Uncertain Yes Varies Data from over 30 000 participants demonstrate that mRNA-1273 vaccine was well tolerated across all populations. Solicited systemic adverse events occurred more often in the mRNA-1273 group than in the placebo group after both the first dose (8320/15168 (54.9%) vs. 6399/15155 (42.2%)), and the second dose (11652/14677 (79.4%) vs. 5323/14566 (36.5%)), with severity increasing after the second dose (1, 15). Both solicited injection-site and systemic adverse events were more common among younger participants (18–64 years) than among older participants (≥65 years). The frequency of grade 3 adverse events in the placebo group (202/15166 (1.3%)) was similar to that in the vaccine group Developmental and reproductive toxicology (DART) studies of mRNA-1273 have not shown harmful effects in pregnant animals and their offspring. ☐ ☐ ☒ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 33 (234/15185 (1.5%)), as were the frequencies of medically attended adverse events (1465/15166 (9.7%) vs. 1372/15185 (9.0%)), and serious adverse events (89/15166 and 93/15185 (0.6% in both groups)). There were no specific safety concerns identified in subgroup analyses by medical comorbidities; occurrence of solicited, unsolicited, and serious adverse events in these subgroups were generally consistent with the overall study population. Reactogenicity data of an additional (third) dose given to ICPs, where reported, were generally similar to those observed for the standard primary series of the vaccine administered. Clinical trial data on safety and immunogenicity in pregnancy are limited. However, a growing body of post-introduction vaccine pharmacovigilance data has not identified any acute safety problems, with obstetric outcomes including spontaneous abortion and neonatal outcomes similar to reported background rates (38-40) Balance between benefits and harms Favours intervention Favours comparison Favours both Favours neither Unclear Efficacy data suggest benefit, and the safety data suggest minimal harms. An extended primary series including an additional (third) dose (100 µg) for ICPs may be required. Further studies will need to be undertaken as part of post- marketing surveillance. ☒ ☐ ☐ ☐ ☐ Effectiveness of the intervention Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 34 What is the overall quality of this evidence for the critical outcomes? No included studies Very low Low Moderate High Please see the related GRADE tables. ☐ ☐ ☐ ☒ ☐ Safety of the intervention No included studies Very low Low Moderate High ☐ ☐ ☒ ☐ ☐ VA LU ES & P R EF ER EN C ES How certain is the relative importance of the desirable and undesirable outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability No known undesirabl e outcomes There is possibly important uncertainty regarding how the target population weighs the desirable and undesirable effects (i.e. the protection conferred by the vaccine weighed against the currently reported safety signals), related to COVID-19 vaccination. Different population groups may have different opinions regarding the relative weights attributed to desirable and undesirable outcomes. ☐ ☒ ☐ ☐ ☐ Values and preferences of the target population: Are the desirable effects large relative to undesirable effects? No Probably No Uncertain Probably Yes Yes Varies Available scientific evidence suggests that the target population probably attaches 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 Considerable resources are needed to ensure the implementation of a COVID-19 vaccination programme, especially given the urgency of vaccination roll-out worldwide. This necessitates additional surge COVAX, the vaccine pillar of the Access to COVID-19 Tools Accelerator (ACT- Accelerator), has now shipped over 1 billion doses of COVID-19 ☒ ☐ ☐ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 35 resources in many settings to accelerate implementation with adequate infection prevention and control procedures in the context of COVID-19. 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. vaccine to 144 countries and territories (18). 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 (19). Cost- effectiveness 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 costs of COVID-19 vaccination in general at global level. Formal cost–effectiveness analyses of mRNA-1273 compared with other vaccines have been conducted in some settings. The ability to use mRNA-1273 in existing cold-chain infrastructure in all country settings may allow higher population-level coverage. 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 reduced business activity and unemployment due to the pandemic. Initial estimates suggest that COVID-19 vaccination will provide substantial economic value in terms ☐ ☐ ☐ ☒ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 36 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. of averted morbidity and mortality costs and averted losses in gross domestic product (20- 26). 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 (33), which offers guidance on the fair allocation of COVID-19 vaccines based on six core ethical principles that should guide distribution. If distributed fairly, COVID-19 vaccines may have considerable impact on reducing health inequities. The temperature storage requirements of the current formulation of the mRNA-1273 vaccine raises equity concerns, both within countries and globally. The required cold-chain capacity is not currently available in many low- and middle-income countries, and in some regions of high-income countries, particularly in hard-to- reach or otherwise already disadvantaged communities. If other vaccines with less demanding storage requirements are not made available, or if vaccines that are feasible and available to deliver are less efficacious or less safe, health inequities will result and existing Vaccine nationalism is seen as a threat to reducing health inequity, particularly 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 (28). ☒ ☐ ☐ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 37 health inequities may be exacerbated. A C C EP TA B IL IT Y Which option is acceptable to key stakeholders (e.g. ministries of health, immunization managers)? Intervention Comparison Both Neither Unclear As vaccination is an important tool to combat COVID-19, it is assumed that key stakeholders, in particular ministries of health and immunization managers, are 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. ☒ ☐ ☐ ☐ ☐ Which option is acceptable to target group? Intervention Comparison Both Neither Unclear 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 receive a COVID-19 vaccine. Acceptance rates ranged from almost 55% to 87% (29). 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 (30, 31). ☒ ☐ ☐ ☐ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 38 FE A SI B IL IT Y Is the intervention feasible to implement? No Probably No Uncertain Probably Yes Yes Varies The temperature storage requirements of the current formulation of the mRNA-1273 vaccine raise feasibility concerns. The required cold-chain capacity is not currently available in many low- and middle-income countries, and in some regions of high-income countries, particularly in hard-to- reach or otherwise already disadvantaged communities. Administration of the vaccine to novel target groups currently not reached by national immunization programmes may pose a challenge in certain settings. ☐ ☐ ☐ ☐ ☐ ☒ 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 RECOMMENDATION 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 RECOMMENDATION (TEXT) Please see the interim recommendations. Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 39 IMPLEMENTATION CONSIDERATIONS Please see the interim recommendations. MONITORING, EVALUATION AND RESEARCH PRIORITIES Please see the interim recommendations. Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 40 Annex 12. SAGE evidence-to-recommendation framework: mRNA-1273 mRNA-1273 vaccine use in children (12–17 years) Question: Should mRNA-1273 vaccine be administered to children (aged 12–17 years) to prevent COVID-19? Population: Children (aged 12–17 years) Intervention: Two doses of mRNA-1273 vaccine Comparison(s): Active control/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 (4). CRITERIA JUDGEMENTS RESEARCH EVIDENCE ADDITIONAL INFORMATION PR O B LE M Is the problem a public health priority? No Uncertain Yes Varies by setting By 1 February 2022, data from 108 countries included in the UNICEF database suggested that children and adolescents aged <20 years accounted for 18% (28.5 million) of the reported COVID-19 cases (41). The COVID-19 situation is evolving rapidly. The cumulative number of COVID-19 deaths globally has surpassed 5 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 Moderna mRNA-1273 vaccine against COVID-19 41 There has been collateral damage to other public health programmes. Although children are less affected by direct morbidity and mortality impacts of infection from SARS- CoV-2 when compared to other age groups, children remain at risk of developing severe illness and complications from COVID-19 (42). Current evidence suggests that children with certain underlying medical conditions, and infants (aged <1 year) may be at increased risk for severe illness from SARS-CoV-2 infection (43). Children infected with SARS-CoV-2 are also at risk for developing Multisystem Inflammatory Syndrome in Children (MIS-C), a severe, potentially fatal, rare multiorgan inflammatory condition with persistent fever (44). Evidence suggests that the case fatality rate (CFR) may be higher in children in low- and middle-income countries than those in high- income countries (43). B EN 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 A recent phase 2/3 trial assessed safety, immunogenicity, and efficacy of mRNA-1273 vaccine in children aged 12–17 years (n=3732). Non-inferiority in Geometric Mean Ratio in neutralization titers between the 12–17 year group and the 18–25 year group was met. ☐ ☐ ☒ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 42 Vaccine efficacy against COVID-19 in children aged 12–17 years was 93% (95%CI: 48–100%), 14 days after dose 2 (3). Harms of the intervention Are the undesirable anticipated effects small? No Uncertain Yes Varies The mRNA-1273 vaccine was well tolerated in children aged 12–17 years and showed a similar pattern to that seen in those aged 18–25 years (3). Pain at the injection site, fatigue, headaches, chills, joint pain and muscle pain were the most predominant effects. Systemic adverse reactions were reported in 69% of the participants after the first injection and in 86% after the second injection. Myocarditis and pericarditis have been reported after vaccination with mRNA COVID-19 vaccines. Reported cases occurred mostly in male adolescents and young adults aged ≥18 years, more often after receiving the second dose of one of the two mRNA COVID-19 vaccines than after the first dose, and typically within several days after vaccination. The Global Advisory Committee on Vaccine Safety noted that myocarditis can occur following SARS-CoV-2 infection (COVID-19 disease) and that mRNA vaccines have clear benefit in preventing hospitalization and death from COVID-19 (16). ☐ ☐ ☒ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 43 An extended interval between dose 1 and dose 2 decreases the risk of myocarditis/pericarditis, while increasing vaccine effectiveness (17). Balance between benefits and harms Favours intervention Favours comparison Favours both Favours neither Unclear In general, children present with less severe COVID-19 disease than adults. To date there are limited follow-up data of the intervention. The possibility to reduce non- pharmaceutical public health measures due to high vaccination coverage in children such as school closures may affect the psychosocial well-being of children. Based on limited safety data, the balance of benefits and harms is highly context-specific and remains unclear to date. Further studies will need to be undertaken as part of post- marketing surveillance. Should be considered in line with the WHO Prioritization Roadmap. ☐ ☐ ☐ ☐ ☒ 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 ☐ ☐ ☒ ☐ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 44 VA LU ES & P R EF ER EN C ES How certain is the relative importance of the desirable and undesirable outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability No known undesirabl e outcomes There is possibly important uncertainty regarding how the target population weighs the desirable and undesirable effects (i.e. the protection conferred by the vaccine weighed against the currently reported limited safety signals), related to COVID-19 vaccination. Different population groups may have different opinions regarding the relative weights attributed to desirable and undesirable outcomes. ☐ ☒ ☐ ☐ ☐ Values and preferences of the target population: Are the desirable effects large relative to undesirable effects? No Probably No Uncertain Probably Yes Yes Varies Available scientific evidence suggests that the target population probably attaches more weight to the desirable effects than the undesirable effects related to COVID-19 vaccination. There was substantial geographic variation in the acceptance of COVID-19 vaccination among pregnant women and mothers of children aged ≤18 years. COVID-19 vaccine acceptance levels among mothers for their children was above 85% in Brazil, Colombia, India and Mexico; and below 52% for Australia, Russia and the USA (45). Targeted studies should assess this aspect. ☐ ☐ ☐ ☒ ☐ ☐ R ES O U R C E U SE Are the resources required small? No Uncertain Yes Varies Considerable resources are needed to ensure the implementation of a COVID-19 vaccination programme, especially given the urgency of vaccination roll-out worldwide. This COVAX, the vaccine pillar of the Access to COVID-19 Tools Accelerator (ACT- Accelerator), has now shipped over 1 billion ☒ ☐ ☐ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 45 necessitates additional surge resources in many settings to accelerate implementation with adequate infection prevention and control procedures in the context of COVID-19. 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. doses of COVID-19 vaccine to 144 countries and territories (18). 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 (19). Cost– effectiveness 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 costs of COVID-19 vaccination in general at global level. Formal cost–effectiveness analyses of mRNA-1273 compared with other vaccines have been conducted in some settings. The ability to use mRNA-1273 in existing cold-chain infrastructure in all country settings may allow higher population-level coverage. 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 reduced business activity and unemployment due to the pandemic. Initial estimates suggest that COVID-19 vaccination will provide ☐ ☐ ☐ ☒ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 46 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. substantial economic value in terms of averted morbidity and mortality costs and averted losses in gross domestic product (20-26). Preliminary cost– effectiveness analysis results for low- and lower-middle-income countries suggest that the cost–effectiveness of COVID-19 vaccination in reducing mortality decreases as coverage expands to younger age cohorts in an age- descending strategy (46). 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 (27), which offers guidance on the fair allocation of COVID-19 vaccines based on six core ethical principles that should guide distribution. If distributed fairly, COVID-19 vaccines may have considerable impact on reducing health inequities. As a matter of global equity, as long as many parts of the world are facing extreme vaccine shortage, WHO recommends that countries that have achieved high vaccination coverage in the high- risk populations consider global sharing of mRNA-1273 vaccine before proceeding to vaccination of children and adolescents who are at low risk for severe disease. 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 (28). ☒ ☐ ☐ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 47 The temperature storage requirements of the current formulation of the mRNA-1273 vaccine raises equity concerns, both within countries and globally. The required cold-chain capacity is not currently available in many low- and middle-income countries, and in some regions of high-income countries, particularly in hard-to- reach or otherwise already disadvantaged communities. If other vaccines with less demanding storage requirements are not made available, or if vaccines that are feasible and available to deliver are less efficacious or less safe, health inequities will result and existing health inequities may be exacerbated. A C C EP TA B IL IT Y Which option is acceptable to key stakeholders (e.g. ministries of health, immunization managers)? Intervention Comparison Both Neither Unclear No scientific evidence is available. As vaccination is an important tool to combat COVID-19, it is assumed that key stakeholders, in particular ministries of health and immunization managers, are 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. ☒ ☐ ☐ ☐ ☐ Which option is acceptable to target group? Intervention Comparison Both Neither Unclear No representative data on vaccine acceptance in the target age-group are available. In the general population, COVID-19 vaccine acceptability varies between (sub)population groups and may be correlated with the perceived risk posed by the disease. ☒ ☐ ☐ ☐ ☐ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 48 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 receive a COVID-19 vaccine. Acceptance rates ranged from almost 55% to 87% (29). There was substantial geographic variation in the acceptance of COVID-19 vaccination among pregnant women and mothers of children aged ≤18 years. COVID- 19 vaccine acceptance levels among mothers for their children was above 85% in Brazil, Colombia, India and Mexico; and below 52% for Australia, Russia and the USA (45). 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 (30, 31). FE A SI B IL IT Y Is the intervention feasible to implement? No Probably No Uncertain Probably Yes Yes Varies The temperature storage requirements of the current formulation of this vaccine raises feasibility concerns. The required cold-chain capacity is not currently available in many low- and middle- income countries, and in some regions of high-income countries, particularly in hard-to-reach or ☐ ☐ ☐ ☐ ☐ ☒ Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19 49 otherwise already disadvantaged communities. Administration of the vaccine to novel target groups currently not reached by national immunization programmes may pose a challenge in certain settings. In certain settings, school-based programmes, such as for HPV vaccines, could be leveraged to administer COVID-19 vaccines to children. 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 RECOMMENDATION 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 RECOMMENDATION (TEXT) Please see the interim recommendations. IMPLEMENTATION CONSIDERATIONS Please see the interim recommendations. 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Всемирная организация здравоохранения (ВОЗ / WHO) · Technical Documents
Annexes to the recommendations for use of the Moderna mRNA-1273 vaccine against COVID-19: grading of evidence: evidence to recommendation tables, first issuance: 3 February 2021 (included in the background document), updated 15 June 2021, updated: 19 November 2021, updated: 23 February 2022
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