Annexes to the interim recommendations for use of the ChAdOx1-S [recombinant] vaccine against COVID-19 (AstraZeneca COVID-19 vaccine AZD1222, SII Covishield, SK Bioscience)

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Annexes to the interim recommendations for use of the ChAdOx1-S [recombinant] vaccine against COVID-19 (AstraZeneca COVID-19 vaccine AZD1222, SII

Covishield, SK Bioscience)

Grading of evidence -

Evidence to recommendations tables

First issued 10 February 2021 Updated 21 April 2021

Background

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 11 January 2021).

Annex 1. GRADE table: Efficacy of ChAdOx1-S recombinant COVID-19 vaccine vaccine in adults ... 2

Annex 2. GRADE table: Safety of ChAdOx1-S recombinant COVID-19 vaccine vaccine in adults ... 3

Annex 3. GRADE table: Efficacy of ChAdOx1-S recombinant COVID-19 vaccine vaccine in older adults ... 4

Annex 4. GRADE table: Safety of ChAdOx1-S recombinant COVID-19 vaccine vaccine in older adults ... 5

Annex 5. GRADE table: Efficacy of ChAdOx1-S recombinant COVID-19 vaccine vaccine in individuals with underlying conditions ... 6

Annex 6. GRADE table: Safety of ChAdOx1-S recombinant COVID-19 vaccine vaccine in individuals with underlying conditions ... 7

Annex 7. SAGE evidence-to-recommendation framework ChAdOx1-S recombinant COVID-19 vaccine vaccine use in adults ... 8

Annex 8. SAGE evidence-to-recommendation framework: ChAdOx1-S recombinant COVID-19 vaccine vaccine use in older adults ... 17

Annex 9. SAGE evidence-to-recommendation framework: ChAdOx1-S recombinant COVID-19 vaccine vaccine

use in individuals with comorbidities ... 26

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Annex 1. GRADE table: Efficacy of ChAdOx1-S recombinant COVID-19 vaccine in adults

Population:

Adults (18–64 years)

Intervention:

Two doses of ChAdOx1-S recombinant vaccine

Comparison:

Placebo/ active control

Outcome:

COVID-19 (PCR-confirmed)

What is the efficacy of two doses of ChAdOx1-S recombinant vaccine compared with placebo/active control in preventing PCR-confirmed COVID-19 in adults (18–64 years)?

Rating Adjustment to rating

Quality Assessment

No. of studies/starting rating 2/ RCT(1;2) 4

Factors decreasing confidence

Limitation in study

design^a

Not serious

^b 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

Summary of Findings

Statement on quality of evidence

Evidence supports a high level of confidence that the true effect lies close to that

of the estimate of the effect on the health outcome (level 4, or ⊕⊕⊕⊕).

Conclusion We are very confident that 2 doses of ChAdOx1-S

recombinant vaccine are efficacious in preventing PCR-confirmed COVID-19 in adults (18–64 years).

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 Data from post-licensure use in selected countries suggests high vaccine effectiveness. SAGE will continue to review any emerging data and adjust the quality assessment as required.

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Annex 2. GRADE table: Safety of ChAdOx1-S recombinant COVID-19 vaccine in adults

Population:

Adults (18–64 years)

Intervention:

Comparison:

Outcome:

Serious adverse events following immunization

What is the risk of serious adverse events following ChAdOx1-S recombinant vaccination compared with placebo/

active control in adults (18–64 years)?

No. of studies/starting rating 3/ RCT (1-6) 4

Limitation in study

design^a

Not serious

^b

0

Inconsistency

Not serious 0

Indirectness

Not serious 0

Imprecision

Not serious 0

Publication bias

Not serious 0

Large effect

Not applicable 0

Dose-response

Not applicable 0

Antagonistic bias

and confounding

Not applicable 0

Summary of Findings

Conclusion

While very rare thromboembolic events following immunization have been reported, we are very confident that the overall risk of serious adverse events following one or two doses of ChAdOx1-S recombinant vaccine in adults (18–64 years) is low.

b The trial was not adequately powered to detect rare adverse events (i.e. fewer than about 1/2000). Data from post-licensure use suggest a very low risk of thrombocytopenic thrombotic serious adverse events following immunization. SAGE will continue to review any emerging data and adjust the quality assessment as required.

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Annex 3. GRADE table: Efficacy of ChAdOx1-S recombinant COVID-19 vaccine in older adults

Population:

Older adults (≥65 years)

Intervention:

Two doses of ChAdOx1-S recombinant vaccine

Comparison:

Placebo/ active control

Outcome:

COVID-19 (PCR-confirmed)

What is the efficacy of two doses of ChAdOx1-S recombinant vaccine compared with placebo/ active control in preventing PCR-confirmed COVID-19 in older adults (≥65 years)?

No. of studies/starting rating 2/ RCT (1;2)

4

Limitation in study

design^a

Not serious

^b

0

Inconsistency

Not serious 0

Indirectness

Not serious 0

Imprecision

Not serious 0

Publication bias

Not serious 0

Large effect

Not applicable 0

Dose-response

Not applicable 0

Antagonistic bias

and confounding

Not applicable 0

Summary of Findings

Conclusion

We are confident that 2 doses of ChAdOx1-S recombinant vaccine are efficacious in preventing PCR-confirmed COVID-19 in older adults (≥65 years).

b Of the participants in phase III clinical trials in Brazil, South Africa, and the United Kingdom, approximately 10% (n=1380) were aged over 65 years.. Recent data from a phase III clinical trial in the Americas, n=5615 were aged 65 or over and vaccine efficacy was 85% (95%CI: 58-94%). Immunogenicity data in this age group suggest that the vaccine elicits an immune response comparable to younger adults.

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Annex 4. GRADE table: Safety of ChAdOx1-S recombinant COVID-19 vaccine in older adults

Population:

Older adults (

≥65

years)

Intervention:

One or two doses of ChAdOx1-S recombinant vaccine

Comparison:

Placebo/ active control

Outcome:

Serious adverse events following immunization

What is the risk of serious adverse events following ChAdOx1-S recombinant vaccination compared with placebo/

active control in older adults (≥65 years)?

No. of studies/starting rating 3/ RCT(1;2;4-7)

4

Limitation in study

design^a

Not serious

^b

0

Inconsistency

Not serious 0

Indirectness

Not serious 0

Imprecision

Not serious 0

Publication bias

Not serious 0

Large effect

Not applicable 0

Dose-response

Not applicable 0

Antagonistic bias

and confounding

Not applicable 0

Summary of Findings Statement on quality of evidence

Conclusion

While very rare thromboembolic events following immunization have been reported, mainly in adults aged <60 years, we are very confident that the risk of serious adverse events following one or two doses of ChAdOx1-S recombinant vaccine in older adults (≥65 years) is low.

.

b The trial was not adequately powered to detect rare adverse events (i.e, about 1/250). Data from post-licensure use suggest a very low risk of thrombocytopenic thrombotic serious adverse events following immunization. SAGE will continue to review any emerging data and adjust the quality assessment as required.

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Annex 5. GRADE table: Efficacy of ChAdOx1-S recombinant COVID-19 vaccine in individuals with underlying conditions

Population:

Individuals with comorbidities or health states that increase risk for severe COVID-19

Intervention:

Two doses of ChAdOx1-S recombinant vaccine

Comparison:

Placebo/ active control

Outcome:

COVID-19 (PCR-confirmed)

What is the efficacy of two doses of ChAdOx1-S recombinant 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?

No. of studies/starting rating 2/ RCT(1;2;8;9) 4

Limitation in study

design^a

Not serious 0

Inconsistency

Not serious 0

Indirectness

Serious

^b

-1

Imprecision

Not serious

^c

0

Publication bias

Not serious 0

Large effect

Not applicable 0

Dose-response

Not applicable 0

Antagonistic bias

and confounding

Not applicable 0

Evidence supports a moderate level of confidence that the true effect lies close

to that of the estimate of the effect on the health outcome (level 3, or ⊕⊕⊕).

Conclusion

We are moderately confident that 2 doses of ChAdOx1-S recombinant 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.

No data were obtained on vaccination of pregnant or breastfeeding women, or persons who were immunocompromised.

b Trial excluded pregnant and breastfeeding women, and persons who were immunocompromised. Comparable immunogenicity was shown between people living with and without HIV. This was considered as constituting a limitation that leads to downgrading of the evidence.

c Underlying comorbidities included BMI ≥ 30 kg/m2, cardiovascular disorder, respiratory disease or diabetes. Approximately 36% of the trial population had at least one comorbidity. This was considered as not constituting a limitation that would lead to downgrading of the evidence. SAGE will continue to review any emerging data and adjust tge quality assessment as required.

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Annex 6. GRADE table: Safety of ChAdOx1-S recombinant COVID-19 vaccine in individuals with underlying conditions

Population:

Individuals with comorbidities or health states that increase risk for severe COVID-19

Intervention:

One or two doses of ChAdOx1-S recombinant vaccine

Comparison:

Placebo/ active control

Outcome:

Serious adverse events following immunization

What is the risk of serious adverse events following ChAdOx1-S recombinant vaccination compared with placebo/

active control in individuals with comorbidities or health states that increase risk for severe COVID-19?

No. of studies/starting rating 2/ RCT(1;2;4-

7;9) 4

Limitation in study

design^a

Not serious 0

Inconsistency

Not serious 0

Indirectness

Serious

^b

-1

Imprecision

Not serious 0

Publication bias

Not serious 0

Large effect

Not applicable 0

Dose-response

Not applicable 0

Antagonistic bias

and confounding

Not applicable 0

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, or ⊕⊕⊕).

Conclusion

While very rare thromboembolic events following immunization have been reported, we have moderate confidence in the quality of evidence that the overall 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 ChAdOx1-S recombinant vaccine is low.

b Trial excluded pregnant and breastfeeding women, and persons who were immunocompromised. Comparable safety profiles were seen in people living with and without HIV. This was considered as constituting a limitation that leads to downgrading of the evidence.

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Annex 7. SAGE evidence-to-recommendation framework ChAdOx1-S recombinant COVID-19 vaccine use in adults

Question:

Should ChAdOx1-S recombinant vaccine be administered to adults to prevent COVID-19?

Population:

Adults (18–64 years)

Intervention:

Two doses of ChAdOx1-S recombinant 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 COVID-19 pandemic. WHO has to date issued interim recommendations on the use of Pfizer–BioNTech, Moderna, AstraZeneca and Janssen vaccines (10-13).

CRITERIA JUDGEMENTS RESEARCH EVIDENCE ADDITIONAL

INFORMATION

PROBLEM

Is the problem a public health priority?

No Uncertain Yes Varies by

setting The cumulative number of COVID-19 cases globally has surpassed 132 730 691with more than 2 880 726deaths.

Cases have been found in 190 different countries or territories throughout the world (status 9 April 2021). There has been collateral damage to other public health programmes.

The COVID-19 situation is evolving rapidly; the most recent epidemiological situation can be found on the following website:

https://covid19.who.int/table

☐ ☐ ☒ ☐

BENE FITS & HAR

No Uncertain Yes Varies Using 7 December 2020 as data cut-off, primary efficacy analysis of trials in Brazil, South Africa and the United

The immunogenicity results from the phase 1/2 United Kingdom study, in 1077

(9)

Benefits of the intervention

Are the desirable

anticipated effects large?

☐ ☐ ☒ ☐

Kingdom shows that ChAdOx1-S recombinant vaccine is 63.1% (95% CI:

52.9–68.6%) efficacious across the study population. In those aged 18–64 years, vaccine efficacy was 63.5%

(95% CI: 52.0–72.2%).

Vaccine efficacy against COVID-19 (14 or more days after the second dose) was 66.7% (95% CI: 57.4–74.0%) (9) but varied by interval between first and second dose:

<4 weeks interval: 66.56% (95% CI: - 221.8–96.5%)

4–8 weeks interval: 56.42% (95% CI:

39.9–68.4%)

9–12 weeks interval: 70.48% (95% CI:

42.4–84.9%)

>12 weeks interval: 77.62% (95% CI:

52–89.6%)(2)

Recent data (data cut-off for primary analysis: 5 March 2021) from a phase III trial (D8110C0001) in 32 449 participants across 88 trial centres in Chile, Peru and the United States, suggest a vaccine efficacy of 78.3%

(95% CI: 67.8–85.3%) against symptomatic COVID-19 in adults aged 18–64 years.

healthy adults aged 18–55 years (3) and a phase 2 cohort in older adults (≥56 years)(7) show the induction of binding and neutralising antibodies, with higher antibody titres after a second dose of vaccine.(3;7;14)

The vaccine further induced CD4⁺ and CD8⁺ T cells in adults aged 18–55 years, up to 8 weeks after vaccination with a single dose of ChAdOx1-S recombinant nCoV-19 vaccine.(15) Vaccine effectiveness ranged from 58% (95% CI 38-72%) 35 days after 1 dose against symptomatic disease (16), 68% (95% CI 34-85%) day 34-48 post dose 1 against infection (17), 80.4% (95% CI 36.4- 94.5%) 14 days post dose 1 against hospitalization (18)and 94% (95%CI 73- 99%) day 28-34 post dose 1 against hospitalization (19) Regarding variants of concern (VoC), laboratory virus neutralization activity by vaccine-induced antibodies was lower against the B.1.1.7 variant than against the Victoria lineage (geometric mean ratio 8·9; 95% CI: 7.2–

11·0%). Clinical vaccine

efficacy against symptomatic NAAT positive

infection was 70.4%

(95% CI: 43.6–84.5%) for B.1.1.7 and 81.5%

(95% CI: 67.9–89.4%) for non-B.1.1.7 lineages.(20)

(10)

Within the South African arm of the randomized clinical trial (RCT)(2), the B.1.351 variant was circulating in the population. Vaccine efficacy and effectiveness may vary according to prevalent VoCs. Therefore the epidemiological situation will need to be taken into consideration when interpreting data from RCTs and post-licensure studies.

Harms of the intervention

Are the undesirable

anticipated effects small?

No Uncertain Yes Varies Data from over 12 021 participants

demonstrate that ChAdOx1-S recombinant vaccine was well tolerated across all populations.

Overall, 86% of subjects in the vaccine group (Days 0-7 after any vaccination) experienced at least one solicited AE compared to 72% in the control group.

The majority of solicited AEs were mild or moderate. Ten percent of subjects in the vaccine group experienced at least one grade ≥3 local solicited adverse event (AE) and 8% at least one grade ≥3 systemic solicited event compared with 6% and 3% in the control group, respectively. Solicited AEs were milder and reported less frequently after the second dose compared with the first.

The most frequently reported systemic solicited AEs in the vaccine dose 1 standard-dose group after any vaccination were fatigue (53%) and headache (53%).

Fewer than 1% of subjects reported a serious adverse event (SAE) and the reporting rate was balanced between the two study groups (0.7% vaccine group, 0.8% control).

There were no clinically meaningful imbalances in SAE incidence for any

The results from the phase 1/2 immunogenicity and safety trial suggest an acceptable safety profile in healthy adults aged 18–55 years (3) and a phase 2 study in older adults (≥56 years)(7)

☐ ☐ ☒ ☐

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subgroup (country, age, serostatus or comorbidity).

Data from phase III trial D8110C0001 suggest no safety concerns and the data and safety monitoring board (DSMB) found no disproportionate risk of events characterized by thrombosis or cerebral venous thrombosis.

Post-licensure safety surveillance data suggest an increase in reports of a rare severe thrombosis with low platelet counts (thrombosis with thrombocytopenia syndrome (TTS)) following vaccination with the AstraZeneca COVID-19 vaccine.

Based on current information, the WHO Global Advisory Committee on Vaccine Safety (GACVS) subgroup concluded on 16 April 2021 that at this stage, a

“platform specific” mechanism related to the adenovirus-vectored vaccines is not certain but cannot be excluded.

Data from theUnited Kingdom suggest the risk is approximately 5 cases per 1 million adults (1 case per 200 000) who receive the vaccine, while the rate is estimated to be approximately 1 case per 100 000 adults in the European Union (EU).(4-6)

Balance between benefits and harms

Favours

intervention Favours

comparison Favours

both Favours

neither Unclear Efficacy data suggest benefit in those aged 18-64 years. Overall, the vaccine is well tolerated. Recent reports of very rare TTS have been reported following vaccination. Balancing benefits and harms of COVID-19 disease and vaccination with ChAdOx1-S recombinant, the benefit of the intervention is larger than the potential harms. .

☒ ☐ ☐ ☐ ☐

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

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evidence for the critical outcomes?

☐ ☐ ☐ ☐ ☒

Safety of the intervention No included

☐ ☐ ☐ ☐ ☒

VALUES & PREFERENCES

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 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), vary.

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 Recent safety signals in younger age groups many have shifted the weighing of desirable effects versus undesirable effects related to COVID-19 vaccination, although this may be in certain regions only where rare serious adverse events have been reported.

☐ ☐ ☐ ☒ ☐ ☐

RESOURCE USE

Are the resources

required small?

No Uncertain Yes Varies ChAdOx1-S recombinant can be

distributed and stored using existing cold chain infrastructure (at 2°-8° C),(21) and does not require ultra-cold chain capacity. In addition, as ChAdOx1-S recombinant can be manufactured with widely available manufacturing capacity around the world(22), its price is expected to be lower than for other COVID-19 vaccines using new and less widely available manufacturing platforms. Prices are also expected to be lower for ChAdOx1-S recombinant compared to many other COVID-19

An estimated US$15.9 billion is needed for the vaccines pillar (COVAX) of the Access to COVID-19 Tools Accelerator (ACT-A) for 2020–21, when the initiative aims to deliver 2 billion doses. This does not include all delivery costs in all countries participating in

COVAX, bilateral procurement deals, or research and development investments outside of

☒ ☐ ☐ ☐

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vaccines due to supplier commitments to forego profits.(23) Nevertheless, considerable resources will be needed to ensure the implementation of a COVID-19 vaccination programme, especially given: (i) that COVID-19 vaccination is likely to be prioritized for populations (e.g. health care workers, older adults) without pre-existing robust immunization programmes in many settings, and (ii) the urgency of vaccination roll-out worldwide, which may necessitate additional surge resources 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 (24). The World Bank has approved a financing window of up to US$12 billion to support low- and middle-income countries in purchasing and distributing vaccine (25).

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 cost of COVID-19 vaccination in general at global level.

No formal cost-effectiveness analyses of ChAdOx1-S recombinant compared to other vaccines have been conducted.

The ChAdOx1-S recombinant vaccine is expected to be less costly than many other COVID-19 vaccines (see previous sub-criterion). The ability to use ChAdOx1-S recombinant in existing cold chain infrastructure in all country settings may enable 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

The global economy is estimated to be losing US$375 billion per month due to 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 GDP losses (24;26-32).

☐ ☐ ☐ ☒

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interventions assessed, analysis perspective, and local cost-effectiveness thresholds used.

EQUITY

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.

Storage and distribution requirements of the ChAdOx1-S recombinant vaccine are the same as those of many other vaccines currently in use globally.

Therefore existing vaccine cold chain capacity, available in almost all countries worldwide could be leveraged for vaccine distribution.

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 (34).

☐ ☐ ☒ ☐

ACCEPTABILITY

Which option is acceptable to key stakeholders

(e.g.

ministries of health,

immunization managers)?

Intervention Comparison Both Neither Un-clear

No scientific evidence is available. As vaccination is an eagerly awaited tool to combat COVID-19, it is assumed that key stakeholders, in particular ministries of health and immunization managers, are strongly in favour of it.

190 economies are participating in COVAX suggests a very high acceptability of COVID-19 vaccination in general.

☒ ☐ ☐ ☐ ☐

Which option is acceptable to target group?

COVID-19 vaccine acceptability in general varies between (sub-) population groups and may be correlated with the perceived risk posed by the vaccine versus 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% (35).

☒ ☐ ☐ ☐ ☐

(15)

Polls have been launched, (periodically) assessing vaccine acceptance in selected countries. These polls confirm overall, not product-specific, vaccine acceptance, with variations across countries. (36;37)

Several European countries have recently seen an increase in skepticism towards the safety of AstraZeneca's COVID-19 vaccine linked to reported vaccine safety signals, according to polling data released by YouGov on 22 March 2021. (38)

FEASIBILITY

Is the intervention

feasible to implement?

No Probably

No Uncertain

Probably

Yes Yes Varies This vaccine is assumed to be easily implementable in settings, including low- and middle-income-countries, with existing vaccine logistics and delivery infrastructure.

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

☐ ☐ ☐ ☐ ☒

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

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RECOMMENDATION (TEXT)

See: www.who.int/publications/i/item/WHO-2019-nCoV-vaccines-SAGE_recommendation-AZD1222-2021.1

IMPLEMENTATION

CONSIDERATIONS See: www.who.int/publications/i/item/WHO-2019-nCoV-vaccines-SAGE_recommendation-AZD1222-2021.1 MONITORING,

EVALUATION AND RESEARCH PRIORITIES

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Annex 8. SAGE evidence-to-recommendation framework: ChAdOx1-S recombinant COVID-19 vaccine use in older adults

Question:

Should ChAdOx1-S recombinant vaccine be administered to older adults to prevent COVID-19?

Population: Older adults (≥65 years)

Intervention:

Two doses of ChAdOx1-S recombinant 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 COVID-19 pandemic. WHO has to date issued interim recommendations on the use of Pfizer–BioNTech, Moderna, AstraZeneca and Janssen vaccines (10-13)

INFORMATION

PROBLEM

setting The cumulative number of COVID-19 cases globally has surpassed 132 730 691 with more than 2 880 726 deaths. Cases have been found in 190 different countries or territories throughout the world (status 9 April 2021).

Older adults are particularly affected by COVID-19 and bear a significantly higher risk of severe COVID-19 outcomes and death.

☐ ☐ ☒ ☐

(18)

BENEFITS & HARMS OF THE OPTIONS

Are the desirable

No Uncertain Yes Varies Around 10% of the study population in the primary analysis (data cut-off 07 December 2020; trial COV001, COV002, COV003, COV005) were aged

≥65 years.

Primary efficacy analysis using SDSD at any interval shows that two doses of ChAdOx1-S recombinant vaccine is 51.9% (95% CI: -60.9%–86.0%) efficacious in adults aged ≥65 years against COVID-19 beginning 15 days after the second dose.

A relatively small proportion of participants were aged ≥65 years and the number of cases of COVID-19 in this age group was too small to assess protection based on the efficacy data alone.

There were no cases of COVID-19 hospitalization, severe COVID-19 disease, or COVID-19 death in participants aged ≥65 years who received the vaccine.(2)

Recent data (data cut-off for primary analysis: 5 March 2021) from a phase 3 trial (D8110C0001) in 32 449 participants across 88 trial centres in Chile, Peru and the United States, suggest a vaccine efficacy of 84.8%

(95% CI: 58.1–94.5%) against symptomatic COVID-19 in those aged

≥65 years (n=5615).

The immunogenicity results from the phase 1/2 United Kingdom study, in 1077 healthy adults aged 18–55 years (3) and a phase 2 cohort in older adults (≥56 years)(7) show the induction of binding and neutralising antibodies, with higher antibody titres after a second dose of vaccine.(3;7;14)

The vaccine further induced CD4⁺ and CD8⁺ T cells in adults aged 18–55 years, up to 8 weeks after vaccination with a single dose of ChAdOx1-S recombinant nCoV-19 vaccine.(15)

Vaccine effectiveness ranged from 58% (95% CI:

38-72%) 35 days after 1 dose against symptomatic disease (16), 68% (95% CI:

34-85%) day 34-48 post dose 1 against infection (17), 80.4% (95% CI: 36.4- 94.5%) 14 days post dose 1 against hospitalization (18) and 94% (95% CI: 73-99%) day 28-34 post dose 1 against hospitalization (19) Regarding variants of concern (VoC), laboratory virus neutralization activity by vaccine-induced antibodies was lower against the B.1.1.7 variant than against the Victoria lineage (geometric mean ratio 8·9; 95% CI: 7.2–

11.0%). Clinical vaccine efficacy against symptomatic NAAT positive infection was 70.4%

(95% CI: 43.6–84.5%) for

☐ ☒ ☐ ☐

(19)

B.1.1.7 and 81.5%

(95% CI: 67.9–89.4%) for non-B.1.1.7 lineages.(20) Within the South African arm of the randomized clinical trial (RCT)(2), the B.1.351 variant was circulating in the population. Vaccine efficacy and effectiveness may vary according to prevalent VoCs. Therefore the epidemiological situation will need to be taken into consideration when interpreting data from RCTs and post-licensure studies.

Are the undesirable

No Uncertain Yes Varies Data from over 12 021 trial participants of all age demonstrate that ChAdOx1-S recombinant vaccine was well tolerated across all populations.

Overall, 86% of subjects in the vaccine group (Days 0-7 after any vaccination) experienced at least one solicited AE compared to 72% in the control group.

The majority of solicited AEs were mild or moderate. Ten percent of subjects in the vaccine group experienced at least one grade ≥3 local solicited adverse event (AE) and 8% at least one grade ≥3 systemic solicited event compared with 6% and 3% in the control group, respectively. Solicited AEs were milder and reported less frequently after the second dose compared with the first.

Reactogenicity was generally milder and less frequent in older adults (≥65 years) compared to younger adults (18-64 years).

☐ ☐ ☒ ☐

(20)

There were no clinically meaningful imbalances in SAE incidence for any subgroup (country, age, serostatus or comorbidity).

Within the recent D8110C00001 phase III trial, no safety concerns were identified by the data and safety monitoring board. The overall reactogenicity profile was favourable and reduced with age.

Data from the United Kingdom suggest the risk is approximately 5 cases per 1 million adults (1 case per 200 000) who receive the vaccine, while the rate is estimated to be approximately 1 case per 100 000 adults in the European Union (EU). (4-6)

Balance between benefits and harms

Favours

both Favours

neither Unclear Evidence on efficacy data suggest significant benefit of the intervention and safety data suggest limited harms.

☒ ☐ ☐ ☐ ☐

(21)

What is the overall quality of this evidence for the critical outcomes?

No included

☐ ☐ ☐ ☐ ☐

☐ ☐ ☐ ☐ ☒

The majority of severe disease occurs in older 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.

Different population groups may have different opinions regarding the weights assigned to desirable and undesirable outcomes.

☐ ☒ ☐ ☐ ☐

Are the desirable

No 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 information campaigns should assess this aspect.

With the most recent data on vaccine efficacy in older adults, the uncertainty around the importance of the desirable effects of the intervention will be likely be reduced.

☐ ☐ ☐ ☒ ☐ ☐

RESOURCE USE

Are the resources

required small?

No Uncertain Yes Varies ChAdOx1-S recombinant can be

distributed and stored using existing cold chain infrastructure (at 2°-8° C),(21) and does not require ultra-cold chain capacity. In addition, as ChAdOx1-S recombinant can be manufactured with widely available manufacturing capacity

An estimated US$15.9 billion is needed for the vaccines pillar (COVAX) of the Access to COVID-19 Tools Accelerator (ACT-A) for 2020–21, when the initiative aims to deliver 2

☐ ☐ ☒ ☐

(22)

around the world(22), its price is expected to be lower than for other COVID-19 vaccines using new and less widely available manufacturing platforms. Prices are also expected to be lower for ChAdOx1-S recombinant compared to many other COVID-19 vaccines due to supplier commitments to forego profits.(23) Nevertheless, considerable resources will be needed to ensure the implementation of a COVID-19 vaccination programme, especially given: (i) that COVID-19 vaccination is likely to be prioritized for populations (e.g. health care workers, older adults) without pre-existing robust immunization programmes in many settings, and (ii) the urgency of vaccination roll-out worldwide, which may necessitate additional surge resources 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.

billion doses. This does not include all delivery costs in all countries participating in

COVAX, bilateral procurement deals, or research and development investments outside of COVAX (24).

The World Bank has approved a financing window of up to US $12 billion to support low- and middle-income countries in purchasing and distributing vaccine (25).

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 cost of COVID-19 vaccination in general at global level.

No formal cost-effectiveness analyses of ChAdOx1-S recombinant vaccine compared to other vaccines have been conducted. The ChAdOx1-S recombinant vaccine is expected to be less costly than many other COVID-19 vaccines (see previous sub- criterion). . The ability to use ChAdOx1- S recombinant vaccine in existing cold

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

☐ ☐ ☐ ☒

(23)

chain infrastructure in all country settings may enable 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.

mortality costs and averted GDP losses (24;26-31).

EQUITY

Storage and distribution requirements of ChAdOx1-S recombinant vaccine is shared by many other vaccines currently in use globally. Therefore existing vaccine cold chain capacity, available in almost all countries worldwide, could be leveraged for vaccine distribution.

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 (34).

☐ ☐ ☒ ☐

ACCEPTABILITY

Which option is acceptable to key stakeholders

(e.g.

No scientific evidence is available. As vaccination is an eagerly awaited 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.

But they may need to convince other partners or stakeholders to support COVID-19 immunization.

190 economies are participating in COVAX which suggests a very high acceptability of COVID-19 vaccination in general, although not necessarily of this vaccine in particular.

☒ ☐ ☐ ☐ ☐

(24)

COVID-19vaccine 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% (35).

Polls have been launched, (periodically) assessing (non-product specific) vaccine acceptance in selected countries. These polls confirm overall non-product specific vaccine acceptance, with variations across countries. (36;37)

Several European countries have recently seen an increase in scepticism towards the safety of AstraZeneca's COVID-19 vaccine during the past month linked to reported vaccine safety signals, according to polling data released by YouGov on 22 March 2021.

(38)

☒ ☐ ☐ ☐ ☐

FEASIBILITY

Is the intervention

No Probably

No Uncertain

Probably

☐ ☐ ☐ ☐ ☒ ☐

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

Desirable consequences clearly outweigh undesirable

(25)

☐ ☐ ☐ ☐ ☒

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) See: www.who.int/publications/i/item/WHO-2019-nCoV-vaccines-SAGE_recommendation-AZD1222-2021.1 IMPLEMENTATION

CONSIDERATIONS See: www.who.int/publications/i/item/WHO-2019-nCoV-vaccines-SAGE_recommendation-AZD1222-2021.1 MONITORING,

EVALUATION AND RESEARCH PRIORITIES

(26)

Annex 9. SAGE evidence-to-recommendation framework: ChAdOx1-S recombinant COVID-19 vaccine use in individuals with comorbidities

a Comorbidity within the phase III trial was defined as BMI ≥ 30 kg/m2, cardiovascular disorder, respiratory disease or diabetes.

Question:

Should ChAdOx1-S recombinant vaccine be administered to individuals with comorbidities or health states that increase risk for severe COVID-19

^a

to prevent COVID-19?

Population:

Individuals with comorbidities or health states that increase risk for severe COVID-19

Intervention:

Two doses of ChAdOx1-S recombinant 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 COVID-19 pandemic. IWHO has to date issued interim recommendations on the use of Pfizer–BioNTech, Moderna, AstraZeneca and Janssen vaccines (10-13).

INFORMATION

PROBLEM

setting The cumulative number of COVID-19 cases globally has surpassed 132 730 691 with more than 2 880 726 deaths. Cases have been found in 190 different countries or territories throughout the world (status 9 April 2021). Individuals with certain comorbidities are particularly affected by COVID-19 and bear a higher risk of severe COVID-19 outcomes and death.

☐ ☐ ☒ ☐

(27)

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 (39). 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 (>75 years).

BENEFITS & HARMS OF THE OPTIONS

Are the desirable

No Uncertain Yes Varies Approximately 36% of participants in the primary efficacy population, as well as of the overall study population, had at least one comorbidity at baseline. The most common comorbid conditions were obesity (54.4%), hypertension (17.4%), and asthma (16.7%).

Primary efficacy analysis (shows that ChAdOx1-S recombinant vaccine is 61.3% efficacious (95% CI: 41.2–

75.3%) against COVID-19 beginning 15 days after the second dose in adults with a comorbid condition at baseline.(2)

The immunogenicity results from the phase 1/2 United Kingdom study, in 1077 healthy adults aged 18–55 years (3) and a phase 2 cohort in older adults (≥56 years)(7) show the induction of binding and neutralising antibodies, with higher antibody titres after a second dose of vaccine.(3;7;14)

The vaccine further induced CD4⁺ and CD8⁺ T cells in adults aged 18–55 years, up to 8 weeks after vaccination with a single dose of ChAdOx1-S recombinant nCoV-19 vaccine.(15)

Vaccine effectiveness ranged from 58% (95% CI:

38-72%) 35 days after 1 dose against symptomatic disease (16), 68% (95% CI:

34-85%) day 34-48 post dose 1 against infection (17), 80.4% (95% CI: 36.4- 94.5%) 14 days post dose 1 against hospitalization (18) and 94% (95% CI: 73-99%) day 28-34 post dose 1 against hospitalization (19)

☐ ☐ ☒ ☐

(28)

Regarding variants of concern (VoC), laboratory virus neutralization activity by vaccine-induced antibodies was lower against the B.1.1.7 variant than against the Victoria lineage (geometric mean ratio 8·9; 95% CI: 7.2–

11.0%). Clinical vaccine

efficacy against symptomatic NAAT positive

infection was 70.4%

(95% CI: 43.6–84.5%) for B.1.1.7 and 81.5%

(95% CI: 67.9–89.4%) for non-B.1.1.7 lineages .(20) Within the South African arm of the randomized clinical trial (RCT)(2), the B.1.351 variant was circulating in the population. Vaccine efficacy and effectiveness may vary according to prevalent VoCs. Therefore the epidemiological situation will need to be taken into consideration when interpreting data from RCTs and post-licensure studies.

Are the undesirable

No Uncertain Yes Varies

Overall, 86% of all subjects in the vaccine group (Days 0-7 after any vaccination), independent of comorbidity, experienced at least one solicited AE compared to 72% in the control group. The majority of solicited AEs were mild or moderate. Ten percent of subjects in the vaccine group experienced at least one grade ≥3 local solicited adverse event (AE) and 8% at least one grade ≥3 systemic solicited event compared with 6% and 3% in the control group, respectively. Solicited AEs were milder and reported less frequently after the second dose compared with the first.

☐ ☐ ☒ ☐

(29)

There were no clinically meaningful imbalances in SAE incidence for any subgroup (country, age, serostatus or comorbidity).

No data are currently available in immunocompromised subjects or in subjects taking immunosuppressants.

Safety profiles in persons living with HIV were favourable.(9)

Data from the United Kingdom suggest the risk is approximately 5 cases per 1 million adults (1 case per 200 000) who receive the vaccine, while the rate is estimated to be approximately 1 case per 100 000 adults in the European Union (EU).(4-6)

Balance between

Favours

both Favours

neither Unclear Efficacy data suggest benefit in those individuals with comorbidities or health

(30)

benefits and harms

☒ ☐ ☐ ☐ ☐

states that increase risk for severe COVID-19 for which there are data.

Recent reports of very rare TTS have been reported following vaccination.

Balancing benefits and harms of COVID- 19 disease and vaccination with ChAdOx1-S recombinant, the benefit of the intervention is larger than the potential harms.

What is the overall quality of this evidence for the critical outcomes?

No included

☐ ☐ ☐ ☒ ☐

There is possibly important uncertainty related to the target population weighing of 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

☐ ☐ ☒ ☐ ☐

Are the desirable

No Probably

Yes Yes Varies Available scientific evidence suggests that the target population probably attached more weight to the desirable effects than the undesirable effects related to COVID-19 vaccination.

Targeted information campaigns should assess this aspect.

☐ ☐ ☐ ☒ ☐ ☐

(31)

RESOURCE USE

Are the resources

required small?

No Uncertain Yes Varies ChAdOx1-S recombinant vaccine can

be distributed and stored using existing cold chain infrastructure (at 2°-8° C),(21) and does not require ultra-cold chain capacity. In addition, as ChAdOx1-S recombinant vaccine can be manufactured with widely available manufacturing capacity around the world(22), its price is expected to be lower than for other COVID-19 vaccines using new and less widely available manufacturing platforms. Prices are also expected to be lower for ChAdOx1-S recombinant vaccine compared to many other COVID-19 vaccines due to supplier commitments to forego profits.(23) Nevertheless, considerable resources will be needed to ensure the implementation of a COVID-19 vaccination programme, especially given: (i) that COVID-19 vaccination is likely to be prioritized for populations (e.g. health care workers, older adults) without pre-existing robust immunization programmes in many settings, and (ii) the urgency of vaccination roll-out worldwide, which may necessitate additional surge resources 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.

An estimated US$15.9 billion is needed for the vaccines pillar (COVAX) of the Access to COVID-19 Tools Accelerator (ACT-A) for 2020–21, when the initiative aims to deliver 2 billion vaccine doses. This does not include all delivery costs in all countries participating in COVAX, bilateral procurement deals, or research and development investments outside of COVAX (24).

The World Bank has approved a financing window of up to US$12 billion to support low- and middle-income countries in purchasing and distributing vaccine (25).

☐ ☐ ☒ ☐

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 cost of COVID-19 vaccination in general at global level.

No formal cost-effectiveness analyses of ChAdOx1-S recombinant vaccine

in domestic economic stimulus to mitigate the economic consequences of

☐ ☐ ☐ ☒

(32)

compared to other vaccines have been conducted. The ChAdOx1-S recombinant vaccine is expected to be less costly than many other COVID-19 vaccines (see previous sub-criterion).

The ability to use ChAdOx1-S recombinant in existing cold chain infrastructure in all country settings may enable 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.

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 GDP losses (24;26-31)

EQUITY

Storage and distribution requirements of ChAdOx1-S recombinant vaccine is shared by many other vaccines currently in use globally. Therefore existing vaccine cold chain capacity, available in almost all countries worldwide could be leveraged for vaccine distribution.

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 (34).

☐ ☐ ☒ ☐

ACCEPT ABILITY Which option is acceptable to key stakeholders

No scientific evidence is available. As vaccination is an eagerly awaited tool to combat COVID-19, it is assumed that key stakeholders, in particular ministries of health and immunization managers

The fact that 190 economies are participating in COVAX suggests a very high acceptability of COVID-19 vaccination in general,

(33)

(e.g.

☒ ☐ ☐ ☐ ☐

are strongly in favour of COVID-19 vaccination.

But they may need to convince other partners or stakeholders to support COVID-19 immunization.

though not necessarily of this vaccine in particular.

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% (35).

Polls have been launched, (periodically) assessing (non-product specific) vaccine acceptance in selected countries. These polls confirm overall vaccine acceptance, with variations across countries. (36;37)

Several European countries have recently seen an increase in scepticism towards the safety of AstraZeneca's COVID-19 vaccine over the past month linked to reported vaccine safety signals, according to polling data released by YouGov on 22 March 2021. (38)

☒ ☐ ☐ ☐ ☐

FEASIBILITY

Is the intervention

No Probably

No Uncertain

Probably

☐ ☐ ☐ ☐ ☒ ☐

Annexes to the interim recommendations for use of the ChAdOx1-S [recombinant] vaccine against COVID-19 (AstraZeneca COVID-19 vaccine AZD1222, SII Covishield, SK Bioscience)