Recommendations on the use of bivalent Omicron-containing mRNA COVID-19 vaccines

Publication date: September 1, 2022

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Organization: Public Health Agency of Canada
Cat.: HP5-142/1-2022E-PDF
ISBN: 978-0-660-45248-7
Pub.: 220386
Published: 2022-09-01

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Preamble

The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.

In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.

The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.

This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

Background

On June 29, 2022, NACI published interim guidance on planning considerations for a fall 2022 COVID-19 vaccine booster program in Canada. The statement outlined recommendations for booster doses in specific populations ahead of the uncertain trajectory of the COVID-19 pandemic in the coming months. Since that time:

NACI continues to recommend a primary series with an authorized mRNA vaccine in all authorized age groups. NACI has also provided recommendations for a booster dose with an authorized COVID-19 vaccine for all adults, adolescents, and children 5 to 11 years of age. Immunization of those who are eligible for vaccination but have not yet received their recommended doses (primary or booster) remains a top priority in Canada. As with previous COVID-19 booster programs, a fall booster dose with any authorized COVID-19 vaccine will be most important for older adults and other populations at increased risk of severe COVID-19 disease, regardless of the number of booster doses previously received.

NACI continues to monitor the rapidly evolving scientific data while recognizing that the trajectory of the COVID-19 pandemic remains unclear. Updated recommendations will be made as needed.

NACI's recommendations remain aligned with the goals of the Canadian COVID-19 Pandemic Response that were updated on February 14, 2022:

Methods

NACI's recommendations on booster doses are based on the decision-making framework outlined in the published statement Interim guidance on booster COVID-19 vaccine doses in Canada. This framework has been updated with evolving evidence (e.g., including considerations of population level cumulative immunity and vaccine coverage) as outlined in the published statement Interim guidance on planning considerations for a fall 2022 COVID-19 vaccine booster program in Canada. Recommendations are based on evidence of the need for (e.g., increased risk of severe illness from COVID-19 and/or increased risk of decreased protection, and waning protection due to increased time since last dose or infection) and benefit of (e.g., safety and effectiveness) booster doses in the Canadian context.

On August 18, 2022, NACI reviewed available evidence on the burden of illness in the Canadian population, as well as booster dose acceptability in the Canadian population. NACI also reviewed the available evidence on the use of the Moderna Spikevax Bivalent COVID-19 vaccine in adults ≥18 years of age (including manufacturer's clinical data in the regulatory submission to Health Canada and published scientific literature). Additionally, NACI reviewed evidence of post-market safety on mRNA vaccines pertaining to myocarditis and/or pericarditis.

Ethical considerations related to the use of and recommendations for bivalent Omicron-containing mRNA COVID-19 vaccines were discussed with the Public Health Ethics Consultative Group (PHECG) on July 12, 2022.

NACI approved the recommendations on the use of bivalent Omicron-containing mRNA COVID-19 vaccines on August 26, 2022.

For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to NACI's: Statements and publications and the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).

Further information on NACI's process and procedures is available elsewhere Footnote 5 Footnote 6.

Overview of evidence

Evolving epidemiology

Hybrid immunity & seroprevalence

Vaccine effectiveness of original COVID-19 booster vaccines

Summary of Moderna Spikevax Bivalent (50 mcg)

Potential benefits of bivalent vaccines

Post-market safety of mRNA booster doses

Ethics, equity, feasibility, and acceptability

Other considerations

Recommendations

Consistent with NACI's Interim guidance on planning considerations for a fall 2022 COVID-19 vaccine booster program in Canada:

  1. NACI strongly recommends that individuals ≥12 years of age* who are at increased risk of severe illness from COVID-19** should be offered a fall COVID-19 vaccine booster dose regardless of the number of booster doses previously received. (Strong NACI recommendation)
  2. NACI recommends that all other individuals 12 to 64 years of age may be offered a fall COVID-19 booster dose regardless of the number of booster doses previously received. (Discretionary NACI recommendation)

*On August 19, 2022 NACI released booster dose recommendations for individuals 5 - 11 years of age which will also be a component of fall booster programs. Please refer to NACI's Recommendations on the use of a first booster dose of Pfizer-BioNTech Comirnaty COVID-19 vaccine in children 5 to 11 years of age.

** For the list of individuals considered to be at an increased risk of severe illness from COVID-19, please refer to NACI's Interim guidance on planning considerations for a fall 2022 COVID-19 vaccine booster program in Canada.

With regard to the product offered;

  1. NACI recommends that the authorized dose of a bivalent Omicron-containing mRNA COVID-19 vaccine should be offered as a booster dose to the authorized age groups (≥18 years of age). If the bivalent Omicron-containing mRNA COVID-19 vaccine is not readily available, an original mRNA COVID-19 vaccine should be offered to ensure timely protection. (Strong NACI recommendation)
    • Individuals eligible for a fall booster dose, particularly those in groups at a higher risk of severe outcomes from COVID-19, should not delay their planned vaccination in anticipation of a bivalent Omicron-containing mRNA vaccine. Individuals choosing to delay a booster dose in anticipation of a new vaccine formulation should carefully assess their individual risks (i.e., risks of SARS-CoV-2 infection and severe outcomes from COVID-19) and benefits associated with deferring a booster dose.
    • NACI continues to recommend that COVID-19 booster doses may be offered at an interval of 6 months after a previous COVID-19 vaccine dose or SARS-CoV-2 infection, regardless of the product offered. However, a shorter interval of at least 3 months may be warranted in the context of heightened epidemiologic risk, as well as operational considerations for the efficient deployment of the vaccine program.
    • NACI continues to recommend that for all currently COVID-19 vaccine-eligible individuals aged 5 years and older, concurrent administration of other vaccines (e.g., seasonal inactivated influenza vaccine) and any dose of a COVID-19 vaccine, regardless of product offered, is acceptable and may increase program efficiency.
  2. NACI recommends that the authorized dose of a bivalent Omicron-containing mRNA COVID-19 vaccine may be offered to adolescents 12 to 17 years of age with moderately to severely immunocompromising conditions and/or who have biological or social risk factors that place them at high risk of severe outcomes from COVID-19. (Discretionary NACI recommendation)
    • Pfizer-BioNTech Comirnaty (30 mcg) is preferred to Moderna Spikevax original (50 mcg) for a booster dose in adolescents 12 to 17 years of age, as there are currently limited data on the use of Moderna Spikevax original (50 mcg). The use of either product as a booster dose is off-label in this age group, with the exception of adolescents 16 to 17 years of age for whom the use of Pfizer-BioNTech Comirnaty (30 mcg) as a booster dose is authorized.
    • There are currently no data available on the efficacy, immunogenicity or safety of bivalent Omicron-containing mRNA COVID-19 vaccines in this age group. The use of bivalent Omicron-containing mRNA COVID-19 vaccines are not currently authorized by Health Canada in adolescents 12 to 17 years of age, and therefore this recommendation is based on expert opinion and constitutes off-label use in this population.
    • The relative risks and benefits of a bivalent Omicron-containing mRNA COVID-19 vaccine in individuals under the age of 18 remains unclear. However, NACI acknowledges that some populations are at an increased risk of severe outcomes from COVID-19 due to various biological (i.e., immunocompromising or other pre-existing medical conditions) and social factors. Factors that contribute to severe outcomes from COVID-19 may also overlap, further increasing risk. Any combination of risk factors, as well as varying access to healthcare services, has the potential for disproportionate consequences for specific populations, characterized by increased rates of severe illness, hospitalizations, and deaths.

Note: No recommendations on the use of bivalent Omicron-containing mRNA COVID-19 vaccines for use in the general adolescent population 12 to 17 years of age are being made at this time, however NACI's previous recommendations for a fall booster dose in this population remain in place with respect to the use of original mRNA COVID-19 vaccines.

Considerations for the use of a bivalent Omicron-containing mRNA COVID-19 vaccine

Please refer to Table 1 for options and considerations regarding which booster (vaccine type and dose) may be preferred in certain populations.

Table 1. Options and considerations for vaccine types and doses offered for COVID-19 booster dose for certain populations, as of September 1, 2022

Population Vaccine type (and dose) for which booster doses may be preferred Rationale
  • Moderna Spikevax Bivalent (50 mcg), Moderna Spikevax original (50 mcg), or Pfizer-BioNTech Comirnaty (30 mcg) should be offered.Footnote a
  • Moderna Spikevax Bivalent (50 mcg), Moderna Spikevax original (50 mcg), and Pfizer-BioNTech Comirnaty (30 mcg) are all authorized by Health Canada as booster doses in individuals ≥18 years of age.
  • Moderna Spikevax Bivalent (50 mcg) elicited higher neutralizing antibody responses against the original SARS-CoV-2 strain, Omicron BA.1 and Omicron BA.4 and BA.5 compared to Moderna Spikevax original (50 mcg), when given as a second booster dose. However, the clinical relevance of these differences in antibody responses is unclear at this time.
  • Moderna Spikevax Bivalent (50 mcg) demonstrated a similar safety profile to Moderna Spikevax original (50 mcg), when given as a second booster dose.
  • Groups at high-risk for severe outcomes from COVID-19 are likely to realize the greatest benefits from a fall COVID-19 booster dose.
  • Maximizing the benefit of protection of a booster dose may be affected by the interval between doses. A longer time between doses may result in a better response after any subsequent dose, as this allows time for the immune response to mature in breadth and strength. A longer interval may, however, also increase the chance of a period with waning (lower) protection while awaiting a next dose.
  • Adults 18 to 29 years of age
  • Moderna Spikevax Bivalent (50 mcg), Moderna Spikevax original (50 mcg), or Pfizer-BioNTech Comirnaty (30 mcg) should be offered.Footnote a
  • In addition to the considerations and rationale listed above, NACI previously recommended that Pfizer-BioNTech (30 mcg) may be preferred to Moderna Spikevax original (50 mcg) as a booster dose in this age group. This recommendation was issued based on precautionary principles, in the absence of direct evidence, informed by the observed product-specific difference in risks of myocarditis and/or pericarditis after the primary series. Evidence of the risks of myocarditis and/or pericarditis following a booster dose was limited at the time and not available in all populations.
  • Post-market safety surveillance data to date indicate that the risk of myocarditis following a booster dose is lower compared to that following the second dose in the primary series, and current data do not show a product-specific difference in the risks of myocarditis and/or pericarditis after a booster dose of an mRNA COVID-19 vaccine. Adults 18 to 29 years of age can receive a booster dose with any available mRNA COVID-19 vaccine for which they are currently eligible.
  • Pfizer-BioNTech Comirnaty (30 mcg) should be offered and is the preferred product. Moderna Spikevax original (50 mcg) and Moderna Spikevax Bivalent (50 mcg) may also be offered.
  • The use of Pfizer-BioNTech Comirnaty (30 mcg) is preferred to Moderna Spikevax original (50 mcg), as there are currently limited data available on the use of Moderna Spikevax original (50 mcg) in this age group. The use of either product as a booster dose is off-label in this age group, with the exception of adolescents 16 to 17 years of age for whom the use of Pfizer-BioNTech Comirnaty (30 mcg) as a booster dose is authorized.
  • Moderna Spikevax Bivalent (50 mcg) is not currently authorized by Health Canada as a booster dose in individuals <18 years of age.
  • There are currently no data on the efficacy, immunogenicity or safety of Moderna Spikevax Bivalent (50 mcg) in individuals <18 years of age.
  • The use of Moderna Spikevax Bivalent (50 mcg) in this age group represents an off-label recommendation and is informed by expert opinion.
  • The inclusion of an Omicron component in Moderna Spikevax Bivalent may provide additional immunological benefits to adolescents at high risk of severe outcomes from COVID-19, which may outweigh the unknowns around potential risks associated with a lack of data with the use of Moderna Spikevax Bivalent in this age group.
  • All other adolescents 12 to 17 years of age
  • Pfizer-BioNTech Comirnaty (30 mcg) may be offered and is the preferred product. Moderna Spikevax original (50 mcg) may also be offered.
  • The use of Pfizer-BioNTech Comirnaty (30 mcg) is preferred to Moderna Spikevax original (50 mcg), as there are currently limited data available on the use of Moderna Spikevax original (50 mcg) in this age group. The use of either product as a booster dose is off-label in this age group, with the exception of adolescents 16 to 17 years of age for whom the use of Pfizer-BioNTech Comirnaty (30 mcg) as a booster dose is authorized.
  • Considering the burden of COVID-19 illness in the general adolescent population, the goals of the Canadian COVID-19 Immunization Program, and rare risks of myocarditis and/or pericarditis following mRNA vaccination, the overall benefit of a bivalent Omicron-containing mRNA booster dose in this population remains unclear.
  • Children 5 to 11 years of age
  • Pfizer-BioNTech Comirnaty (10 mcg)
  • Pfizer-BioNTech Comirnaty (10 mcg) is authorized by Health Canada as a booster dose in individuals 5 to 11 years of age.
  • No other COVID-19 vaccines are currently authorized or recommended for use as booster doses in this age group.
  • For all other populations in whom booster doses are recommended that have not been specified above
  • Moderna Spikevax Bivalent (50 mcg), Moderna Spikevax original (50 mcg), or Pfizer-BioNTech Comirnaty (30 mcg) should be offered.Footnote a
  • Individuals in this cohort can receive any available, authorized, mRNA COVID-19 vaccine as a booster dose, as any option is expected to provide strong protection against severe outcomes from COVID-19.
  • Maximizing the benefit of protection of a booster dose may be affected by the interval between doses. A longer time between doses may result in a better response after any subsequent dose, as this allows time for the immune response to mature in breadth and strength. A longer interval may, however, also increase the chance of a period with waning (lower) protection while awaiting a next dose.
Footnote a

For a first or second booster dose for adults 18 years of age and older who are not able or willing to receive an mRNA COVID-19 vaccine, a protein subunit COVID-19 vaccine (Novavax Nuvaxovid) may be offered to adults without contraindications to the vaccine. Novavax Nuvaxovid is not currently authorized for use as a booster dose in Canada. Medicago Covifenz is not currently authorized for use as a booster dose in Canada. Janssen Jcovden COVID-19 vaccine may be offered as a first booster to individuals 18 years of age and older without contraindications to the vaccine only when all other COVID-19 vaccines are contraindicated.

Return to footnote a referrer

NACI research priorities

  1. Continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of both the original, and bivalent mRNA COVID-19 vaccines, through clinical trials and studies in real-world settings, including the degree and duration of protection conferred by each booster dose against circulating variants. The research should also consider the clinical implications of previous SARS-CoV-2 infection; repeated immunization; and outcomes after any infection such as Multisystem Inflammatory Syndrome in Children (MIS-C), post-COVID-19 condition (long COVID), or infection induced myocarditis or pericarditis in older and younger adult, adolescent, and pediatric populations.
  2. Continuous monitoring of vaccine uptake and acceptance in the Canadian population, specifically following the authorization of new bivalent Omicron (BA.1)-containing mRNA COVID-19 vaccines.
  3. Further evaluations of the optimal interval between booster dose and primary series, and between any subsequent booster doses as well as further evaluations of the optimal interval between previous SARS-CoV-2 infection and booster dose administration.
  4. Vigilant monitoring and reporting of adverse events of special interest, including myocarditis and/or pericarditis, in order to accurately inform potential risks associated with booster doses, for all COVID-19 vaccines, including bivalent Omicron (BA.1)-containing mRNA vaccines. Global collaboration should be prioritized to enable data sharing so decision makers around the world can weigh benefits and risks of multiple booster doses of COVID-19 vaccines.
  5. Evaluations of whether bivalent Omicron-containing mRNA COVID-19 vaccines can be used as part of a primary series.
  6. Continuous monitoring of COVID-19 epidemiology and VE in special populations (e.g., those with high-risk medical conditions) and the long-term consequences of COVID-19 in these populations.

Abbreviations

CI
Confidence Interval
CIG
Canadian Immunization Guide
COVID-19
Coronavirus disease 2019
GMR
Geometric mean ratio
ICU
Intensive Care Unit
mcg
Micrograms
mRNA
Messenger Ribonucleic Acid
NACI
National Advisory Committee on Immunization
PHAC
Public Health Agency of Canada
PHECG
Public Health Ethics Consultative Group
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
US
United States
VE
Vaccine effectiveness
VOC
Variant of Concern

Acknowledgments

This statement was prepared by: J Montroy, E Wong, R Krishnan, R Pless, J Zafack, N Islam, M Salvadori, MC Tunis, R Harrison, S Wilson and S Deeks, on behalf of NACI.

NACI gratefully acknowledges the contribution of: C Mauviel, M Laplante, K Ramotar, SH Lim, and E Tarratacca.

NACI Members: S Deeks (Chair), R Harrison (Vice-Chair), M Andrew, J Bettinger, N Brousseau, H Decaluwe, P De Wals, E Dubé, V Dubey, K Hildebrand, K Klein, M O'Driscoll, J Papenburg, A Pham-Huy, B Sander, and S Wilson.

Liaison representatives: L Bill (Canadian Indigenous Nurses Association), LM Bucci (Canadian Public Health Association), E Castillo (Society of Obstetricians and Gynaecologists of Canada), A Cohn (Centers for Disease Control and Prevention, United States), J Comeau (Association of Medical Microbiology and Infectious Disease Control), L Dupuis (Canadian Nurses Association), E Adams (Indigenous Physicians Association of Canada), J Hu (College of Family Physicians of Canada), M Lavoie (Council of Chief Medical Officers of Health), D Moore (Canadian Paediatric Society), M Naus (Canadian Immunization Committee), and A Ung (Canadian Pharmacists Association).

Ex-officio representatives: V Beswick-Escanlar (National Defence and the Canadian Armed Forces), E Henry (Centre for Immunization and Respiratory Infectious Diseases (CIRID), PHAC), M Lacroix (Public Health Ethics Consultative Group, PHAC), C Lourenco (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada), D MacDonald (COVID-19 Epidemiology and Surveillance, PHAC), S Ogunnaike-Cooke (CIRID, PHAC), K Robinson (Marketed Health Products Directorate, HC), M Routledge (National Microbiology Laboratory, PHAC), and T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada).

NACI COVID-19 Working Group

Members: S Wilson (Chair), M Adurogbangba, M Andrew, Y-G Bui, H Decaluwe, P De Wals, V Dubey, S Hosseini-Moghaddam, M Miller, D Moore, S Oliver, and E Twentyman.

PHAC Participants: NK Abraham, P Doyon-Plourde, N Forbes, M Hersi, N Islam, S Ismail, C Jensen, F Khan, R Krishnan, C Mauviel, N Mohamed, J Montroy, A Nunn, R Pless, M Salvadori, A Stevens, E Tice, MC Tunis, E Wong, R Ximenes, and J Zafack.

Appendix A: Moderna Spikevax Bivalent clinical trial data

Vaccine Characteristics

For complete prescribing information for Moderna Spikevax Bivalent, consult the product leaflet or information contained within Health Canada's authorized product monographs available through the Drug Product Database.

Table 2. Moderna Spikevax Bivalent vaccine characteristics

Product characteristics Moderna Spikevax Bivalent
Date of authorization September 1, 2022
Age Indication 18 years of age and older
Dose 50 mcg (25 mcg original SARS-CoV-2 + 25 mcg Omicron BA.1)
Diluent None required
Presentation
  • 0.10 mg/mL
  • 5 doses per vial
  • Royal blue cap vial
  • Green label border
Potential Allergens
  • Polyethylene glycol (PEG)
  • Tromethamine (Tris, Trometamol)
StorageFootnote a
  • Frozen until expiry date printed on the label
  • Refrigerated for up to 30 days
  • Unpunctured vials may be stored between 8° to 25°C (46° to 77°F) for up to 24 hours
  • Once needle-punctured, vials can be stored at room temperature or refrigerated up to 24 hours but cannot be refrozen.
Transport If transport at -50° to -15°C is not feasible, thawed vials in a liquid state may be transported at +2°C to +8°C for up to 12 hours.
Footnote a

Frozen is -25°C to -15°C; Refrigerated is +2°C to +8°C; Room temperature is +15°C to +25°C

Return to footnote a referrer

Trial design

The Moderna Spikevax Bivalent COVID-19 vaccine was evaluated in an ongoing, Phase 2/3 open-label clinical trial in participants ≥18 years of age in the United States (Study P205) Footnote 35. The study evaluated the safety, reactogenicity and immunogenicity of Moderna Spikevax Bivalent (50 mcg) when administered as a second booster dose to adults 18 years of age and older, who had previously received 2 doses of Moderna Spikevax original (100 mcg) as a primary series and a booster dose of Moderna Spikevax original (50 mcg) at least 3 months prior to enrollment. Individuals with a confirmed SARS-CoV-2 infection within 3 months from screening were not eligible for inclusion. Participants were enrolled between March 8, 2022, and March 23, 2022. A within-study, non-contemporaneous comparator group was used, in which participants received Moderna Spikevax original (50 mcg) as a second booster. Participants for the comparator group were enrolled between February 18, 2022, and March 8, 2022.

Study Population

Overall, demographic and baseline characteristics were similar between the Moderna Spikevax Bivalent (50 mcg) and Moderna Spikevax original (50 mcg) groups.

A total of 437 individuals (median of 60 years of age; range 20-88) received Moderna Spikevax Bivalent (50 mcg) as a second booster dose, at a median of 136 days (range 88-408) following their first booster dose. At baseline, 96 of 437 participants (22%) had evidence of previous SARS-CoV-2 infection. Median follow-up from injection was 43 days (range 22-51). Of the 437 participants, 2 discontinued from the study (withdrawal of consent to participate).

A total of 377 individuals (median of 60 years of age; range 20-96) received Moderna Spikevax original (50 mcg) as a second booster dose, at a median of 134 days (range 90-310) following their first booster dose. At baseline, 101 of 377 participants (27%) had evidence of previous SARS-CoV-2 infection. Median follow-up from injection was 57 days (range 51-66). All participants remained in the study as of the current data cut-off date.

Efficacy

Currently, there are no estimates of vaccine efficacy available for Moderna Spikevax Bivalent (50 mcg), as study P205 was not designed to evaluate vaccine efficacy. In the Moderna Spikevax Bivalent (50 mcg) group, with a median follow-up of 43 days, 11 participants (3.2%) had a confirmed SARS-CoV-2 infection starting at least 14 days after the administration of the booster dose. Of the 11 infections, 6 were asymptomatic. In the Moderna Spikevax original (50 mcg) group, with a median follow-up of 57 days, 5 participants (1.9%) had a confirmed SARS-CoV-2 infection starting at least 14 days after the administration of the booster dose. Of the 5 infections, 4 were asymptomatic. None of the participants with a confirmed SARS-CoV-2 infection in either group had an emergency room visit or hospitalization due to COVID-19.

Immunogenicity

In this study, the primary immunogenicity analysis was based on the primary immunogenicity set which includes participants with no evidence of SARS-CoV-2 infection at baseline (pre-booster). For the pre-specified primary objectives, there were four corresponding endpoints:

Non-inferiority was considered met when the lower bound of the 97.5% confidence interval (CI) of GMR is ≥0.67 and of SRR difference is > -10%. Superiority was considered met when the lower bound of the 97.5% CI of GMR is >1 and for the difference in SRR >0.

Non-inferiority of Moderna Spikevax Bivalent based on GMR against Omicron

Non-inferiority of Moderna Spikevax Bivalent based on SRR against Omicron

Non-inferiority of Moderna Spikevax Bivalent based on GMR against original SARS-CoV-2

Superiority of Moderna Spikevax Bivalent based on GMR against Omicron

Individuals with prior SARS-CoV-2 infection

Table 3. Original SARS-CoV-2 and Omicron neutralizing antibody titers for Moderna Spikevax Bivalent (50 mcg) and Moderna Spikevax original (50 mcg) administered as second booster doses

Antibody: PsVNA nAb ID50 titres Omicron Variant Original SARS-CoV-2 Omicron BA.4 and BA.5
Moderna Spikevax Bivalent
(50 mcg)
Moderna Spikevax original
(50 mcg)
Moderna Spikevax Bivalent
(50 mcg)
Moderna Spikevax original
(50 mcg)
Moderna Spikevax Bivalent
(50 mcg)
Moderna Spikevax original (50 mcg)
All individuals
Sample size (n) 428 367 428 367 428 367
Pre-booster GMT (95% CI) 432.051
(372.466, 501.168)
511.984
(433.386, 604.836)
1603.353
(1420.264, 1810.045)
1944.781
(1725.353, 2192.116)
172.72 (147.45, 202.31) 209.31 (179.48, 244.10)
Day 29 GMT (95% CI) 3070.379
(2685.375, 3510.581)
1932.785
(1681.186, 2222.037)
6619.010
(5941.728, 7373.494)
6047.489
(5465.873, 6690.994)
940.57 (826.32, 1070.61) 645.37 (570.11, 730.55)
GMFR (95% CI) 7.107
(6.484, 7.789)
3.775
(3.422, 4.165)
4.128
(3.840, 4.438)
3.110
(2.877, 3.361)
5.44 (5.01, 5.92) 3.08 (2.84, 3.35)
GMR (95% CI) 1.781
(1.557, 2.037)
1.237
(1.117, 1.369)
1.68 (1.52, 1.84)
No evidence of prior SARS-CoV-2 infection
Sample size (n) 334 260 334 260 334 260
Pre-booster GMT (95% CI) 298.127
(258.753, 343.492)
1473.462
(1270.849, 1708.379)
1266.743
(1120.190, 1432.469)
1520.998
(1352.766, 1710.151)
115.59 (98.51, 135.64) 139.68 (119.51, 163.26)
Day 29 GMT (95% CI) 2372.424
(2070.634, 2718.200)
1473.462
(1270.849, 1708.379)
5977.257
(5321.897, 6713.320)
5649.331
(5056.848, 6311.231)
727.43 (632.85, 836.14) 492.13 (431.05, 561.85)
GMFR (95% CI) 7.958
(7.181, 8.819)
4.438
(3.971, 4.960)
4.719
(4.358, 5.109)
3.714
(3.420, 4.034)
6.30 (5.74, 6.91) 3.52 (3.21, 3.86)
GMR (95% CI) 1.745
(1.493, 2.040)
1.215
(1.078, 1.370)
1.69 (1.51, 1.90)
Prior SARS-CoV-2 infection
Sample size (n) 94 98 94 98 94 98
Pre-booster GMT (95% CI) 1614.640
(1149.671, 2267.658)
1558.360
(1088.941, 2230.136)
3703.953
(2793.198, 4911.670)
3637.972
(2742.046, 4826.629)
719.54 (531.64, 973.86) 609.12 (448.08, 828.05)
Day 29 GMT (95% CI) 7676.226
(5618.245,
10488.050)
3885.596
(2877.774, 5246.367)
9509.727
(7345.948,
12310.856)
7003.503
(5592.574, 8770.390)
2337.44 (1825.51, 2992.92) 1270.82 (987.28, 1635.80)
GMFR (95% CI) 4.754
(3.954, 5.716)
2.493
(2.058, 3.021)
2.567
(2.245, 2.936)
1.925
(1.649, 2.247)
3.25 (2.78, 3.80) 2.09 (1.80, 2.43)
GMR (95% CI) 1.898
(1.499, 2.403)
1.272
(1.070, 1.512)
1.60 (1.34, 1.91)

Safety

The safety and reactogenicity of Moderna Spikevax Bivalent (50 mcg) administered as a second booster dose was similar to that of Moderna Spikevax original (50 mcg), given as a second booster dose Footnote 33 Footnote 53. Also, the frequency of adverse events following immunization with Moderna Spikevax Bivalent Footnote 33 Footnote 35 Footnote 53 was similar or lower relative to that of a first booster dose of Moderna Spikevax original (50 mcg) Footnote 54, and of the second dose of the Moderna Spikevax original primary series (100 mcg) Footnote 55. No new safety signals were identified. There were no vaccine related cases of death, myocarditis and/or pericarditis reported during the study period Footnote 33 Footnote 53. Given the trial was limited to 814 participants receiving the Moderna Spikevax Bivalent (n=437) and Moderna Spikevax original (n=377) vaccines Footnote 33 Footnote 53, it is unlikely that any rare adverse event would be detected. NACI will monitor post-market safety surveillance data as it emerges and update the recommendations as needed.

References

Footnote 1

COVID-19 epidemiology update. Data cut-off July 28, 2022 [Internet]. Ottawa (ON): Government of Canada; 2022 July 28 [cited 2022 July 28]. Available from: https://health-infobase.canada.ca/covid-19/.

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Footnote 2

Davies M, Morden E, Rosseau P, Arendse J, Bam J, Boloko L, et al. Outcomes of laboratory-confirmed SARS-CoV-2 infection during resurgence driven by Omicron lineages BA.4 and BA.5 compared with previous waves in the Western Cape Province, South Africa. medRxiv. 2022 Jul 01. https://doi.org/10.1101/2022.06.28.22276983.

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Footnote 3

Hansen CH, Friis NU, Bager P, Stegger M, Fonager J, Fomsgaard A, et al. Risk of Reinfection, Vaccine Protection, and Severity of Infection with the BA.5 Omicron Subvariant: A Danish Nation-Wide Population-Based Study. SSRN. 2022 Jul 18. doi: 10.2139/ssrn.4165630.

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Footnote 4

Kislaya I, Casaca P, Borges V, Sousa C, Ferreira BI, Fernandes E, et al. SARS-CoV-2 BA.5 vaccine breakthrough risk and severity compared with BA.2: a case-case and cohort study using Electronic Health Records in Portugal. medRxiv. 2022 Jul 25. https://doi.org/10.1101/2022.07.25.22277996.

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Footnote 5

Ismail SJ, Langley JM, Harris TM, Warshawsky BF, Desai S, FarhangMehr M. Canada's National Advisory Committee on Immunization (NACI): Evidence-based decision-making on vaccines and immunization. Vaccine. 2010;28:A58,63. doi: 10.1016/j.vaccine.2010.02.035.

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Footnote 6

Ismail SJ, Hardy K, Tunis MC, Young K, Sicard N, Quach C. A framework for the systematic consideration of ethics, equity, feasibility, and acceptability in vaccine program recommendations. Vaccine. 2020 Aug 10;38(36):5861,5876. doi: 10.1016/j.vaccine.2020.05.051.

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Footnote 7

Lewnard JA, Hong V, Tartof SY. Association of SARS-CoV-2 BA.4/BA.5 Omicron lineages with immune escape and clinical outcome. medRxiv. 2022 Aug 02. https://doi.org/10.1101/2022.07.31.22278258.

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Footnote 8

Altarawneh HN, Chemaitelly H, Ayoub HH, Hasan MR, Coyle P, Yassine HM, et al. Protection of SARS-CoV-2 natural infection against reinfection with the Omicron BA.4 or BA.5 subvariants. medRxiv. 2022 Jul 12. https://doi.org/10.1101/2022.07.11.22277448.

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Footnote 9

Malato J, Ribeiro RM, Leite PP, Casaca P, Fernandes E, Antunes C, et al. Risk of BA.5 infection in individuals exposed to prior SARS-CoV-2 variants. medRxiv. 2022 Jul 28. https://doi.org/10.1101/2022.07.27.22277602.

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Footnote 10

Carazo S, Skowronski DM, Brisson M, Barkati S, Sauvageau C, Brousseau N, et al. Protection against Omicron BA.2 reinfection conferred by primary Omicron or pre-Omicron infection with and without mRNA vaccination. medRxiv. 2022 Jun 27. https://doi.org/10.1101/2022.06.23.22276824.

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Footnote 11

Public Health Agency of Canada (PHAC). COVID-19 vaccination in Canada. Data cut-off July 17, 2022 [Internet]. Ottawa (ON): Government of Canada; 2022 July 22 [cited 2022 Aug 10]. Available from: https://health-infobase.canada.ca/covid-19/vaccination-coverage/.

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Footnote 12

Report #21: April 2022 Survey The advance of Omicron [Internet]. Montreal (QC): COVID-19 Immunity Task Force (CITF); 2022 Jun 3 [cited 2022 Aug 10]. Available from: https://www.covid19immunitytaskforce.ca/wp-content/uploads/2022/06/covid-19-full-report-apr-2022-june-3-2022.pdf.

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Footnote 13

Amirthalingam G, Bernal JL, Andrews NJ, Whitaker H, Gower C, Stowe J, et al. Serological responses and vaccine effectiveness for extended COVID-19 vaccine schedules in England. Nature Communications. 2021 Dec 10;12(1):7217. https://doi.org/10.1038/s41467-021-27410-5.

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Footnote 14

Ireland G, Whitaker H, Ladhani SN, Baawuah F, Subbarao V, Linley E, et al. Serological responses to COVID-19 booster vaccine in England. medRxiv. 2021 Nov 24. https://doi.org/10.1101/2021.11.22.21266692.

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Footnote 15

UK Health Security Agency (UKHSA). COVID-19 vaccine surveillance report: Week 24 [Internet]. London (UK): Department of Health and Social Care; 2022 Jun 16 [cited 2022 Aug 10]. Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1083443/Vaccine-surveillance-report-week-24.pdf.

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Footnote 16

De Serres G, Febriani Y, Ouakki M, Talbot D, Gilca R, Deceuninck G, et al. Efficacité du vaccin contre la COVID-19 causée par le variant Omicron au Québec. INSPQ. 2022 Feb 16. https://www.inspq.qc.ca/covid-19/vaccination/efficacite-omicron.

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Footnote 17

Šmíd M, Berec L, Přibylová L, Májek O, Pavlík T, Jarkovský J, et al. Protection by vaccines and previous infection against the Omicron variant of SARS-CoV-2. J Infect Dis. 2022 Apr 28. doi: 10.1093/infdis/jiac161.

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Footnote 18

Tseng HF, Ackerson BK, Luo Y, Sy LS, Talarico CA, Tian Y, et al. Effectiveness of mRNA-1273 against SARS-CoV-2 Omicron and Delta variants. Nat Med. 2022 May;28(5):1063,1071. doi:10.1038/s41591-022-01753-y.

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Footnote 19

Gram MA, Emborg H, Schelde AB, Friis NU, Nielsen KF, Moustsen-Helms I, et al. Vaccine effectiveness against SARS-CoV-2 infection and COVID-19-related hospitalization with the Alpha, Delta and Omicron SARS-CoV-2 variants: a nationwide Danish cohort study. medRxiv. 2022 Apr 20. https://doi.org/10.1101/2022.04.20.22274061.

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Footnote 20

Andeweg SP, de Gier B, Eggink D, van den Ende C, van Maarseveen N, Ali L, et al. Protection of COVID-19 vaccination and previous infection against Omicron BA.1, BA.2 and Delta SARS-CoV-2 infections. medRxiv. 2022 May 12. https://doi.org/10.1101/2022.02.06.22270457.

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Footnote 21

Buchan SA, Nguyen L, Wilson SE, Kitchen SA, Kwong JC. Vaccine Effectiveness of BNT162b2 Against Delta and Omicron Variants in Adolescents. Pediatrics. 2022 Jun 16. doi: 10.1542/peds.2022-057634.

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Footnote 22

Patalon T, Saciuk Y, Peretz A, Perez G, Lurie Y, Maor Y, et al. Waning effectiveness of the third dose of the BNT162b2 mRNA COVID-19 vaccine. Nat Commun. 2022 Jun 9;13(1):3203. doi: 10.1038/s41467-022-30884-6.

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Footnote 23

Link-Gelles R, Levy ME, Gaglani M, Irving SA, Stockwell M, Dascomb K, et al. Effectiveness of 2, 3, and 4 COVID-19 mRNA Vaccine Doses Among Immunocompetent Adults During Periods when SARS-CoV-2 Omicron BA.1 and BA.2/BA.2.12.1 Sublineages Predominated - VISION Network, 10 States, December 2021-June 2022. MMWR Morb Mortal Wkly Rep. 2022 Jul 22;71(29):931,939. doi: 10.15585/mmwr.mm7129e1.

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Footnote 24

Ferdinands JM, Rao S, Dixon BE, Mitchell PK, DeSilva MB, Irving SA, et al. Waning 2-Dose and 3-Dose Effectiveness of mRNA Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance - VISION Network, 10 States, August 2021-January 2022. MMWR Morb Mortal Wkly Rep. 2022 Feb 18;71(7):255,263. doi: 10.15585/mmwr.mm7107e2.

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Footnote 25

Stowe J, Andrews N, Kirsebom F, Ramsay M, Bernal JL. Effectiveness of COVID-19 vaccines against Omicron and Delta hospitalisation: test negative case-control study. medRxiv. 2022 Apr 01. https://doi.org/10.1101/2022.04.01.22273281.

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Footnote 26

Skowronski D. Update on two- and three-dose SARS-CoV-2 vaccine effectiveness, British Columbia [video presentation containing slides presented at BCCDC GRAND ROUNDS SERIES] [Internet]. British Columbia: BC CDC; 2022 Feb 15 [cited 2022 Aug 11]. Available from: https://nexuswebcast.mediasite.com/mediasite/Showcase/bc-cdc-showcase/Presentation/9a0df1fd7fe340eeb3b2a8ee764901131d.

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Footnote 27

Chemaitelly H, Ayoub HH, AlMukdad S, Coyle P, Tang P, Yassine HM, et al. Duration of mRNA vaccine protection against SARS-CoV-2 Omicron BA.1 and BA.2 subvariants in Qatar. Nat Commun. 2022 Jun 2;13(1):30822. doi: 10.1038/s41467-022-30895-3.

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Footnote 28

Breznik JA, Rahim A, Kajaks T, Hagerman M, Bilaver L, Colwill K, et al. Protection from Omicron infection in residents of nursing and retirement homes in Ontario, Canada. medRxiv. 2022 Jun 29. https://doi.org/10.1101/2022.06.28.22277016.

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Footnote 29

Grewal R, Kitchen SA, Nguyen L, Buchan SA, Wilson SE, Costa AP, et al. Effectiveness of a fourth dose of covid-19 mRNA vaccine against the omicron variant among long term care residents in Ontario, Canada: test negative design study. BMJ. 2022 Jul 6;378:e071502. doi: 10.1136/bmj-2022-071502.

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Footnote 30

Gazit S, Saciuk Y, Perez G, Peretz A, Pitzer VE, Patalon T. Relative Effectiveness of Four Doses Compared to Three Dose of the BNT162b2 Vaccine in Israel. medRxiv. 2022 Mar 24. https://doi.org/10.1101/2022.03.24.22272835.

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Footnote 31

Regev-Yochay G, Gonen T, Gilboa M, Mandelboim M, Indenbaum V, Amit S, et al. 4th Dose COVID mRNA Vaccines' Immunogenicity & Efficacy Against Omicron VOC. medRxiv. 2022 Feb 15. https://doi.org/10.1101/2022.02.15.22270948.

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Footnote 32

Bar-On Y, Goldberg Y, Mandel M, Bodenheimer O, Amir O, Freedman L, et al. Protection by 4th dose of BNT162b2 against Omicron in Israel. medRxiv. 2022 Feb 1. https://doi.org/10.1101/2022.02.01.22270232.

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Footnote 33

Hoge S. mRNA-1273.214 Moderna COVID-19 Investigational Bivalent Vaccine (Original + Omicron) [slides presented at Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting June 28, 2022] [Internet]. Atlanta (GA): Centers for Disease Control and Prevention (CDC); 2022 Jun 28 [cited 2022 Aug 11]. Available from: https://www.fda.gov/media/159492/download.

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Footnote 34

Interim statement on the composition of current COVID-19 vaccines [Internet]. Geneva (CH): World Health Organization (WHO); 2022 Jun 17 [cited 2022 Aug 10]. Available from: https://www.who.int/news/item/17-06-2022-interim-statement-on--the-composition-of-current-COVID-19-vaccines.

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Footnote 35

Chalkias S, Harper C, Vrbicky K, Walsh SR, Essink B, Brosz A, et al. A Bivalent Omicron-containing Booster Vaccine Against Covid-19. medRxiv. 2022 Jun 25. https://doi.org/10.1101/2022.06.24.22276703.

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Footnote 36

Richardson SI, Madzorera VS, Spencer H, Manamela NP, van der Mescht MA, Lambson BE, et al. SARS-CoV-2 Omicron triggers cross-reactive neutralization and Fc effector functions in previously vaccinated, but not unvaccinated, individuals. Cell Host Microbe. 2022 Jun 8;30(6):880,886.e4. doi: 10.1016/j.chom.2022.03.029.

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Footnote 37

Khan K, Karim F, Ganga Y, Bernstein M, Jule Z, Reedoy K, et al. Omicron sub-lineages BA.4/BA.5 escape BA.1 infection elicited neutralizing immunity. medRxiv. 2022 May 01. https://doi.org/10.1101/2022.04.29.22274477.

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Footnote 38

Shimabukuro T. Myocarditis following mRNA COVID-19 vaccination [slides presented at Advisory Committee on Immunization Practices (ACIP) meeting July 19, 2022] [Internet]. Atlanta (GA): Centers for Disease Control and Prevention (CDC); 2022 July 19 [cited 2022 Aug 08]. Available from: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-07-19/03-COVID-Shimabukuro-508.pdf.

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Footnote 39

Medicines and Healthcare products Regulatory Agency (MHRA). Coronavirus vaccine - weekly summary of Yellow Card reporting. Data cut-off July 27, 2022 [Internet]. London (UK): Department of Health and Social Care; 2022 Aug 4 [cited 2022 Aug 08]. Available from: https://www.gov.uk/government/publications/coronavirus-covid-19-vaccine-adverse-reactions/coronavirus-vaccine-summary-of-yellow-card-reporting.

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Footnote 40

Le Vu S, Bertrand M, Jabagi MJ, Botton J, Droulin J, Baricault B, Bouillon K, et al. Vaccins Covid-19 à ARN messager et risque de myocardite: effets de la troisième dose et du délai entre les doses [Internet]. Paris (FR): EPI-PHARE; 2022 Jul 22 [cited 2022 Aug 08]. Available from: https://www.epi-phare.fr/rapports-detudes-et-publications/myocardite-rappel-vaccin-covid19/.

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Footnote 41

Le Vu S, Bertrand M, Jabagi M, Botton J, Weill A, Dray-Spira R, et al. Risk of Myocarditis after Covid-19 mRNA Vaccination: Impact of Booster Dose and Dosing Interval. medRxiv. 2022 Aug 01. https://doi.org/10.1101/2022.07.31.22278064.

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Footnote 42

Simone A, Herald J, Chen A, Nayak R, Shen YA, Lee MS. Acute myocarditis following a third dose of COVID-19 mRNA vaccination in adults. Int J Cardiol. 2022 Jul 21;365:41,43. doi: 10.1016/j.ijcard.2022.07.031.

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Footnote 43

Hartling L, Pillay J, Gaudet LA, Wingert A, Bialy L, Dyson M, Mackie A, et al. Incidence, Natural History, Specific Populations and Hypothesized Mechanisms of Myocarditis and Pericarditis Following mRNA COVID-19 Vaccination: Living Evidence Synthesis [Internet]. Toronto (ON): SPOR Evidence Alliance; 2022 May 17 [cited 2022 Aug 08]. Available from: https://sporevidencealliance.ca/wp-content/uploads/2022/06/COVID-END_SPOR-EA_Myo-and-Pericarditis-after-COVID-19-vaccines_Update2-05182022.pdf.

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Footnote 44

Ontario Agency for Health Protection and Promotion (Public Health Ontario). Weekly summary: adverse events following immunization (AEFIs) for COVID-19 in Ontario: December 13, 2020 to March 27, 2022. Data cut-off Aug 14, 2022 [Internet]. Toronto (ON): Queen's Printer for Ontario; 2022 Aug 14. Table A3, Myocarditis/pericarditis crude reporting rates per million doses administered following COVID-19 mRNA vaccines: Ontario, December 13, 2020 to August 14, 2022; p. 31 [cited 2022 Aug 14]. Available from: https://www.publichealthontario.ca/-/media/Documents/nCoV/epi/covid-19-aefi-report.pdf?sc_lang=en.

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Footnote 45

Hause AM, Baggs J, Marquez P, Abara WE, Baumblatt J, Blanc PG, et al. Safety Monitoring of COVID-19 mRNA Vaccine Second Booster Doses Among Adults Aged ≥50 Years - United States, March 29, 2022-July 10, 2022. MMWR Morb Mortal Wkly Rep. 2022 Jul 29;71(30):971,976. doi: 10.15585/mmwr.mm7130a4.

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Footnote 46

Hause AM, Zhang B, Yue X, Marquez P, Myers TR, Parker C, et al. Reactogenicity of Simultaneous COVID-19 mRNA Booster and Influenza Vaccination in the US. JAMA Netw Open. 2022 Jul 1;5(7):e2222241. doi: 10.1001/jamanetworkopen.2022.22241.

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Footnote 47

Wagenhäuser I, Reusch J, Gabel A, Höhn A, Lâm T, Almanzar G, et al. Immunogenicity and safety of coadministration of COVID-19 and influenza vaccination among healthcare workers. medRxiv. 2022 Jun 14. https://doi.org/10.1101/2022.06.09.22276030.

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Footnote 48

Chilimuri S, Mantri N, Shrestha E, Sun H, Gongati S, Zahid M, et al. BNT162b2 mRNA Vaccine Interference with Co-Administration of Tdap Vaccine. Am J Case Rep. 2021 Jul 25;22:e933003. doi: 10.12659/AJCR.933003.

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Footnote 49

Izikson R, Brune D, Bolduc JS, Bourron P, Fournier M, Moore TM, et al. Safety and immunogenicity of a high-dose quadrivalent influenza vaccine administered concomitantly with a third dose of the mRNA-1273 SARS-CoV-2 vaccine in adults aged ≥65 years: a phase 2, randomised, open-label study. Lancet Respir Med. 2022 Apr 01;10(4):392,402. doi: 10.1016/S2213-2600(21)00557-9.

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Footnote 50

Lazarus R, Baos S, Cappel-Porter H, Carson-Stevens A, Clout M, Culliford L, et al. Safety and immunogenicity of concomitant administration of COVID-19 vaccines (ChAdOx1 or BNT162b2) with seasonal influenza vaccines in adults in the UK (ComFluCOV): a multicentre, randomised, controlled, phase 4 trial. Lancet. 2021 Dec 18;398(10318):2277,2287. doi: 10.1016/S0140-6736(21)02329-1.

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Footnote 51

Toback S, Galiza E, Cosgrove C, Galloway J, Goodman AL, Swift PA, et al. Safety, immunogenicity, and efficacy of a COVID-19 vaccine (NVX-CoV2373) co-administered with seasonal influenza vaccines: an exploratory substudy of a randomised, observer-blinded, placebo-controlled, phase 3 trial. Lancet Respir Med. 2022 Feb;10(2):167,179. doi: 10.1016/S2213-2600(21)00409-4.

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Footnote 52

Wang S, Chen B, Duan X, Deng X, Wang Z, Zhang H, et al. Safety and Immunogenicity of a SARS-CoV-2 Inactivated Vaccine Administered Simultaneously with an Inactivated Quadrivalent Influenza Vaccine: A Randomized, Open-Label, Controlled Study in Healthy Adults Aged 18 to 59 Years in China. SSRN. 2021 Aug 23. http://dx.doi.org/10.2139/ssrn.3909773.

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Footnote 53

Product Monograph Including Patient Medication Information: Spikevax Bivalent (Original / Omicron) [Internet]. Mainz (RP): BioNTech Manufacturing; 2022. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html.

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Footnote 54

Choi A, Koch M, Wu K, Chu L, Ma L, Hill A, et al. Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis. Nat Med. 2021 Nov;27(11):2025,2031. doi: 10.1038/s41591-021-01527-y.

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Footnote 55

Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021 Feb 4;384(5):403,416. doi: 10.1056/NEJMoa2035389.

Return to footnote 55 referrer

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