Summary Basis of Decision for Spikevax Bivalent

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Spikevax Bivalent is located below.

Recent Activity for Spikevax Bivalent

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Spikevax Bivalent

Updated: 2024-05-17

The following table describes post-authorization activity for Spikevax Bivalent, a product which contains the medicinal ingredients elasomeran and imelasomeran. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

 

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Drug Identification Number (DIN):

  • DIN - 02530252 - 0.05 mg/mL elasomeran and 0.05 mg/mL imelasomeran, dispersion, intramuscular administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
PBRER # 278579 2023-08-25 Review completed 2024-04-05 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. PBRER for the period 2022-12-18 to 2023-06-17. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
DIN 02530252 cancelled (post market) Not applicable Discontinuation date: 2024-01-19 The manufacturer notified Health Canada that sale of the drug has been discontinued post market. Health Canada cancelled the DIN pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.
NDS # 278389 2023-08-21 Issued NOC 2023-10-04 Submission filed to transfer ownership of the drug product from ModernaTX, Inc. to Moderna Biopharma Canada Corporation. An NOC was issued.

Monthly safety report
Control # 276271

2023-06-15 Review completed 2023-09-26 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report for the period 2023-04-18 to 2023-05-17. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

Monthly safety report
Control # 275274

2023-05-15 Review completed 2023-09-20 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report for the period 2023-03-18 to 2023-04-17. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Monthly safety report Control # 274400 2023-04-17 Review completed 2023-06-29 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report for the period 2023-02-18 to 2023-03-17. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Monthly safety report Control # 273353 2023-03-16 Review completed 2023-06-29 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report for the period 2023-01-18 to 2023-02-17. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Monthly safety report Control # 272456 2023-02-16 Review completed 2023-06-15 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report for the period 2022-12-18 to 2023-01-17. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

Amended Terms and Conditions
Control # 265656

Not applicable

Terms and conditions amended post authorization
2023-06-09

Health Canada updated the Risk Management Plan Terms and Conditions for Spikevax Bivalent to reflect the accumulation of safety data and information gained in the post-market setting for this vaccine.
PBRER # 272831 2023-03-02 Review completed 2023-06-02 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. PBRER for the period 2022-06-19 to 2022-12-17. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Monthly safety report Control # 271447 2023-01-16 Review completed 2023-03-13 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report for the period 2022-11-19 to 2022-12-17. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.
Monthly safety report Control # 270694 2022-12-15 Review completed
2023-02-27

Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report for the period 2022-10-19 to 2022-11-18. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

SNDS # 269428 2022-11-04 Issued NOC (subject to terms and conditions)
2023-02-17

Submission filed as a Level I – Supplement to seek authorization for an extension of the age indication for a booster dose of an mRNA-based vaccine formulation Spikevax Bivalent, containing two components (Original SARS-CoV2 mRNA vaccine Spikevax, and Omicron BA.1) in a 50 mcg dose for adolescents 12 to 17 years of age and a 25 mcg dose for children 6 to 11 years of age. The submission was reviewed and considered acceptable, and an NOC was issued. Terms and conditions were imposed on the authorization. A Regulatory Decision Summary was published.

Monthly safety report Control # 269720 2022-11-15 Review completed
2023-01-24

Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report for the period 2022-09-19 to 2022-10-18. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

Monthly safety report Control # 268784 2022-10-17 Review completed
2022-12-08

Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. Monthly safety report for the period 2022-08-19 to 2022-09-18. The sponsor was asked to provide updated assessments for the ongoing monitoring of safety events.

Drug product (DIN 02530252) market notification Not applicable Date of first sale:
2022-09-12

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

Health Product Risk Communication Not applicable Posted
2022-09-02
Health Product Risk Communication posted (Distribution of Spikevax Bivalent [elasomeran/imelasomeran] COVID-19 Vaccine with English-only Vial and Carton Labels), containing important information about labelling, packaging and product safety for healthcare professionals.
NDS # 265656 2022-06-30 Issued NOC (subject to terms and conditions)
2022-09-01
NOC issued for New Drug Submission. Terms and conditions were imposed on the authorization.
Summary Basis of Decision (SBD) for Spikevax Bivalent

Date SBD issued: 2022-10-27

The following information relates to the New Drug Submission for Spikevax Bivalent.

Elasomeran, imelasomeran

Drug Identification Number (DIN):

  • DIN 02530252 - 0.05 mg/mL elasomeran and 0.05 mg/mL imelasomeran, dispersion, intramuscular administration

ModernaTX, Inc.

New Drug Submission Control Number: 265656

 

On September 1st, 2022, Health Canada issued a Notice of Compliance (NOC), subject to terms and conditions, to ModernaTX, Inc. for the Spikevax Bivalent vaccine.

The Food and Drug Regulations were amended on March 18, 2021 to incorporate flexibilities into the existing new drug submission (NDS) regulatory pathway, thereby facilitating the regulatory process for authorization of new drugs that treat or prevent coronavirus disease 2019 (COVID-19). The modified requirements allow an NDS for a designated COVID-19 drug to be filed through a rolling submission process, i.e., as the information becomes available. Sponsors are responsible for completing the required documentation and providing the necessary evidence to Health Canada. Health Canada will issue an NOC for a COVID-19 drug if it is determined that the benefits and risks of the product are supported by evidence of the safety, efficacy, and consistent quality of the drug.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-risk profile of Spikevax Bivalent is favourable as a booster dose for active immunization against COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in individuals 18 years of age and older.

Spikevax Bivalent is authorized in accordance with the Food and Drug Regulations, subject to terms and conditions that need to be met by the sponsor. Terms and conditions may be imposed or amended at any time. Additionally, failure to comply with the terms and conditions may result in compliance and enforcement actions being taken by Health Canada.

For further information on the amended regulatory pathway, refer to the Guidance on Amendments to the Food and Drug Regulations for Drugs for Use in Relation to COVID-19.

1 What was approved?

Spikevax Bivalent, an active immunizing agent, was authorized as a booster dose for active immunization against coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in individuals 18 years of age and older.

The National Advisory Committee on Immunization (NACI) provides additional guidance on the use of the COVID-19 vaccines in Canada, through the COVID-19 vaccine: Canadian Immunization Guide and current vaccine statements.

The efficacy and safety of Spikevax Bivalent in individuals under 18 years of age have not been established. Spikevax Bivalent is therefore not authorized for pediatric use.

Clinical studies of Spikevax Bivalent include subjects 65 years of age and older, and their data contribute to the overall assessment of efficacy and safety.

Spikevax Bivalent (0.05 mg/mL elasomeran and 0.05 mg/mL imelasomeran) is presented as a dispersion. In addition to the medicinal ingredients, the dispersion contains acetic acid, cholesterol, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), PEG2000-DMG (1,2-dimyristoyl-rac-glycerol,methoxy-polyethyleneglycol), lipid SM-102, sodium acetate trihydrate, sucrose, trometamol, trometamol hydrochloride, and water for injection.

The use of Spikevax Bivalent is contraindicated in individuals who are hypersensitive to the active ingredients or to any ingredients in the formulation, including any non-medicinal ingredient, or component of the container.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Spikevax Bivalent Product Monograph is available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

2 Why was Spikevax Bivalent approved?

Health Canada considers that the benefit-risk profile of Spikevax Bivalent is favourable as a booster dose for active immunization against coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in individuals 18 years of age and older.

The National Advisory Committee on Immunization (NACI) provides additional guidance on the use of the COVID-19 vaccines in Canada, through the COVID-19 vaccine: Canadian Immunization Guide and current vaccine statements.

Spikevax Bivalent is authorized in accordance with the Food and Drug Regulations, subject to terms and conditions that need to be met by the sponsor.

Coronavirus disease 2019 is the infectious disease caused by the novel coronavirus, SARS-CoV-2, which has spread rapidly and globally since its emergence in late 2019. On March 11, 2020, the World Health Organization declared COVID-19 a pandemic. In Canada, there have been 4,158,491 confirmed cases of COVID-19 and approximately 43,797 deaths as of September 1, 2022, the date of authorization of Spikevax Bivalent.

Severe acute respiratory syndrome coronavirus 2 is a highly transmissible and pathogenic coronavirus. The majority of SARS-CoV-2-infected patients experience mild to moderate respiratory disease and recover without requiring special treatment. However, following infection, some patients develop severe disease that requires oxygen support or critical disease with complications such as respiratory failure, sepsis and septic shock, thromboembolism, and/or multiorgan failure, including acute kidney injury and cardiac injury. Medical conditions or other factors that place patients at high risk for progression to severe COVID-19 include older age, obesity, current smoker, chronic kidney disease, diabetes, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, chronic lung disease, sickle cell disease, neurodevelopmental disorders, active cancer, and medically related technological dependence. Other medical conditions or factors (e.g., race or ethnicity) may also place individual patients at high risk for progression to severe COVID-19. Some people continue to experience a range of effects (known as long COVID) for months after recovery, and damage to organs has been observed.

Health Canada has authorized the following vaccines for protection against COVID-19: Comirnaty (previously Pfizer-BioNTech COVID-19 Vaccine), Spikevax (previously COVID-19 Vaccine Moderna), Vaxzevria (previously AstraZeneca COVID-19 Vaccine), Covishield, Jcovden (previously Janssen COVID-19 Vaccine), Nuvaxovid, and Covifenz.

All countries continue to be impacted by the pandemic. Furthermore, the emergence of SARS-CoV-2 variants poses a major threat to public health. Rapid genetic changes have altered viral characteristics such as transmissibility and the ability to evade infection-induced and vaccination-induced immunity, which contribute to continuing significant disruptions to healthcare systems and social and economic activities.

The emergence of more antigenically divergent variants necessitates the development of vaccine formulations to match the circulating variants, in order to provide better protection. Spikevax Bivalent is a bivalent vaccine formulation targeting both the ancestral SARS-CoV-2 strain and its Omicron BA.1 variant. Spikevax Bivalent has been proposed for use as a booster dose based on an immunogenicity bridging (immunobridging) study using the authorized Spikevax vaccine (hereafter also referred to as the original Spikevax), a monovalent vaccine targeting the ancestral SARS-CoV-2 strain, as a comparator. Additionally, long-term safety data were reviewed from a study conducted with a bivalent formulation that targets the ancestral SARS-CoV-2 strain and Beta variant, from which findings could be extrapolated to support the authorization of Spikevax Bivalent.

The immunogenicity and safety of Spikevax Bivalent were evaluated based on an interim analysis of the Phase II/III study mRNA-1273-P205 (Study P205), which was ongoing at the time of authorization. The study design includes multiple cohorts to assess different variant-modified candidate vaccines. The pivotal immunogenicity data were obtained from Part G and Part F of Study P205. At enrolment, subjects in both parts of this study were adults (18 years of age and older) who had previously received two 100 mcg doses of the original Spikevax vaccine as a primary series and one 50 mcg dose of the original Spikevax as a first booster at least three months prior to enrolment, for a total of three previous doses. Second booster doses (fourth dose overall) were administered on Day 1 of the study, with 437 subjects receiving a 50 mcg dose of Spikevax Bivalent (Part G), and 377 subjects receiving a 50 mcg dose of the original Spikevax (Part F). The median follow-up times were 43 days and 57 days, respectively. Demographic and baseline characteristics were similar between the two groups.

The effectiveness of Spikevax Bivalent was inferred by immunobridging between Study P205 and Study P301, the pivotal study which provided the main evidence on which the authorization of the original Spikevax vaccine was based. In Study P205, the group that received the original Spikevax as a second booster serves as the within-study comparator against Spikevax Bivalent as a second booster.

The co-primary endpoints were the geometric mean titres (GMTs) and seroresponse rates (SRRs) for the serum neutralizing antibody titres against the ancestral SARS-CoV-2 strain and Omicron BA.1 variant at Days 29 and 91. Data up to Day 29 were submitted as part of an interim analysis. It is required that further data up to Day 91 be submitted as part of the terms and conditions. The primary efficacy analysis was conducted using the immunogenicity set which included 334 subjects from Part G and 260 subjects from Part F, all of whom had no evidence of SARS-CoV-2 infection at baseline (prior to receiving the second booster dose). These two comparator groups will hereafter be referred to as the Spikevax Bivalent group and the original Spikevax group, respectively. At baseline, there were no major imbalances between the two groups. Neutralization against the ancestral SARS-CoV-2 strain and Omicron BA.1 variant was measured using a validated pseudovirus neutralization assay.

For each of the comparator groups, immunobridging analyses were conducted 29 days after the administration of the second booster does to compare neutralizing antibody titers (measured as the inhibitory dilutions at which 50% neutralization [ID50] was attained) against the ancestral SARS-CoV-2 strain and the Omicron BA.1 variant. At Day 29, the neutralizing antibody GMTs against the Omicron BA.1 variant were 2,479.9 (95% confidence interval [CI]: 2,264.5, 2,715.8) in the Spikevax Bivalent group, and 1,421.2 (95% CI: 1,283.0, 1,574.4) in the original Spikevax group. For neutralization against the Omicron BA.1 variant, Spikevax Bivalent was superior to the original Spikevax, as the GMT ratio (GMR) between the two groups was 1.75 (97.5% CI: 1.49, 2.04). The neutralizing antibody GMTs against the ancestral SARS-CoV-2 strain were 5,977.26 (95% CI: 5,321.90, 6,713.32) in the Spikevax Bivalent group and 5,649.33 (95% CI: 5,056.85, 6,311.23) in the original Spikevax group. For neutralization against ancestral SARS-CoV-2, non-inferiority was demonstrated between Spikevax Bivalent and the original monovalent Spikevax vaccine, as the GMR was 1.22 (97.5% CI: 1.08, 1.37).

Vaccine efficacy success criteria

 

Neutralizing antibody geometric mean titre (GMT)

 

Omicron BA.1 variant

Ancestral SARS-CoV-2 strain

Spikevax Bivalent

(95% confidence interval [CI])

2,479.90

(2,264.50, 2,715.80)

5,977.26

(5,321.90, 6,713.32)

Original Spikevax

(95% CI)

1,421.20

(1,283.00, 1,574.40)

5,649.33

(5,056.85, 6,311.23)

GMT ratio (GMR)

(97.5% CI)

1.75

(1.49, 2.04)

1.22

(1.08, 1.37)

Outcome

Spikevax Bivalent shown to be superior to the original Spikevax for neutralization against Omicron BA.1 variant

Spikevax Bivalent shown to be non-inferior to the original Spikevax for neutralization against ancestral variant

Seroresponse rate (SRR)

(95% CI)

100.00%

(98.90, 100.00)

99.20%

(97.20, 99.90)

Estimated Difference in SRR

(97.5% CI)

1.50%

(-1.10, 4.00)

The SRRs against the Omicron BA.1 variant at Day 29 were 100% (95% CI: 98.9, 100) in the Spikevax Bivalent group and 99.2% (95% CI: 97.2, 99.9) in the original Spikevax group. The estimated difference in SRR between the two groups was 1.5% (97.5% CI: -1.1, 4.0). The results in subgroups of subjects who were SARS-CoV-2-positive at baseline and subjects who were 65 years of age and older were consistent with the results of the primary analysis. Compared to the original monovalent Spikevax vaccine, these findings indicate that Spikevax Bivalent is associated with a superior neutralizing antibody response against the Omicron BA.1 variant and a similar neutralizing antibody response against the ancestral SARS-CoV-2 strain. These observations were consistent regardless of age or the presence of antibodies resulting from natural infection.

Neutralization against the Omicron BA.4/5 variant, the dominant circulating variant at the time of market authorization, was measured as an exploratory endpoint using a research-grade pseudovirus neutralization assay. The resulting data suggest that a second booster with Spikevax Bivalent would provide a superior neutralizing antibody response against the Omicron BA.4/5 variant relative to a second booster with the original monovalent Spikevax vaccine.

Supportive immunogenicity data were submitted from Part A1 of Study P205 which consisted of data up to Day 181 from the evaluation of mRNA-1273.211, a bivalent vaccine containing equal amounts of the ancestral SARS-CoV-2 strain and Beta variant spike protein sequences, administered as a first booster. These data suggest some persistence of the neutralizing antibodies induced by a bivalent messenger ribonucleic acid (mRNA) vaccine against ancestral and variant strains. These data also provide some supportive evidence to extrapolate Spikevax Bivalent to the first booster setting.

Exploratory results regarding neutralization against the Beta and Delta variants were also provided from a convenience sample of the first 50 subjects in Parts G and F of Study P205. These data suggest that Spikevax Bivalent may be at least as effective as the original monovalent Spikevax vaccine in protecting against variants that were previously dominant.

When administered as a second booster, Spikevax Bivalent is associated with a superior neutralizing antibody response against the Omicron BA.1 variant and a similar neutralizing antibody response against the ancestral virus, relative to the original monovalent Spikevax vaccine. Data from exploratory analyses suggest that a second booster using Spikevax Bivalent would provide a superior neutralizing antibody response against the Omicron BA.4/5 variant compared to a second booster using the original monovalent Spikevax vaccine. Additionally, binding antibody data suggest that Spikevax Bivalent could offer superior cross-protection compared to the original monovalent Spikevax vaccine against previously dominant variants.

From a regulatory perspective, the non-randomized, cross-arm comparison of the safety data between the groups that received Spikevax Bivalent as a second booster and the original monovalent Spikevax vaccine as a second booster constitute the basis for the clinical safety decision regarding Spikevax Bivalent. The safety data available for review as part of the interim analysis covered a median follow-up time of 43 days.

Longer-term data, including supportive safety and reactogenicity data, were presented from a pre-specified comparison between Parts A and B of Study P205 which had a median follow-up time of 245 days. Subjects in both parts received two 100 mcg doses of the original monovalent Spikevax vaccine as a primary series. In Part A, 300 subjects received a 50 mcg dose of mRNA-1273.211 as a first booster. This formulation contains equal amounts of the ancestral SARS-CoV-2 strain and Beta variant spike protein sequences. In Part B, 177 subjects received a 50 mcg dose of the original Spikevax vaccine as a first booster.

The size of the pivotal safety database was found to be acceptable given the considerable safety experience accumulated with the monovalent mRNA-based COVID-19 platforms in the mass vaccination setting. Furthermore, Spikevax Bivalent retains the ancestral SARS-CoV-2 spike protein mRNA sequence that is already licensed and with which there is experience in routine use.

Pronounced reactogenicity was observed with both local and systemic adverse reactions. Solicited adverse reactions were reported in 380 subjects (87%) in the Spikevax Bivalent group and 301 subjects (85%) in the original Spikevax group. The majority of events were Grade 1 or 2 in severity and resolved with a median time of 1-3 days. The frequency and severity of solicited adverse reactions were similar between the two groups. The most common local solicited adverse reactions (reported in ≥10% of subjects in the Spikevax Bivalent and original Spikevax groups, respectively) were pain at the injection site (77.9% and 77.2%) and axillary swelling (17.1% and 19.6%). The most common systemic solicited adverse reactions (reported in ≥10% of subjects in the Spikevax Bivalent and original Spikevax groups, respectively) were fatigue (54.9% and 51.4%), headache (43.9% and 41.1%), myalgia (39.6% and 38.6%), arthralgia (31.1% and 31.7%), chills (23.8% and 21.1%), and nausea/vomiting (10.3% and 10.0%). The frequency of Grade 3 adverse reactions was 8.0% in both groups. There were no Grade 4 solicited adverse reactions in either group.

No safety concerns or differences regarding solicited or unsolicited adverse reactions were identified between the two groups based on SARS-CoV-2 infection status prior to receiving the booster dose.

The reactogenicity profile of Spikevax Bivalent as a second booster is expected to be similar to the reactogenicity profile of the original Spikevax as a first or second booster. This is based on the high degree of similarity observed in the reactogenicity profiles of subjects who received Spikevax Bivalent as a second booster, original Spikevax as a first booster, or the bivalent mRNA-1273.211 as a first booster (targeting the ancestral strain and Beta variant, given to subjects in Part A).

The incidence of unsolicited adverse reactions was similar between the two groups up to 28 days after the second booster dose. Unsolicited adverse reactions were reported in 18.5% of subjects in the Spikevax Bivalent group and 20.7% of subjects in the original Spikevax group. Medically-attended adverse events occurred with similar frequencies in the Spikevax Bivalent and original Spikevax groups (9.8% and 13.8%, respectively) up to 28 days after vaccination. There were no fatal events or adverse reactions leading to study discontinuation.

An enhanced assessment of myocarditis and pericarditis events confirmed that rates of myocarditis continue to appear to be lower following Dose 3 compared with Dose 2. This finding applied to both sexes and almost all age strata including the range reported to be at the highest risk (12 to 39 years), with the caveat that post-market data for Dose 3 are limited and estimates may change as the demographic characteristics of Dose 3 recipients change over time. The observed data align with the historical data on the epidemiology of myocarditis and pericarditis following a booster dose of a COVID-19 vaccine.

The safety and reactogenicity data indicate that the safety profiles of both bivalent vaccines (Spikevax Bivalent and mRNA-1273.211) are similar to that of the original Spikevax vaccine, regardless of the number of prior booster doses or the intervals between prior booster doses. As the study conducted with the mRNA-1273.211 bivalent formulation provides more comprehensive safety data (median follow-up time of 245 days), Spikevax Bivalent is expected to elicit a similar safety profile with a longer follow-up time. Based on the data available at the time of authorization, no new safety concerns are expected. However, the long-term safety of Spikevax Bivalent needs further characterization. This requirement has been added to the terms and conditions of the authorization.

Non-clinical repeat-dose toxicity studies using the ancestral monovalent modified platform and the Spikevax Bivalent platform did not reveal any evidence of a link between Spikevax Bivalent and vaccine-associated enhanced respiratory disease (VAERD) or other harms. No new safety concerns are expected with the use of the bivalent mRNA-based platform further to those already characterized.

The demographic and baseline disease characteristics of the subjects enrolled in Study P205 are comparable to those of the subjects who contributed to the pooled safety information for the original Spikevax vaccine, and to the overall indicated population. Therefore, the clinical safety data obtained from the original monovalent Spikevax vaccine in the post-market setting may be closely extrapolated to apply to Spikevax Bivalent.

No new risks have been identified for Spikevax Bivalent beyond those listed in the approved labelling for the original Spikevax vaccine. The key safety risks for Spikevax Bivalent are documented adverse events which are recognized as class effects, including hypersensitivity and anaphylaxis, cardiovascular events (myocarditis and pericarditis), acute illness, hematologic events, immune-related events, and syncope. The risks associated with Spikevax Bivalent are listed in the Product Monograph. The potential safety hazards posed by the administration of Spikevax Bivalent are expected to be manageable through routine monitoring and standard medical practice.

A Core Risk Management Plan (RMP) and a Canadian Addendum for Spikevax Bivalent were submitted by ModernaTX, Inc. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. The RMP for Spikevax Bivalent includes three important identified risks (anaphylaxis, myocarditis, and pericarditis) and two important potential risks (vaccine-associated enhanced disease [VAED] and VAERD). The RMP also identified nine areas of missing information (limited/no clinical data): “use during pregnancy”; “use while breastfeeding”; “use in immunocompromised subjects”; “use in patients with autoimmune or inflammatory disorders”; “use in frail subjects with unstable health conditions and comorbidities”; “interaction with other vaccines”; “long-term safety”; “long-term effectiveness”; and “use in the population less than 18 years of age”.

Overall, the RMP was considered to be acceptable and identified appropriate monitoring (pharmacovigilance) activities and risk minimization measures (i.e., Product Monograph and labelling) based on the known safety profile of the original monovalent Spikevax vaccine. The identified limitations and areas of missing information are managed through labelling and the RMP. These will continue to be investigated through planned and ongoing studies, including the studies undertaken for the original monovalent Spikevax vaccine and Study P205, which provided the main evidence of the clinical efficacy and safety of Spikevax Bivalent. Post-authorization commitments for monitoring the long-term safety and effectiveness of Spikevax Bivalent have also been established. As outlined in the terms and conditions, the RMP will be updated to reflect additional safety information, including that which is relevant to the Canadian-specific context, as it becomes available. In addition to meeting the regulatory requirements for post-market monitoring and prioritized reporting of adverse events following immunization, monthly safety summary reports will be provided to Health Canada and will include information related to special populations (e.g., pregnant women). Results related to safety and effectiveness from ongoing and planned studies will be submitted as they become available. For more information, refer to the terms and conditions available on the Health Canada COVID-19 vaccines and treatments portal.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Spikevax Bivalent Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

Spikevax Bivalent has been shown to have a favourable benefit-risk profile and an acceptable safety profile based on non-clinical and clinical studies. Collectively, the results of the clinical efficacy and safety evaluation demonstrated that Spikevax Bivalent met the requirements as specified in Health Canada's Guidance for Market Authorization Requirements for COVID-19 Vaccines. The vaccine was determined to be safe and well tolerated in participants 18 years of age and older when administered according to the recommended dosage regimen. Notably, Study P205 is ongoing and will collect additional information on the long-term safety and efficacy of the vaccine. These data will be submitted to Health Canada when available.

At the time of authorization, important limitations of the data included the lack of information on the long-term safety and efficacy of the vaccine, the duration of protection, protection against current and emerging variants, and the lack of or limited data for special populations. These limitations are considered adequately managed through labelling, terms and conditions associated with the authorization of Spikevax Bivalent, the RMP, and adequate monitoring. Appropriate warnings and precautions are in place in the Spikevax Bivalent Product Monograph to address the identified risks.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued an NOC pursuant to section C.08.004 of the Food and Drug Regulations. The NOC in respect of Spikevax Bivalent is accompanied by terms and conditions imposed in accordance with section C.01.014.21 of the Food and Drug Regulations. Of note, terms and conditions may be imposed or amended at any time. All terms and conditions are enforceable under section 21.7 of the Food and Drugs Act. Failure to comply with the terms and conditions may result in compliance and enforcement actions being taken by Health Canada.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Spikevax Bivalent?

The Food and Drug Regulations were amended on March 18, 2021 to incorporate flexibilities into the existing new drug submission (NDS) regulatory pathway, thereby facilitating the regulatory process for authorization of new drugs that treat or prevent coronavirus disease 2019 (COVID-19). For example, to expedite the review process, the modified requirements allow an NDS for a designated COVID-19 drug to be filed through a rolling submission process, i.e., as the information becomes available. This in turn allows Health Canada to commence a rolling review process of the information submitted. As outlined in the Guidance on amendments to the Food and Drug Regulations for drugs for use in relation to COVID-19, Health Canada will begin its review using the information submitted by the sponsor and accept new evidence as it becomes available until the submission is deemed complete. The rolling process can reduce the time it takes to authorize these critical new drugs while maintaining appropriate standards of safety, efficacy, and quality. Sponsors are responsible for completing the required documentation and providing the necessary evidence to Health Canada. Health Canada will issue a Notice of Compliance (NOC) for a COVID-19 drug if it is determined that the benefits and risks of the product are supported by evidence of the safety, efficacy, and consistent quality of the drug. Importantly, the amended regulations also allow the use of terms and conditions in order to ensure appropriate oversight, manage uncertainties or mitigate risks related to the drug in the context of the public health need due to COVID-19.

The information for this NDS was provided on a rolling basis. Following an expedited review of the data submitted, Health Canada determined that sufficient evidence was provided to support the conclusion that the benefits of Spikevax Bivalent outweigh the risks under the conditions of use recommended, with consideration given to the uncertainties relating to those benefits and risks as well as the public health need related to COVID-19. Health Canada issued an NOC for Spikevax Bivalent, with imposed terms and conditions, on September 1, 2022.

The review of the quality, non-clinical, clinical, and clinical pharmacology components of the New Drug Submission (NDS) for Spikevax Bivalent was based on a critical assessment of the data package submitted to Health Canada. The reviews completed by the European Medicines Agency, Australia’s Therapeutic Goods Administration, the United Kingdom’s Medicines and Healthcare products Regulatory Agency, and the Swiss Agency for Therapeutic Products (Swissmedic) were used as added references, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Spikevax Bivalent NDS was made independently based on the Canadian review.

For further information on the amended regulatory pathway, refer to the Guidance on Amendments to the Food and Drug Regulations for Drugs for Use in Relation to COVID-19.

 

Submission Milestones: Spikevax Bivalent

Submission Milestone Date
Pre-submission meeting 2022-06-24
Initial New Drug Submission filed by sponsor 2022-06-30
Initial non-clinical data submitted by sponsor 2022-06-30
Initial quality data submitted by sponsor 2022-06-30
Initial clinical data submitted by sponsor 2022-07-08
Risk Management Plan submitted by sponsor 2022-07-08
Screening Acceptance Letter issued 2022-07-22
Health Canada non-clinical evaluation completed 2022-08-28
Health Canada clinical/medical evaluation completed 2022-08-28
Health Canada quality evaluation completed 2022-08-29
Health Canada Risk Management Plan evaluation completed 2022-08-30
Final Product Monograph (English) submitted by sponsor 2022-08-30
Final Product Monograph (French) submitted by sponsor 2022-08-30
Health Canada labelling evaluation completed 2022-08-31
Terms and conditions finalized by Health Canada 2022-09-01
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate 2022-09-01
4 What follow-up measures will the company take?

The Notice of Compliance issued in respect of Spikevax Bivalent is accompanied by terms and conditions imposed on the drug identification number assigned to Spikevax Bivalent in accordance with section C.01.014.21 of the Food and Drug Regulations. Of note, terms and conditions may be imposed or amended at any time. Failure to comply with the terms and conditions may result in compliance and enforcement actions being taken by Health Canada.

These terms and conditions set out requirements relating to clinical, quality (chemistry and manufacturing), labelling, and pharmacovigilance information. They were put in place to ensure appropriate oversight, manage uncertainties or mitigate risks, and ascertain the continued quality, safety, and efficacy of the product.

The terms and conditions include (but are not limited to) the requirements listed below.

With respect to information on clinical and non-clinical studies, the sponsor is required to submit the following as soon as the data become available:

  • The results for immunogenicity and safety at Day 91 should be provided and included in the Spikevax Bivalent Product Monograph.
  • The Day 181 immunogenicity and safety data from Study P205 Part F (cohort 2) and Part G.
  • The full Clinical Study Report (interim and final analysis) for Study P205 Part F (cohort 2) and Part G, as soon as they become available.

Additionally, the sponsor is required to:

  • Submit stability updates for the drug substance in a timely manner.
  • Submit the final validation report related to the messenger ribonucleic acid (mRNA) ratio method, final validation to support extrapolation of the ribonucleic acid (RNA) ratio results, stability updates, and final Certificates of Analyses for the drug product.
  • Submit stability data updates for the new drug product manufacturing facility in a timely manner.
  • Submit as a priority and without delay, reports of adverse reactions associated with Spikevax Bivalent.
  • Submit Monthly Safety Summary Reports (MSSRs) for Spikevax Bivalent, unless otherwise determined by Health Canada.
  • Submit Periodic Safety Update Reports (PSURs) or Periodic Benefit Risk Evaluation Reports (PBRERs) every 6 months for Spikevax Bivalent, unless otherwise determined by Health Canada.
  • Submit an updated core RMP with the Canadian Addendum in a timely manner if a safety issue is identified that requires immediate regulatory action, or as requested by Health Canada.
  • Submit final snapshots of all components of the electronic platform containing the approved Canadian-specific information for Spikevax Bivalent in French and English for Health Canada’s review and records, prior to launch of the electronic platform.
  • Develop Canadian-specific bilingual labelling for Spikevax Bivalent and implement such labelling once supplies are transitioned to Canadian-dedicated supplies. Health Canada should be kept informed of estimated timelines and proposed strategies concerning the development and implementation of Canadian-specific bilingual labels.
6 What other information is available about drugs?

Up-to-date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

The New Drug Submission (NDS) for Spikevax Bivalent (elasomeran, imelasomeran) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance (NOC) was issued in relation to Spikevax Bivalent, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug.

Clinical Pharmacology

Spikevax Bivalent contains the medicinal ingredients elasomeran and imelasomeran, both of which are messenger ribonucleic acid (mRNA) constructs. Elasomeran encodes the pre-fusion stabilized spike protein of the ancestral strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Imelasomeran encodes the pre-fusion stabilized spike protein of the Omicron BA.1 variant of SARS-CoV-2. The mRNAs are enclosed in lipid nanoparticles which are taken up by cells following intramuscular injection, effectively delivering the mRNA sequences into cells for the expression of the SARS-CoV-2 spike antigens. The delivered mRNAs do not enter the cellular nucleus or interact with the genome, are non-replicating, and are expressed transiently. The proteins encoded by the mRNAs undergo post-translational modification and trafficking resulting in properly folded and fully functional spike proteins that are inserted into the cellular membrane of the expressing cells. The spike proteins are membrane-bound, mimicking the presentation of natural infection. The vaccine induces both neutralizing antibody and cellular immune responses (T-cell and B-cell) to the spike antigens, which may contribute to protection against coronavirus disease 2019 (COVID-19).

Pharmacokinetic studies to demonstrate absorption, distribution, metabolism, and excretion of elasomeran and imelasomeran were not conducted and are typically not required for vaccines.

Immunogenicity was assessed as part of the clinical efficacy evaluation of Spikevax Bivalent.

At the time of authorization, there were no data regarding the co-administration of Spikevax Bivalent with other vaccines.

For further details, please refer to the Spikevax Bivalent Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

Clinical Efficacy

Clinical evidence of the immunogenicity of Spikevax Bivalent was assessed through an interim analysis of the results from the Phase II/III study mRNA-1273-P205 (Study P205), which was ongoing at the time of authorization. Study P205 was designed to include multiple cohorts to assess the immunogenicity, safety, and reactogenicity of mRNA-based variant-modified candidate vaccines administered as booster doses. The pivotal immunogenicity data presented in support of this NDS were from Part G and Part F, of Study P205. At enrolment, subjects in both parts were adults (18 years of age and older) who had previously received two 100 mcg doses of the original monovalent Spikevax vaccine (hereafter also referred to as the original Spikevax) as a primary series and one 50 mcg dose of the original Spikevax as a first booster at least three months prior to enrolment, for a total of three previous doses. Second booster doses (fourth dose overall) were administered on Day 1 of the study. At the time of analysis, the 437 subjects in Part G received a 50 mcg dose of Spikevax Bivalent and were followed for a median of 43 days (range: 22 to 51 days). The 377 subjects in Part F received a 50 mcg dose of the original Spikevax and were followed for a median of 57 days (range: 51 to 66 days).

In the Spikevax Bivalent group, 59.0% of subjects were female, 41.0% were male, 89.2% were White, and 10.8% were Hispanic or Latino. The median age was 60 years (range: 20 to 88 years), and 39.8% of subjects were 65 years of age or older. Demographic and baseline characteristics were similar between the two groups. No immunocompromised or pregnant individuals were included in the study.

Immunogenicity

The effectiveness of Spikevax Bivalent was established by comparing its immunogenicity profile to that of the previously authorized original Spikevax vaccine. This was inferred by immunogenicity bridging (immunobridging) between Study P205 and Study P301, the pivotal study which provided the main evidence for the authorization of the original Spikevax vaccine. In Study P205, subjects in Part F, who received the original Spikevax as a second booster, served as the within-study comparator for subjects in Part G, who received Spikevax Bivalent as a second booster.

The co-primary endpoints are the geometric mean titres (GMTs) and seroresponse rates (SRRs) for the serum neutralizing antibody titres against the ancestral SARS-CoV-2 strain and the Omicron BA.1 variant at Days 29 and 91. Data up to Day 29 have been submitted as part of an interim analysis. Data up to Day 91 are required as part of the terms and conditions of authorization. The primary efficacy analysis was conducted in the immunogenicity set, which included 334 subjects from Part G and 260 subjects from Part F, all of whom had no evidence of SARS-CoV-2 infection at baseline (prior to receiving the second booster dose). These two comparator groups will hereafter be referred to as the Spikevax Bivalent group and the original Spikevax group, respectively. There were no major imbalances between the two groups at baseline. Neutralization against the ancestral SARS-CoV-2 strain and Omicron BA.1 variant was measured using a validated pseudovirus neutralization assay.

Immunobridging analyses compared the neutralizing antibody titers (measured as the inhibitory dilutions at which 50% neutralization [ID50] was attained) of subjects in the two comparator groups against the Omicron BA.1 variant and the ancestral SARS-CoV-2 strain 29 days after administration of the second booster dose. At Day 29, the neutralizing antibody GMTs against the Omicron BA.1 variant were 2,479.9 (95% confidence interval [CI]: 2,264.5, 2,715.8) in the Spikevax Bivalent group, and 1,421.2 (95% CI: 1,283.0, 1,574.4) in the original Spikevax group. For neutralization against the Omicron BA.1 variant, Spikevax Bivalent was shown to be superior to the original Spikevax, as the GMT ratio (GMR) between the two groups was 1.75 (97.5% CI: 1.49, 2.04). The neutralizing antibody GMTs against the ancestral SARS-CoV-2 strain were 5,977.26 (95% CI: 5,321.90, 6,713.32) in the Spikevax Bivalent group, and 5,649.33 (95% CI: 5,056.85, 6,311.23) in the original Spikevax group. For neutralization against the ancestral SARS-CoV-2 strain, non-inferiority was demonstrated between Spikevax Bivalent and the original Spikevax vaccine, as the GMR was 1.22 (97.5% CI: 1.08, 1.37).

The SRRs against the Omicron BA.1 variant at Day 29 were 100% (95% CI: 98.9, 100) in the Spikevax Bivalent group and 99.2% (95% CI: 97.2, 99.9) in the original Spikevax group. The estimated difference in SRR between the two groups was 1.5% (97.5% CI: -1.1, 4.0). The results in subgroups of subjects who were SARS-CoV-2-positive at baseline and subjects 65 years of age and older were consistent with the results of the primary analysis. Compared with the original Spikevax, Spikevax Bivalent is associated with a superior neutralizing antibody response against the Omicron BA.1 variant and a similar neutralizing antibody response against the ancestral SARS-CoV-2 strain. These observations were consistent regardless of age or the presence of antibodies resulting from natural infection.

The duration of the protection conferred by booster doses using Spikevax Bivalent remain unknown, and waning protection has been observed with the previously approved monovalent vaccine. Post-market epidemiological studies continue to monitor the effectiveness of all COVID-19 vaccines. Additionally, the long-term persistency of antibodies following the third and fourth doses (first and second booster doses, respectively) remains unknown. Correlation of protection with a specific neutralizing antibody titre has not been established. Monitoring of neutralizing antibody titres in clinical study subjects has been included in the terms and conditions that were put in place at the time of authorization. Together with the evaluation of breakthrough infections, this is expected to provide insights into the duration of immunity in vaccinated individuals.

Neutralization against the Omicron BA.4/5 variant, the dominant circulating variant at the time of market authorization, was measured as an exploratory endpoint using a research grade pseudovirus neutralization assay. The resulting data suggest that a second booster with Spikevax Bivalent would provide a superior neutralizing antibody response against the Omicron BA.4/5 variant than a second booster with the original monovalent Spikevax vaccine.

For all subjects regardless of prior SARS-CoV-2 infection, the estimated Day 29 neutralizing antibody GMTs against the Omicron BA.4/5 variant were 985.38 (95% CI: 914.77, 1,061.434) in the Spikevax Bivalent group and 588.36 (95% CI: 544.08, 636.24) in the original Spikevax group. The GMR was 1.68 (95% CI: 1.52, 1.84).

For subjects without prior SARS-CoV-2 infection, the estimated Day 29 neutralizing antibody GMTs against the Omicron BA.4/5 variant were 776.45 (95% CI: 719.49, 837.92) in the Spikevax Bivalent group and 458.28 (95% CI: 420.62, 499.32) in the original Spikevax group. The GMR was 1.69 (95%CI: 1.51, 1.90).

For subjects with prior SARS-CoV-2 infection, the estimated Day 29 neutralizing antibody GMTs against the Omicron BA.4/5 variant were 2,246.25 (95% CI: 1,975.52, 2,554.09) in the Spikevax Bivalent group and 1,406.89 (95% CI: 1,227.88, 1,612.01) in the original Spikevax group. The GMR was 1.60 (95% CI: 1.34, 1.91).

Additionally, supportive immunogenicity data were submitted from Part A1 of Study P205 which consisted of data up to Day 181 for mRNA-1273.211, a bivalent vaccine containing equal amounts of the ancestral SARS-CoV-2 strain and the Beta variant spike protein sequences, administered as a first booster. These data suggest some persistence of the neutralizing antibodies induced by a bivalent mRNA vaccine against ancestral and variant strains. These data also provide some supportive evidence to extrapolate Spikevax Bivalent to the first booster setting.

Exploratory results were also provided from a convenience sample of the first 50 subjects in Parts G and F of Study P205, regarding neutralization against the Beta and Delta variants. These data suggest that Spikevax Bivalent may be at least as effective as the original Spikevax vaccine in protecting against variants that were previously dominant. Immunoglobulin G binding antibody data up to Day 29 were provided from Parts G and F against the ancestral strain and Omicron, Alpha, Beta, Delta, and Gamma variants. Although there was no multiplicity adjustment due to the exploratory nature of these analyses, the binding antibody data suggest that Spikevax Bivalent could offer superior cross-protection relative to the original Spikevax vaccine against the ancestral virus and the variants that were previously dominant.

When administered as a second booster, Spikevax Bivalent is associated with a superior neutralizing antibody response against the Omicron BA.1 variant and a similar neutralizing antibody response against the ancestral virus, relative to the original monovalent Spikevax vaccine. Data from exploratory analyses suggest that a second booster using Spikevax Bivalent would provide a superior neutralizing antibody response against the Omicron BA.4/5 variant compared to a second booster using the original Spikevax vaccine. Additionally, binding antibody data suggest that Spikevax Bivalent could offer superior cross-protection compared to the original Spikevax vaccine against the variants that were previously dominant.

Indication

Sponsor's proposed indication

Health Canada-approved indication

Spikevax Bivalent (elasomeran/imelasomeran) Original/Omicron mRNA vaccine is indicated for active immunization against coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in individuals 12 years of age and older.

Spikevax Bivalent (elasomeran/imelasomeran) Original/Omicron mRNA vaccine is indicated as a booster dose for active immunization against coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in individuals 18 years of age and older.

The proposed indication was revised to more accurately reflect the population from which the pivotal immunogenicity (efficacy) data were obtained, as well as the circumstances in which the vaccine was administered in the clinical study. Therefore, the age range for which Spikevax Bivalent was authorized is individuals 18 years of age and older (rather than 12 years of age and older), and the approved indication specifies that it is authorized for use as a booster dose.

For more information, refer to the Spikevax Bivalent Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

Clinical Safety

The clinical safety of Spikevax Bivalent was evaluated in Study P205 (see Clinical Efficacy section). From a regulatory perspective, the non-randomized, cross-arm comparison of the safety data between the groups that received Spikevax Bivalent (Part G) and the original Spikevax vaccine (Part F) as a second booster constitute the basis for the clinical safety decision regarding Spikevax Bivalent. The safety data available as part of this interim analysis covered a median follow-up time of 43 days.

Supportive safety and reactogenicity data were also presented from a pre-specified comparison between Parts A and B of Study P205. In Part A, a 50 mcg dose of a bivalent vaccine (mRNA-1273.211) containing equal amounts of the ancestral SARS-CoV-2 strain and Beta variant spike protein sequences was administered as a first booster dose to 300 subjects who had received two 100 mcg doses of the original Spikevax vaccine as a primary series. In Part B, 177 subjects who had received two 100 mcg doses of the original Spikevax vaccine as a primary series received a 50 mcg dose as a first booster dose.

The size of the pivotal safety database was acceptable given the considerable safety experience accumulated with the monovalent mRNA-based COVID-19 platforms in the mass vaccination setting. Furthermore, Spikevax Bivalent retains the ancestral SARS-CoV-2 spike protein mRNA sequence that is already licensed and with which there is experience in routine use.

Pronounced reactogenicity was observed with both local and systemic adverse reactions. Solicited adverse reactions were reported in 380 subjects (87%) in the Spikevax Bivalent group and 301 subjects (85%) in the original Spikevax group. The majority of events were Grade 1 or 2 in severity and resolved with a median time of 1-3 days. The frequency and severity of solicited adverse reactions were similar between the two groups. The most common local solicited adverse reactions (reported in ≥10% of subjects in the Spikevax Bivalent and original Spikevax groups, respectively) were pain at the injection site (77.9% and 77.2%) and axillary swelling (17.1% and 19.6%). The most common systemic solicited adverse reactions (reported in ≥10% of subjects in the Spikevax Bivalent and original Spikevax groups, respectively) were fatigue (54.9% and 51.4%), headache (43.9% and 41.1%), myalgia (39.6% and 38.6%), arthralgia (31.1% and 31.7%), chills (23.8% and 21.1%), and nausea/vomiting (10.3% and 10.0%). The frequency of Grade 3 adverse reactions was 8.0% in both groups. There were no Grade 4 solicited adverse reactions in either group.

No safety concerns or differences regarding solicited or unsolicited adverse reactions were identified between the two groups based on SARS-CoV-2 infection status prior to receiving the booster dose.

A high degree of similarity was observed in the reactogenicity profiles of subjects who received Spikevax Bivalent as a second booster, original Spikevax as a first booster, and the bivalent mRNA-1273.211 as a first booster (targeting the ancestral strain and Beta variant, given to subjects in Part A). In individuals who received two 100 mcg doses of the original monovalent Spikevax vaccine as the primary series, the reactogenicity profile of Spikevax Bivalent when used as a second booster is expected to be similar to the reactogenicity profile of the original Spikevax when used as a first or second booster.

The incidence of unsolicited adverse reactions was similar between the two groups up to 28 days after the second booster dose. Unsolicited adverse reactions were reported in 18.5% of subjects in the Spikevax Bivalent group and 20.7% of subjects in the original Spikevax group. Two serious adverse events (prostate cancer and traumatic fracture) were reported in the Spikevax Bivalent group, while one (spinal osteoarthritis) was reported in the original Spikevax group. Medically-attended adverse events occurred with similar frequencies in the Spikevax Bivalent and original Spikevax groups (9.8% and 13.8%, respectively) up to 28 days after vaccination. There were no fatal events or adverse reactions leading to study discontinuation.

In general, no adverse events of special interest which could raise safety concerns were identified through the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries tools. An enhanced assessment of myocarditis and pericarditis events using custom MedDRA Queries confirmed that rates of myocarditis continue to appear to be lower following Dose 3 compared with Dose 2 of the original Spikevax and other COVID-19 vaccines. This finding applied to both sexes and almost all age strata including the range reported to be at the highest risk (12 to 39 years), with the caveat that post-market data for Dose 3 are limited and estimates may change as the demographic characteristics of Dose 3 recipients change over time. The observed data align with the historical data on the epidemiology of myocarditis and pericarditis following a booster dose of a COVID-19 vaccine.

The safety profiles of both bivalent vaccines (Spikevax Bivalent and mRNA-1273.211) appear to be similar to that of the original Spikevax vaccine, regardless of the number of prior booster doses or the intervals between prior booster doses. The safety data for the bivalent vaccines were consistent across study arms. As the study conducted with the mRNA-1273.211 bivalent formulation provides more comprehensive safety data (median follow-up time of 245 days), Spikevax Bivalent is expected to elicit a similar safety profile with a longer follow-up time. Based on the data available at the time of authorization, no new safety concerns are expected, however, the long-term safety of Spikevax Bivalent needs further characterization. This requirement has been added to the terms and conditions of authorization. Safety data from monovalent vaccine platforms also serve as supportive evidence that can be extrapolated to the Spikevax Bivalent setting.

The non-clinical toxicology data also provided supportive safety information that factored into the final clinical decision. Repeat-dose toxicity studies using the ancestral monovalent modified platform and the Spikevax Bivalent platform did not reveal any evidence of a link between Spikevax Bivalent and vaccine-associated enhanced respiratory disease (VAERD) or other harms. Together, the data submitted to support the authorization of the original Spikevax and the aggregate data from non-clinical toxicology studies indicate that no new safety concerns are expected with the use of the bivalent mRNA-based platform further to those already characterized safety concerns.

The demographic and baseline disease characteristics of the subjects enrolled in Study P205 are comparable to those of the subjects who contributed to the pooled safety information for the original Spikevax vaccine, and to the overall indicated population. Therefore, the clinical safety data obtained from the original Spikevax vaccine in the post-market setting may be closely extrapolated to apply to Spikevax Bivalent.

No new risks have been identified for Spikevax Bivalent beyond those that are listed in the approved labelling for the original monovalent Spikevax vaccine. The key safety risks for Spikevax Bivalent are documented adverse events which are recognized as class effects, including hypersensitivity and anaphylaxis, cardiovascular events (myocarditis and pericarditis), acute illness, hematologic events, immune-related events, and syncope. The risks associated with Spikevax Bivalent are listed in the Product Monograph. The potential safety hazards posed by the administration of Spikevax Bivalent are expected to be manageable through routine monitoring and standard medical practice.

Risk Management Plan

A Core Risk Management Plan (RMP) and a Canadian RMP Addendum for Spikevax Bivalent were submitted by ModernaTX, Inc. to Health Canada as part of the submission for authorization. The RMP is designed to describe known and potential safety issues, to present the monitoring plan and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The following information relates to the RMP submitted by ModernaTX, Inc. as part of the New Drug Submission for Spikevax Bivalent. It is the sponsor’s responsibility to monitor the safety profile of this vaccine and to submit an update to the RMP if there is a significant change to the benefits, harms or uncertainties associated with this vaccine. Updates to the RMP will be reflected in the Post-Authorization Activity Table for Spikevax Bivalent.

Based on the available data, the RMP included three important identified risks (anaphylaxis, myocarditis, and pericarditis) and two important potential risks (vaccine-associated enhanced disease [VAED] and VAERD). Nine areas of missing information (limited/no clinical data) were identified: “use during pregnancy”; “use while breastfeeding”; “use in immunocompromised subjects”; “use in patients with autoimmune or inflammatory disorders”; “use in frail subjects with unstable health conditions and comorbidities”; “interaction with other vaccines”; “long-term safety”; “long-term effectiveness”; and “use in the population less than 18 years of age”.

The proposed routine and additional pharmacovigilance activities for the risks listed above are considered to be acceptable. The sponsor confirmed that they would be applied in the Canadian context. Additional pharmacovigilance activities include continued safety surveillance of ongoing clinical trials undertaken for the original Spikevax vaccine, with the addition of Study P205, from which Parts F and G provide the main evidence of the clinical efficacy and safety of Spikevax Bivalent. Routine risk minimization measures (i.e., Product Monograph and labelling) are also considered to be appropriate.

The sponsor is expected to provide an updated Core European Union RMP and Canadian Addendum in a timely manner if a signal of a safety issue is identified in ongoing post-authorization surveillance. Specifically, through the submission of monthly safety reports to Health Canada, the sponsor will provide the following information for the sub-populations listed below in the post-market period:

  • Children: Children were not included in the clinical development program. This sub-population was identified as missing information in the Canadian Addendum.
  • Pregnant women: More information is needed about vaccine use in pregnant women. This sub-population was identified as missing information in the RMPs.
  • Breastfeeding women: This sub-population was identified as missing information in the RMPs.
  • Immunocompromised individuals and patients with chronic or debilitating conditions: These individuals were not included in the clinical development program. This sub-population was identified as missing information in the RMPs.
  • Anaphylaxis: This was identified as an important identified risk in the Canadian Addendum. This will be assessed via routine pharmacovigilance activities, and reported in monthly summary safety reports.
  • Vaccine-associated enhanced disease including VAERD: This was identified as an important potential risk in the RMPs. This will be assessed via routine pharmacovigilance activities, and reported in monthly summary safety reports.
  • Myocarditis and pericarditis: These were identified as important identified risks in the RMPs. These will be assessed via routine pharmacovigilance activities, and reported in monthly summary safety reports.

The sponsor will also provide prompt reporting of adverse reactions. The submission of the post-market safety summary reports have been adjusted to a monthly basis for enhanced monitoring of this expanded booster dose.

The sponsor is expected to provide an updated RMP to address any additional pharmacovigilance activities evaluating the long-term safety and effectiveness for Spikevax Bivalent. The sponsor is also expected to address any additional pharmacovigilance activities for pregnant women and breastfeeding women. The real world use of this vaccine will provide data related to use in the population less than 18 years of age, pregnant and breastfeeding women, immunocompromised patients, frail patients with comorbidities, patients with autoimmune or inflammatory disorders, interaction with other vaccines, long-term safety, and long-term effectiveness.

There are no significant outstanding issues requiring risk management beyond labelling or that warrant consideration in addition to the outstanding safety requirements outlined in the terms and conditions and in the RMP that would preclude the approval of this submission for Spikevax Bivalent.

Collectively, the results of the clinical safety evaluation demonstrated that Spikevax Bivalent met the vaccine safety requirements as specified in Health Canada's Guidance for Market Authorization Requirements for COVID-19 Vaccines. The vaccine was determined to be safe and well tolerated in subjects 18 years of age and older when administered as a booster dose according to the recommended dosage regimen. Study P205 is ongoing, and subjects continue to be followed for assessments of safety and efficacy of the vaccine. This authorization is accompanied by terms and conditions to manage uncertainties and mitigate risks related to the drug. Appropriate warnings and precautions are in place in the Spikevax Bivalent Product Monograph to address the identified risks.

For more information, refer to the Spikevax Bivalent Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

7.2 Non-Clinical Basis for Decision

The New Drug Submission (NDS) for Spikevax Bivalent (elasomeran, imelasomeran) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance (NOC) was issued in relation to Spikevax Bivalent, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug.

As described above, the review of the non-clinical component of the NDS for Spikevax Bivalent was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The Spikevax Bivalent vaccine is a dispersion of two messenger ribonucleic acid (mRNA) constructs. The first mRNA (mRNA-1273), which is also in the original Spikevax vaccine, encodes the prefusion-stabilized spike protein of the ancestral (Wuhan-1-like) strain of the SARS-CoV-2 virus. The second mRNA (mRNA-1273.529) encodes the prefusion-stabilized spike protein of the Omicron (B.1.1.529, BA.1 sublineage) variant. Combined, this bivalent platform is referred to as mRNA-1273.214.

The NDS included pharmacology and toxicology data obtained from the original Spikevax vaccine previously authorized by Health Canada. This is in line with the current scientific understanding that new vaccines using coronavirus disease 2019 (COVID-19) mRNA-based platform technologies can rely on existing toxicology data. In addition, the submission included new data from non-clinical studies involving either mRNA-1273.529 or mRNA-1273.214.

Using the same animal model in toxicology and biodistribution studies across platforms has allowed for the appropriate correlation of possible toxicity to the presence or absence of the mRNA platform that is being investigated. Non-clinical pharmacodynamic studies (immunogenicity and protection) conducted in mice and non-human primates demonstrated that the bivalent formulations induced a strong and broad cross-variant neutralizing antibody response when compared to monovalent formulations. These observations have been confirmed in clinical trials (see Clinical Efficacy section) and have supported further development of bivalent formulations containing mRNAs that encode spike protein sequences targeting the ancestral SARS-CoV-2 strain and circulating variants. Additional studies evaluating the stimulation of cross-reactive B cells in mice and non-human primates confirmed that bivalent formulations are more efficient in inducing a broad response across variants.

Updated information derived from a biodistribution study was consistent with data provided as part of the NDS for the original Spikevax vaccine. The study used an mRNA-modified (mRNA-1647) platform that was manufactured using the same procedure used for the original Spikevax vaccine. It was formulated with 100 mcg of mRNA in lipid nanoparticles (LNPs) which contain SM-102, a proprietary lipid component of both mRNA-1273 and mRNA-1273-variant platforms. In addition, results from two biodistribution studies using SM-102 suggest that Spikevax Bivalent, upon repeat intramuscular dosing in humans, is unlikely to result in accumulation of the lipid or present a long-term safety concern in subjects with impaired hepatic or renal functions.

Aggregate toxicology data was derived from six Good Laboratory Practice (GLP)-compliant repeat-dose toxicology studies conducted in Sprague-Dawley rats using five different mRNA-based vaccine programs formulated with SM-102-containing LNPs. Along with data from GLP and non-GLP rat repeat-dose toxicity studies using mRNA-1273 and genotoxicity assessments of SM-102, these data support the development of mRNA-1273 and mRNA-1273-variant vaccines, including the bivalent formulation.

To assess reproductive and developmental toxicology, a GLP-compliant study was conducted to assess the potential effects of mRNA-1273 on fertility and pre- and postnatal development in pregnant and lactating female Sprague Dawley rats. Administration of a 100 mcg dose of mRNA-1273 did not result in any adverse effects on the parental (F0) and first filial (F1) generations. A small increase in the common, non-adverse malformation of wavy ribs/nodules was observed in mRNA-1273-treated animals at this dose. Maternal-to-fetal and maternal-to-pup transfer of SARS-CoV-2 spike antibodies was observed in mRNA-1273-treated animals.

In conclusion, no new safety concerns were raised with Spikevax Bivalent in the non-clinical pharmacology studies. The new data reviewed in this submission, along with the aggregate non-clinical data that were filed and evaluated as part of the original Spikevax NDS, were considered sufficient to characterize and support the use of Spikevax Bivalent in the clinical development program.

No evidence of a link between Spikevax Bivalent and vaccine-associated enhanced respiratory disease or other harms have been identified. Adding to the previous information which led to the authorization of the original Spikevax vaccine, these aggregate data further demonstrate that no new safety concerns are expected with the use of the bivalent mRNA-based platform in addition to the already characterized safety concerns.

Overall, the non-clinical pharmacology and toxicology profile of Spikevax Bivalent supports its proposed clinical use. The results of the non-clinical studies as well as the potential risks to humans have been included in the Spikevax Bivalent Product Monograph. Considering the intended use of Spikevax Bivalent, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Spikevax Bivalent Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

7.3 Quality Basis for Decision

The New Drug Submission (NDS) for Spikevax Bivalent (elasomeran, imelasomeran) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance (NOC) was issued in relation to Spikevax Bivalent, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug.

As described above, the review of the quality component of the NDS for Spikevax Bivalent was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The Spikevax Bivalent vaccine is a prophylactic vaccine developed to prevent coronavirus disease 2019 (COVID-19) caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The vaccine is a dispersion of two messenger ribonucleic acid (mRNA) constructs which encode the prefusion-stabilized spike protein of the ancestral (Wuhan-1-like) strain and the Omicron (B.1.1.529, BA.1 sublineage) variant of SARS-CoV-2. The mRNAs are encapsulated in lipid nanoparticles (LNPs) to provide protection against degradation and to mediate delivery of the mRNAs into the host’s cells.

Characterization of the Drug Substance

The Spikevax Bivalent vaccine is a dispersion of two constituent mRNA drug substances, elasomeran (mRNA-1273) and imelasomeran (mRNA-1273.529). Both drug substances are single-stranded, 5'-capped mRNAs that encode the prefusion stabilized spike glycoproteins of SARS-CoV-2 of the ancestral (Wuhan-1-like) strain and the Omicron BA.1 variant, respectively. The resulting spike glycoproteins are full-length transmembrane proteins with two point modifications, leading to antigenically stable prefusion conformations. These conformations improve the stimulation neutralizing antibody production against SARS-CoV-2.

Both mRNA drug substances are encapsulated in SM-102 LNPs to produce two monovalent LNP intermediates (mRNA-1273 LNP and mRNA-1273.529 LNP, respectively). The LNPs consist of four distinct lipid types (SM-102; PEG2000-DMG; 1,2-distearoyl-sn-glycero-3-phosphocholine; and cholesterol), each with a specific purpose.

The Spikevax Bivalent vaccine utilizes a platform approach to new variant LNPs, which builds on the sponsor’s experience with the original monovalent Spikevax vaccine. Originally developed for pediatric populations and later approved as a booster dose formulation, it contains a lower-dose (0.10 mg/mL) mRNA representation and an optimal LNP composition based on an extensive evaluation of alternative lipids with biodegradable and mRNA delivery properties.

Detailed characterization studies were performed to provide assurance that both drug substances and LNPs consistently exhibit the desired characteristic structures and biological activities.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

The pharmaceutical development of the Spikevax Bivalent vaccine is based on platform knowledge from the sponsor’s original monovalent Spikevax vaccine (previously approved), principles described in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines (Q8), and sound scientific knowledge and prior experience with the development of mRNA-lipid nanoparticle vaccines.

The Spikevax Bivalent drug substances, elasomeran and imelasomeran, are manufactured separately using in vitro transcription reactions. The resulting mRNAs are then mixed with SM-102 LNP to produce two monovalent LNP intermediates, elasomeran mRNA-LNP (mRNA-1273 LNP) and imelasomeran mRNA-LNP (mRNA-1273.529 LNP). Each mRNA-LNP intermediate is then buffered, filtered, and frozen between -60 ºC and -90 ºC.

The Spikevax Bivalent drug product is a dispersion for intramuscular injection, supplied in a multi-dose vial (5 doses per vial) at a concentration of 0.10 mg/mL.

The manufacture of the drug product involves the thawing of each mRNA-LNP intermediate complex followed by pooling, filtration, and dilution to a target drug substance concentration. Next, the two mRNA-LNPs are mixed together in a 1:1 ratio by weight and diluted to a target concentration of 0.10 mg/mL. The diluted drug product solution is sterile filtered, aseptically filled into vials, stoppered and capped, visually inspected, labelled, and then frozen and stored between -50 ºC and -15 ºC.

The inclusion of a second mRNA in the Spikevax Bivalent drug product requires updates to the manufacturing and control strategies that were in place for the original monovalent Spikevax vaccine. Changes made throughout development are considered acceptable upon review and were informed by the sponsor’s cumulative manufacturing history with the original monovalent Spikevax vaccine and information gained from the development of the sponsor’s platform approach to new variant LNPs.

The method of manufacturing and the controls used during the manufacturing process for both the drug substances and the drug product are validated and considered to be adequately controlled within justified limits. The lot release tests for the drug substances and drug product are appropriately validated/qualified and are based on scientifically relevant assays and appropriate specifications to monitor key quality attributes. The sponsor provided enough information to support the consistency of production. This information, together with additional characterization studies and the experience of the sponsor with the original monovalent Spikevax vaccine, is sufficient to support issuance of an NOC. Terms and conditions relating to the manufacturing process and process controls have been put in place.

Control of the Drug Substance and Drug Product

The drug substances are tested against suitable reference standards to verify that they meet approved specifications, and analytical procedures are validated and in compliance with ICH guidelines. A platform approach to validation was found to be sufficient based on its similarity to the original monovalent Spikevax vaccine. Supportive release and extended characterization data for the second mRNA (imelasomeran) drug substance batches confirm that minor changes to the mRNA sequence do not affect process performance or drug substance quality.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final drug product lots are tested using a subset of release methods. However, validation of the drug product manufacturing process is ongoing, as final labelling of the drug product has not yet taken place. As a result, final identity and purity testing of the drug product lots is pending and will be complete once final testing/release has taken place. This information will be provided, once available, through requirements outlined in the terms and conditions imposed on the NOC.

Spikevax Bivalent is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the available stability data submitted, the proposed shelf life and storage conditions for the elasomeran and imelasomeran drug substances support the proposed shelf life of 36 months at -90 °C to -60 °C.

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug product support the proposed shelf life of 9 months when stored at -50 °C to -15 °C protected from light, including up to 30 days of storage at 2 °C to 8 °C. On the day of dose administration, the product is allowed an additional in-use time of up to 24 hours at 8 °C to 25 °C. The Spikevax Bivalent vaccine is preservative-free. Once the vial has been needle-punctured, it can be stored at room temperature or refrigerated, but must be discarded after 24 hours.

The stability profiles were extrapolated from data for commercial-scale original monovalent Spikevax drug substance and drug product batches, and development and clinical trial batches for the Spikevax Bivalent drug substance and drug product. The aggregate data demonstrate that the stability profiles of the drug substance and drug product are highly similar, regardless of the sequence of the mRNA drug substance used. Stability studies for Spikevax Bivalent drug substance and drug product are ongoing, and updates will be required under terms and conditions imposed on the NOC to further support the stability assessments.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

Expedited submission review timeframes under the NDS for a designated COVID-19 drug prevented Health Canada from conducting on-site evaluations (OSEs) of the drug substance and drug product manufacturing facilities. However, all but one of the facilities have been previously authorized by Health Canada for the manufacture and testing of the original monovalent Spikevax vaccine. The one new drug product manufacturing site is a Health Canada-accredited facility with a Canadian Establishment License and has high-quality manufacturing standards. Additionally, successful OSEs have been recently performed on two of the facilities involved in the production of the Spikevax Bivalent drug substances.

Adventitious Agents Safety Evaluation

The drug substance manufacturing processes incorporate adequate control measures to prevent contamination and maintain microbial control.

There are no materials of animal or human origin used in the production of this vaccine. Therefore, control measures to reduce the potential risk of viral contaminants of animal or human origin are not necessary.