Summary Basis of Decision (SBD) for Comirnaty Omicron XBB.1.5

Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Comirnaty Omicron XBB.1.5 is located below.

Recent Activity for Comirnaty Omicron XBB.1.5

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

The following table describes post-authorization activity for Comirnaty Omicron XBB.1.5, a product which contains the medicinal ingredient raxtozinameran. 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 Management of Drug Submissions and Applications Guidance.

Updated: 2023-11-22

Drug Identification Number (DIN):

  • DIN 02541823 – 30 mcg/0.3 mL raxtozinameran, suspension, intramuscular administration

  • DIN 02541831 - 10 mcg/0.2 mL raxtozinameran, suspension, intramuscular administration

  • DIN 02541858 - 10 mcg/0.3 mL raxtozinameran, suspension, intramuscular administration

  • DIN 02541866 - 3 mcg/0.2 mL raxtozinameran, suspension, intramuscular administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

Drug product (DIN 02541866) market notification

Not applicable

Date of first sale: 2023‑10‑24

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

Drug product (DIN 02541858) market notification Not applicable Date of first sale: 2023‑10‑23 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

Drug product (DIN 02541823) market notification

Not applicable

Date of first sale: 2023‑10‑10

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

NDS # 276302

2023-06-29

Issued NOC (subject to terms and conditions) 2023-09-28

NOC issued for the New Drug Submission. Terms and conditions were imposed on the authorization.

Summary Basis of Decision (SBD) for Comirnaty Omicron XBB.1.5

Date SBD issued: 2023-11-22

The following information relates to the New Drug Submission for Comirnaty Omicron XBB.1.5.

Raxtozinameran

Drug Identification Number (DIN):

  • DIN 02541823 - 30 mcg/0.3 mL raxtozinameran, suspension, intramuscular administration

  • DIN 02541831 - 10 mcg/0.2 mL raxtozinameran, suspension, intramuscular administration

  • DIN 02541858 - 10 mcg/0.3 mL raxtozinameran, suspension, intramuscular administration

  • DIN 02541866 - 3 mcg/0.2 mL raxtozinameran, suspension, intramuscular administration

BioNTech Manufacturing GmbH

New Drug Submission Control Number: 276302

Submission Type: New Drug Submission (New Active Substance) (COVID-19)

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): J07 Vaccines

Date Filed: 2023-06-29

Authorization Date: 2023-09-28

On September 28, 2023, Health Canada issued a Notice of Compliance (NOC), subject to terms and conditions, to BioNTech Manufacturing GmbH for Comirnaty Omicron XBB.1.5.

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 Comirnaty Omicron XBB.1.5 is favourable for active immunization against COVID‑19 caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) in individuals 6 months of age and older.

Comirnaty Omicron XBB.1.5 is authorized in accordance with the Food and Drug Regulations, subject to terms and conditions that need to be met by the sponsor (described in the What follow-up measures will the company take? section). 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?

Comirnaty Omicron XBB.1.5 (coronavirus disease 2019 [COVID-19] messenger ribonucleic acid [mRNA] vaccine, monovalent [Omicron XBB.1.5]) was authorized for active immunization against COVID‑19 caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) in individuals 6 months of age and older.

The safety and effectiveness of Comirnaty Omicron XBB.1.5 for individuals 6 months of age and older are inferred from studies which evaluated the primary series and booster vaccination with the original Comirnaty vaccine and supported by studies which evaluated a booster dose of Comirnaty Original & Omicron BA.4/BA.5 in individuals 6 months of age and older.

The safety and efficacy of Comirnaty Omicron XBB.1.5 in children under 6 months of age have not yet been established.

Clinical studies using the original Comirnaty vaccine and Comirnaty Original & Omicron BA.4/BA.5 included participants 65 years of age and older and their data contributes to the overall assessment of the safety and efficacy of Comirnaty Omicron XBB.1.5. The safety and efficacy of Comirnaty Omicron XBB.1.5 in geriatric individuals have not yet been established in clinical studies.

Comirnaty Omicron XBB.1.5 (30 mcg/0.3 mL, 10 mcg/0.2 mL, 10 mcg/0.3 mL, and 3 mcg/0.2 mL raxtozinameran) is presented as a suspension. In addition to the medicinal ingredient, the suspension contains the following non-medicinal ingredients: ((4‑hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) (also known as ALC‑0315), 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide (also known as ALC‑0159), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine (also known as DSPC), sodium chloride, sucrose, tromethamine, tromethamine hydrochloride, and water for injection. Sodium chloride is not present in Comirnaty Omicron XBB.1.5 for patients 12 years of age and older (gray cap and gray label border) and for patients 5 years to less than 12 years of age (blue cap and blue label border).

The use of Comirnaty Omicron XBB.1.5 is contraindicated in individuals who are hypersensitive to the active substance or to any ingredient in the formulation.

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 Comirnaty Omicron XBB.1.5 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 Comirnaty Omicron XBB.1.5 approved?

Health Canada considers that the benefit-risk profile of Comirnaty Omicron XBB.1.5 is favourable for the active immunization against coronavirus disease 2019 (COVID‑19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) in individuals 6 months of age and older.

The safety and effectiveness of Comirnaty Omicron XBB.1.5 for individuals 6 months of age and older are inferred from studies which evaluated the primary series and booster vaccination with the original Comirnaty vaccine and supported by studies which evaluated a booster dose of Comirnaty Original & Omicron BA.4/BA.5 in individuals 6 months of age and older.

Comirnaty Omicron XBB.1.5 is authorized in accordance with the Food and Drug Regulations, subject to terms and conditions that need to be met by the sponsor (described in the What follow-up measures will the company take? section).

Coronavirus disease 2019 is the infectious disease caused by 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, as of September 23, 2023, there were 4,739,791 confirmed cases of COVID‑19 and approximately 54,012 deaths.

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.

All countries continue to be impacted by the SARS-CoV-2 virus and are currently in a state of transition from managing the COVID-19 pandemic to mitigating the risk of a respiratory virus of ongoing public health concern. Furthermore, the emergence of SARS-CoV-2 variants continues to pose a 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.

To date, 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)CovishieldJcovden (previously Janssen COVID-19 Vaccine)NuvaxovidCovifenzSpikevax BivalentComirnaty Original & Omicron BA.4/BA.5, Comirnaty Original/Omicron BA.1, Spikevax Bivalent Original / Omicron BA.4/5, and Spikevax XBB.1.5.

The emergence of immune‑evasive Omicron sub‑lineages has caused global seroprevalence rates to rise considerably. Current seroprevalence surveys suggest that most Canadians 5 years of age and older have some level of immunity against SARS‑CoV‑2 via vaccination and/or prior infection. Individuals with hybrid immunity (immune protection from both infection and vaccination) have the highest magnitude and durability of protection against all outcomes, regardless of age, when compared to individuals with a previous infection only or vaccination only. Current data also suggest that vaccination among individuals with prior infection provides the greatest protection against severe outcomes.

To best respond to the evolution of COVID‑19, periodic updates to vaccine formulations are needed to adequately match the epidemiological context and meet current medical needs. At the time of submission, the Omicron XBB sublineages accounted for the majority of COVID‑19 cases in Canada and globally. These sublineages are antigenically distant from prior circulating SARS-CoV-2 lineages, including Omicron BA.4/BA.5 and the ancestral SARS-CoV-2 strain and have shown increased transmissibility and immune escape to past infections and/or vaccination. Notably, XBB is poorly neutralised by plasma from recipients of the BA.5 bivalent messenger ribonucleic acid (mRNA) vaccine. In response to the emergence of the immune‑evasive Omicron sublineages, the World Health Organization (WHO) and the WHO‑Strategic Advisory Group of Experts in Immunization advised that the composition of future COVID‑19 vaccines be based on strains more genetically and antigenically close to the circulating SARS‑CoV‑2 variants of concern. The WHO Technical Advisory Group on COVID‑19 Vaccine Composition further recommends the removal of the ancestral Wuhan strain and the inclusion of XBB descendent lineages in a monovalent vaccine formulation, and regulators in many countries have agreed. To that aim, the monovalent Comirnaty Omicron XBB.1.5 was developed to closely match the ongoing circulating variant, XBB.

Comirnaty Omicron XBB.1.5 contains mRNA with a genetic sequence that encodes for the viral spike protein of the SARS‑CoV‑2 Omicron subvariant lineage XBB.1.5. The mRNA is formulated in lipid nanoparticles, which enable delivery of the RNA into host cells to allow expression of the SARS-CoV-2 spike antigen. The vaccine elicits both neutralizing antibody and cellular immune responses to the spike antigen, which may contribute to protection against COVID-19 disease.

No data were submitted from clinical studies using Comirnaty Omicron XBB.1.5, however, clinical studies with Comirnaty Omicron XBB.1.5 in the age brackets associated with the indication were ongoing at the time of authorization. The outcomes of these clinical studies have been requested as part of the imposed terms and conditions. The authorization of Comirnaty Omicron XBB.1.5 was largely supported by data from the authorized original Comirnaty vaccine, Comirnaty Original & Omicron BA.4/BA.5, and Comirnaty Original/Omicron BA.1. The safety and effectiveness of Comirnaty Omicron XBB.1.5 were extrapolated from the following data, taking into consideration the current epidemiological context:

  • safety and effectiveness data accrued from the use of the original Comirnaty vaccine administered as a two-dose primary series and as booster doses in individuals 5 years of age and older and as a three-dose primary series in individuals 6 months to less than 5 years of age;

  • the extrapolation of safety data for participants 5 to less than 12 years of age in Group 2 – Substudy D of Study C4591048 following the administration of Comirnaty Original & Omicron BA.4/BA.5 vaccine (10 mcg) as a booster (fourth dose);

  • preliminary immunogenicity and safety data from participants in Cohort 2 (12 years of age and older) and Cohort 3 (18 years of age and older) of Study C4591044 following administration of Comirnaty Original & Omicron BA.4/BA.5 (30 or 60 mcg) as a booster (fourth dose);

  • preliminary immunogenicity and safety data for a subset of participants 6 months to less than 5 years of age in Group 2 – Substudy B of Study C4591048 following administration of Comirnaty Original & Omicron BA.4/BA.5 (3 mcg) as a booster (fourth dose);

  • estimates of current seroprevalence rates; and

  • non-clinical data.

Immunogenicity data accrued with the original Comirnaty vaccine together with preliminary data accrued with the bivalent formulations encoding previously circulating variants of concern, particularly Comirnaty Original & Omicron BA.4/BA.5, administered as booster doses, suggest that Comirnaty Omicron XBB.1.5 will induce neutralizing antibodies against the currently circulating Omicron sublineages. Furthermore, through analogy, it is expected that this updated formulation will induce superior antibody responses to the Omicron XBB.1.5 virus and non-inferior responses to the reference strain when compared to the previously approved formulations. Comirnaty Omicron XBB.1.5 is also expected to provide a broader antibody response against circulating and emerging variants, while retaining cross-reactive immunity and cross-protection from severe illness caused by the reference strain and other variants. Information on the design and results of the studies carried out in the indicated age ranges are described in the Clinical Efficacy section.

Overall, safety data accrued with the original Comirnaty vaccine, Comirnaty Original & Omicron BA.1, and Comirnaty Original & Omicron BA.4/BA.5 (primary series or booster doses) suggest that the safety profiles are comparable dose per dose and vaccination scheme per vaccination scheme. By extension, it is anticipated that the safety profile of Comirnaty Omicron XBB.1.5 will be no different from that of the previously-approved formulations encoding for variants of concern.

The inference of clinical data is in line with the current clinical considerations for COVID-19 mRNA-based formulations which incorporate the addition of a change to the coding sequence related to the new variant of concern (Omicron XBB.1.5) to the current sequence (reference strain). No new safety concerns were identified in studies using Comirnaty Original & Omicron BA.1 and Comirnaty Original & Omicron BA.4/BA.5 when compared to the original Comirnaty vaccine. No deaths or adverse events of special interest including cases of myocarditis or pericarditis occurred. It should be noted that the safety profile of the original Comirnaty vaccine and Comirnaty Original & Omicron BA.4/BA.5 is well characterized in the post-market setting. Based on these safety profiles it is anticipated that the safety of Comirnaty Omicron XBB.1.5 will bear no differences to these formulations. Appropriate warnings and precautions are in place in the Comirnaty Omicron XBB.1.5 Product Monograph to address the identified safety concerns.

An updated core European Union (EU) Risk Management Plan (RMP) and a Canadian Addendum for Comirnaty Omicron XBB.1.5 were submitted by BioNTech Manufacturing GmbH 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.

While clinical data for Comirnaty Omicron XBB.1.5 were not available at the time of authorization, based on the extrapolation of clinical and post-market safety data for the original Comirnaty vaccine, Comirnaty Original/Omicron BA.1, and Comirnaty Original & Omicron BA.4/BA.5 to date, the RMP adequately captured the known and potential risks of this vaccine. The RMP for Comirnaty Omicron XBB.1.5 includes three important identified risks (anaphylaxis, myocarditis, and pericarditis). The RMP also identified eight areas of missing information (limited/no clinical data): "use in pregnancy and while breastfeeding", "use in immunocompromised patients", "use in frail patients with comorbidities", "use in patients with autoimmune or inflammatory disorders", "interaction with other vaccines", "long-term safety", "vaccine effectiveness", and "use in pediatric individuals less than 6 months of age". An important limitation of the data for all approved age groups continues to be the long‑term safety and effectiveness of the vaccine. This limitation is managed through labelling and the RMP.

Overall, the RMP was considered to be acceptable and identified appropriate monitoring (pharmacovigilance) activities and risk minimization measures for Comirnaty Omicron XBB.1.5 based on the known safety profiles of the original Comirnaty vaccine, Comirnaty Original/Omicron BA.1, and Comirnaty Original & Omicron BA.4/BA.5. This included providing information in the Comirnaty Omicron XBB.1.5 Product Monograph and identifying populations where more data are needed. Additional pharmacovigilance activities include continued safety surveillance using data collected from ongoing clinical and post-authorization studies undertaken for the currently authorized Comirnaty vaccines and the addition of two clinical studies (studies C4591048 and C4591054) evaluating the safety of Comirnaty Omicron XBB.1.5 vaccine in healthy individuals 12 years and older, and 6 months to less than 5 years of age. Two additional post-market studies are planned to evaluate the real-world effectiveness of the vaccine. The RMP will be updated to reflect additional safety information as this is collected.

Terms and conditions have been imposed for the submission of Periodic Safety Update Reports/Periodic Benefit Risk Evaluation Reports and RMPs to Health Canada, in addition to regulatory requirements for post-market monitoring. The RMP will be updated to reflect additional safety information, including that which is relevant in a Canadian‑specific context, as it becomes available. 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.

Comirnaty Omicron XBB.1.5 has been shown to have a favourable benefit-risk profile and an acceptable safety profile based on the non-clinical data and clinical studies conducted with the original Comirnaty vaccine, Comirnaty Original & Omicron BA.4/BA.5, and Comirnaty Original/Omicron BA.1. Collectively, the results of the clinical efficacy and safety evaluation demonstrated that Comirnaty Omicron XBB.1.5 met the requirements as specified in Health Canada's Guidance for Market Authorization Requirements for COVID‑19 Vaccines. The vaccine is expected to have the same profile as the currently authorized Comirnaty formulations in the indicated population when administered according to the recommended dosage regimen. Notably, studies C4591048 and C4591054 are 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, as part of the terms and conditions.

At the time of authorization, important limitations of the data included limited information on the long-term safety and effectiveness of the vaccine, including in sub-populations (e.g., pregnant or breastfeeding women, immunosuppressed patients, and children under 6 months of age). These limitations are considered to be adequately managed through labelling, terms and conditions associated with the authorization of Comirnaty Omicron XBB.1.5, the RMP, and adequate monitoring. Appropriate warnings and precautions are in place in the Comirnaty Omicron XBB.1.5 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 a Notice of Compliance (NOC) pursuant to section C.08.004 of the Food and Drug Regulations. The NOC in respect of Comirnaty Omicron XBB.1.5 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 Comirnaty Omicron XBB.1.5?

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 Comirnaty Omicron XBB.1.5 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 Comirnaty Omicron XBB.1.5, with imposed terms and conditions (described in the What follow-up measures will the company take? section), on September 28, 2023.

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: Comirnaty Omicron XBB.1.5

Submission Milestone

Date

Pre-submission meeting

2023-06-09

Initial New Drug Submission filed by sponsor

2023-06-29

Initial non-clinical data submitted by sponsor

2023-06-29

Initial clinical data submitted by sponsor

2023-06-29

Screening Acceptance Letter issued

2023-07-21

Initial quality data submitted by sponsor

2023-07-28

Risk Management Plan submitted by sponsor

2023-07-28

Health Canada quality evaluation completed

2023-09-13

Final Product Monograph (English) submitted by sponsor

2023-09-14

Final Product Monograph (French) submitted by sponsor

2023-09-18

Health Canada non-clinical evaluation completed

2023-09-18

Health Canada clinical/medical evaluation completed

2023-09-18

Health Canada labelling evaluation completed

2023-09-20

Health Canada Risk Management Plan evaluation completed

2023-09-25

Terms and conditions finalized by Health Canada

2023-09-28

Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate

2023-09-28

4 What follow-up measures will the company take?

The Notice of Compliance issued in respect of Comirnaty Omicron XBB.1.5 (raxtozinameran) is accompanied by terms and conditions imposed on the drug identification numbers assigned to Comirnaty Omicron XBB.1.5 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, 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:

  • Interim analyses of the immunogenicity and safety data at 1 month from Study C4591048 – Substudy A, Phase I.

  • Interim analyses of the immunogenicity and safety data at 1 month from Study C4591048 – Substudy A, Phase II/III.

  • Interim analyses at of the safety data at 6 months from Study C4591048 – Substudy A, Phase I.

  • Final analyses of the safety data at 6 months from Study C4591048 – Substudy A, Phase II/III.

  • Interim analyses of the safety and immunogenicity data at 1 month from Study C4591048 – Substudy E.

  • Final analyses of the safety data at 6 months from Study C4591048 – Substudy E.

  • Interim analyses of the immunogenicity and safety data at 1 month from Study C4591054 – Substudy A.

  • Final analyses of the safety and immunogenicity data at 6 months from Study C4591054 – Substudy A.

  • Interim analyses of the immunogenicity and safety data at 1 month from Study C4591054 – Substudy B.

  • Final analyses of the safety and immunogenicity data at 6 months from Study C4591054 – Substudy B.

Additionally, the sponsor is required to:

  • Submit Periodic Safety Update Reports/Periodic Benefit Risk Evaluation Reports every 6 months for Comirnaty Omicron XBB.1.5, unless otherwise determined by Health Canada.

  • Submit an updated core Risk Management Plan (RMP) with the Canadian Addendum in a timely manner as requested by Health Canada.

  • Provide a summary of the changes made to the website for Health Canada’s review with each update.

  • Develop and distribute a company-led customer communication, in English and French, should a decision be made to import non-Canadian labelled supplies for Canadian sites.

  • Develop Canadian‑specific bilingual labelling for Comirnaty Omicron XBB.1.5 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.

5 What post-authorization activity has taken place for Comirnaty Omicron XBB.1.5?

Summary Basis of Decision documents (SBDs) for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (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. The PAAT will continue to be updated during the product life cycle.

The PAAT for Comirnaty Omicron XBB.1.5 is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

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 for Comirnaty Omicron XBB.1.5 (raxtozinameran) 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 was issued in relation to Comirnaty Omicron XBB.1.5, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug (described in the What follow-up measures will the company take? section).

The World Health Organization (WHO) and the WHO Strategic Advisory Group of Experts on Immunization advise that the composition of current and future vaccines for coronavirus disease 2019 (COVID‑19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) be based on strains that are genetically and antigenically close to circulating SARS‑CoV‑2 variants. In the interim, the Technical Advisory Group on COVID‑19 Vaccine Composition encourages COVID‑19 vaccine manufacturers to generate and provide data on the performance of current and Omicron‑specific COVID‑19 vaccines, including the breadth, magnitude, and durability of humoral and cell mediated immune responses to variants through monovalent and/or multivalent vaccines. It is anticipated that the safety, reactogenicity, and immunogenicity of the updated vaccine composition will be comparable to those of the currently authorized vaccines based on the index virus. To that aim, Comirnaty Omicron XBB.1.5 is a monovalent vaccine containing messenger ribonucleic acid (mRNA) that encodes for the viral spike protein of the SARS-CoV-2 Omicron variant lineage XBB.1.5. Comirnaty Omicron XBB.1.5 vaccine is manufactured by the same process as the currently authorized (original) Comirnaty vaccine, Comirnaty Original & Omicron BA.4/BA.5, and Comirnaty Original/Omicron BA.1 vaccines.

Clinical Pharmacology

Comirnaty Omicron XBB.1.5 contains the medicinal ingredient raxtozinameran, which is an mRNA construct. The mRNA in Comirnaty Omicron XBB.1.5 encodes for the viral spike protein of SARS-CoV-2 Omicron variant lineage XBB.1.5. The mRNA is formulated in lipid nanoparticles, which enable delivery of the RNA into host cells to allow expression of the SARS-CoV-2 spike antigen. The vaccine elicits both neutralizing antibody and cellular immune responses to the spike antigen, which may contribute to protection against COVID-19 disease.

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

Immunogenicity was assessed as part of the clinical efficacy evaluation of Comirnaty Omicron XBB.1.5.

No drug interaction studies have been performed with Comirnaty Omicron XBB.1.5. At the time of authorization, there was no information on the co-administration of Comirnaty Omicron XBB.1.5 with other vaccines.

For further details, please refer to the Comirnaty Omicron XBB.1.5 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

No data were submitted from clinical studies with Comirnaty Omicron XBB.1.5, as they were ongoing at the time of authorization. The outcomes of these studies have been requested as terms and conditions imposed. The authorization of Comirnaty Omicron XBB.1.5 was largely supported by clinical data from the authorized original Comirnaty vaccine, Comirnaty Original & Omicron BA.4/BA.5, and Comirnaty Original/Omicron BA.1.

The effectiveness of Comirnaty Omicron XBB.1.5 was evaluated based on the following considerations taken within the current epidemiological landscape of SARS-CoV-2 variants of concern in Canada and globally:

  • clinical immunogenicity data accrued from the use of the original Comirnaty vaccine administered as a two-dose primary series and as booster doses in individuals 5 years of age and older and as a three-dose primary series in individuals 6 months to less than 5 years of age;

  • supportive preliminary immunogenicity data from Study C4591044, Cohort 2 (participants 12 years of age and older) and Cohort 3 (participants 18 years of age and older) following administration of Comirnaty Original & Omicron BA.4/BA.5 (30 or 60 mcg) as a booster (fourth dose);

  • supportive preliminary immunogenicity data from Substudy B of Study C4591048 (a subset of participants 6 months to less than 5 years of age in Group 2) following administration of Comirnaty Original & Omicron BA.4/BA.5 (3 mcg) as a booster (fourth dose);

  • estimates of current seroprevalence rates; and

  • non-clinical data.

Immunogenicity

The Original Comirnaty Vaccine

The immunogenicity of the primary series and booster doses of the original Comirnaty vaccine has been extensively characterized in several clinical studies conducted globally. These data were previously supplied to Health Canada to support the authorization of the original Comirnaty vaccine as a two-dose primary series and as a booster dose for individuals aged 5 and older, as well as a three-dose primary series in individuals 6 months to less than 5 years of age.

Primary Series Individuals 16 years of age and older

The original Comirnaty vaccine was first authorized for individuals over the age of 16 years based on data from the pivotal Study C4591001. This randomized, international, placebo‑controlled, observer‑blind study was conducted in healthy individuals. Phase III of the study included 43,651 participants 12 years of age and older. Although participants 12 to 15 years of age were enrolled in Phase III, the data included in the final efficacy analysis provided with the initial submission were from participants 16 years of age and older only.

The authorization of the original Comirnaty vaccine was also supported by immunogenicity data from Part A of the first‑in‑human study (Study BNT162‑01), and in Phase II of the pivotal study (Study C4591001). For more information on the designs of these studies and their results, refer to the Summary Basis of Decision for the original Comirnaty vaccine.

Primary Series Individuals 12 to 15 years of age and older

An updated analysis of Phase III of the pivotal Study C4591001 provided supportive safety and efficacy data for the original Comirnaty vaccine in individuals 12 to 15 years of age. This data also provided follow-up safety information in adults 16 to 55 years old collected up to 6 months after Dose 2. For more information on the design and results of this study, refer to the Regulatory Decision Summary for the expansion of the indication for the original Comirnaty vaccine in individuals 12 to 15 years of age.

Booster Dose Individuals 18 years of age and older

Immune response and safety were evaluated in a subset of participants in Study C4591001 who were 18 to 55 years of age. These participants had received a booster dose of the original Comirnaty vaccine (30 mcg) approximately 6 months after the second dose of the primary series of the original Comirnaty vaccine. An assessment was conducted in participants who had no evidence of past SARS-CoV-2 infection up to 1 month after the booster vaccination to compare the non-inferiority of immune responses 1 month after a booster dose with the original Comirnaty vaccine compared to 1 month after completion of the primary two-dose series. For more information on the design and results of this study, refer to the Regulatory Decision Summary for the use of the original Comirnaty vaccine as a booster dose.

Primary Series Individuals 5 to less than 12 years of age

Immunogenicity was evaluated in vaccinated children (5 to less than 12 years of age; 10 mcg dose) in a subset of Study C4591007 and compared to the vaccinated young adult population (16 to 25 years; 30 mcg dose) from Study C4591001, in which vaccine efficacy has been demonstrated.

An analysis provided supplemental evidence of vaccine efficacy in children 5 to less than 12 years of age. For more information on the design and results of this study, refer to the Regulatory Decision Summary for the expansion of the indication for the original Comirnaty vaccine to children 5 to less than 12 years of age.

Booster Dose Individuals 16 and 17 years of age

Data from studies C4591031 and C4591001 (previously submitted) provided support for the use of a single booster dose of the original Comirnaty vaccine in individuals 16 and 17 years of age, at least six months following completion of the primary two-dose series.

Study C4591031 was a randomized, placebo-controlled, observer-blind Phase III study to evaluate the safety and efficacy of a booster dose of the original Comirnaty vaccine in participants 16 years of age and older.

For more information on the design and results of these studies, refer to the Regulatory Decision Summary for the expansion of the indication for the original Comirnaty vaccine as a single booster dose in individuals 16 to 17 years of age.

Booster Dose Individuals 5 to less than 12 years of age

Immune response was evaluated in a subset of children 5 to less than 12 years of age from Study C4591007. These participants received a booster dose of 10 mcg of the original Comirnaty vaccine approximately 6 months after the second dose of the primary series. Immune response 1 month after the booster dose was compared to that 1 month after completion of the primary two-dose series in participants who had no evidence of past SARS-CoV-2 infection up to 1 month after the booster vaccination. For more information on the design and results of these studies, refer to the Regulatory Decision Summary for the expansion of the indication for the original Comirnaty vaccine as a booster dose in children 5 to less than 12 years of age.

Primary Series Individuals 6 months to less than 5 years of age

Immunogenicity data were generated in pediatric participants 6 months to 4 years of age as part of an international Phase II/III randomized, observer-blind and placebo-controlled study. Vaccine effectiveness was inferred by immunobridging, based on a comparison of immune responses for each age group (6 months to 2 years and 2 years to 4 years) to a young adult age group (16 to 25  years) for whom vaccine efficacy had previously been demonstrated. Immunobridging success criteria were met in each age group after Dose 3. For more information on the design and results of this studies, refer to the Regulatory Decision Summary for the expansion of the indication for the original Comirnaty vaccine as a primary series for children 6 months to less than 5 years of age.

Comirnaty Original & Omicron BA.4/BA.5

The safety and immunogenicity of Comirnaty Original & Omicron BA.4/BA.5 have been characterized in several clinical studies, and were also inferred using clinical data from the original Comirnaty vaccine and Comirnaty Original/Omicron BA.1. These data were previously provided to Health Canada to support the authorization of Comirnaty Original & Omicron BA.4/BA.5 as a two-dose primary series (in individuals 5 years of age and older) or as a three-dose primary series (in children 6 months to less than 5 years of age) and as a booster dose across several age groups.

Preliminary immunogenicity data was evaluated in individuals 12 years of age and older (Cohort 2) and 18 years of age and older (Cohort 3) from Study C4591044 following administration of Comirnaty Original & Omicron BA.4/BA.5 at 30 or 60 mcg as a booster (fourth dose). Additional preliminary immunogenicity data was also evaluated in a Substudy B of Study C4591048 in subset of individuals 6 months to less than 5 years of age following administration of Comirnaty Original & Omicron BA.4/BA.5 at 3 mcg as a booster (fourth dose).

For further details on the original authorization of Comirnaty Original & Omicron BA.4/BA.5 as a booster dose in individuals 12 years of age and older, refer to the Summary Basis of Decision. For information on subsequent authorizations, please refer to the following documents for Comirnaty Original & Omicron BA.4/BA.5:

Ongoing Clinical Studies with Comirnaty Omicron XBB.1.5

The immunogenicity of Comirnaty Omicron XBB.1.5 will be evaluated in the two ongoing studies (C4591048 and C4591054). The outcomes of these studies have been requested as terms and conditions associated with the authorization.

Study C4591048 Substudy A (Phase I) is designed to evaluate the safety, tolerability, and immunogenicity of a three-dose series of Comirnaty Original & Omicron BA.4/BA.5 followed by a fourth dose with Comirnaty XBB.1.5 (at 3, 6 or 10 mcg) in COVID-19 vaccine-naïve subjects 6 months through 5 years of age. The study protocol has also been amended such that Comirnaty Omicron XBB.1.5 will be used instead of Comirnaty Original/Omicron BA.4/BA.5 as follows:

  • Substudy A (Phase II/III):

    • assess a single dose of either a 6 mcg or 10 mcg dose in individuals 2 to less than 5 years of age with 6 months of safety follow-up after a single dose.

    • assess a two-dose primary series with either a 6 mcg or 10 mcg dose, separated by an increased interval of 8 weeks comparing to a three-dose primary series at 0, 3, and 11 weeks in individuals 6 months to less than 2 years of age, allowing for both potentially improved immunogenicity and a better fit with existing immunization schedules.

  • Substudy E:

    • evaluate immunogenicity and safety of a single dose of the age-appropriate authorized dose of Comirnaty Omicron XBB.1.5 in infants and children 2  to less than 12 years of age.

Comirnaty Omicron XBB.1.5 will also be evaluated in Study C4591054, a Phase II/III protocol designed to investigate the safety, tolerability, and immunogenicity of Comirnaty vaccine candidates for new SARS-CoV-2 variants in healthy individuals. This study will include two substudies:

  • Substudy A:

    • assess a single open-label 30 mcg dose of Comirnaty Omicron XBB.1.5 in subjects 12 through 55 years of age and greater than 55 years of age.

  • Substudy B:

    • assess the anti-XBB.1.5 immune responses elicited by a single dose 30 mcg of Comirnaty Omicron XBB.1.5 in subjects 12 years of age or older who have not been previously vaccinated with a COVID-19 vaccine and who were previously SARS-CoV-2 exposed.

Data outcomes from these substudies are required as terms and conditions associated with the authorization.

Summary of Immunogenicity

Immunogenicity data accrued with the original Comirnaty vaccine together with preliminary data accrued with the bivalent formulations, particularly Comirnaty Original & Omicron BA.4/BA.5, administered as booster doses, suggest that Comirnaty Omicron XBB.1.5 will induce neutralizing antibodies against the currently circulating Omicron sub-lineages. Furthermore, through analogy, it is expected that this updated formulation will induce superior antibody responses to the Omicron XBB.1.5 virus and non-inferior responses to the reference strain when compared to the previously approved formulations. Comirnaty Omicron XBB.1.5 is also expected to provide a broader antibody response against circulating and emerging variants, while retaining cross-reactive immunity and cross-protection from severe illness caused by the reference strain and other variants.

Estimates of Current Seroprevalence Rates

The emergence of immune-evasive Omicron sublineages has caused global seroprevalence rates to rise considerably. Current seroprevalence surveys suggest that most Canadians 5 years of age and older have some level of immunity against SARS‑CoV‑2 via vaccination and/or prior infection. Cumulative data comparing immune protection from a prior infection alone, vaccination alone, and hybrid immunity (immune protection from both vaccination and infection) suggests that individuals with hybrid immunity have the highest magnitude and durability of protection against all outcomes, including severe outcomes. Rapidly accumulating epidemiologic and immunogenetic evidence pertaining to hybrid protection against Omicron infection suggests that vaccination among individuals with prior heterologous SARS-CoV-2 infection provides the greatest protection against severe outcomes as a result of reinfection with Omicron sub-lineages. Given the ever-evolving epidemiological context, an updated vaccine composition that contains constructs encoding the spike protein for Omicron XBB sub-lineages (the most antigenically distinct SARS-CoV-2 variant of concern to date), may provide a broader antibody response against circulating and emerging variants, while retaining cross-protective immunity against severe disease. In this respect, Comirnaty Omicron XBB.1.5 incorporates the change to the coding sequence (Omicron sub-lineage, active substance) related to the new variant of concern, XBB.1.5.

Posology

Two studies (BNT162-17 and C4591001) provided an analysis of immunogenicity data from COVID-19 vaccine-naïve subjects 18 to less than 85 years of age with evidence of prior SARS-CoV-2 infection after a single 30 mcg dose of an investigational variant-modified bivalent Comirnaty (B.1.1.7 + B.1.617.2) formulation. These formulations encoded spike antigens for the Alpha and Delta SARS-CoV-2 variants.

Study BNT162-17 was a Phase II study designed to evaluate the safety and immunogenicity of multivalent and monovalent formulations of Comirnaty in healthy subjects 18 to 85 years of age.

Study C4591001 was a Phase I/II/III, placebo-controlled, randomized, observer-blind, dose-finding study to evaluate the safety, tolerability, immunogenicity, and efficacy of Comirnaty SARS-CoV-2 mRNA vaccine candidates against COVID-19 in healthy individuals. It included an evaluation of the safety and immunogenicity of the original Comirnaty vaccine in subjects 12 years of age and older.

Data from these two studies showed robust immune responses against the reference strain and the Alpha, Delta, and Omicron BA.5 variants. Notwithstanding the limitations of the cross-study comparisons, based on the variant neutralization results, a single dose of a more closely matched formulation in seropositive COVID-19 vaccine-naïve individuals should perform at least as well against the XBB-matched strain. Given the current seroprevalence rates in Canada, immunization with a single dose of Comirnaty Omicron XBB.1.5 is expected to lead to significant increases in serum neutralizing antibody responses and memory B-cell expansion against the Omicron XBB sub-lineages, as well as other emerging variants. Terms and conditions were imposed on the authorization to mitigate these limitations.

The approved dosing interval for Comirnaty Omicron XBB.1.5 reflects both the currently authorized dosing schedule for other Comirnaty formulations (both monovalent and bivalent) and the intervals used in previous and ongoing clinical studies for all formulations. Furthermore, since immune imprinting decreases sharply as a function of antigenic drift, concerns about immune imprinting from prior exposure and re-exposure to previous formulations remains a concern with shorter dosing intervals. Longer intervals are assumed to allow reimmunization with divergent viral glycoproteins, which produces de novo antibody responses targeting epitopes absent from the priming variant and offers a better chance of protection against the currently circulating variants. The approved dosing intervals are supported by the reviewed clinical evidence within the context of the current seroprevalence rates.

Indication

The New Drug Submission for Comirnaty Omicron XBB.1.5 was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Comirnaty Omicron XBB.1.5 (COVID-19 mRNA Vaccine, Monovalent [Omicron XBB.1.5]) is indicated for active immunization against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) in individuals 6 months of age and older.

The safety and effectiveness of Comirnaty Omicron XBB.1.5 for individuals 6 months of age and older are inferred from studies which evaluated the primary series and booster vaccination with the original Comirnaty vaccine and supported by studies which evaluated a booster dose of Comirnaty Original & Omicron BA.4/BA.5 in individuals 6 months of age and older.

For more information, refer to the Comirnaty Omicron XBB.1.5 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

At the time of authorization, clinical studies with Comirnaty Omicron XBB.1.5 were ongoing and no safety data were available. The safety profile of Comirnaty Omicron XBB.1.5 was therefore evaluated based on the established safety of, and cumulative experience with the authorized original Comirnaty vaccine, Comirnaty Original & Omicron BA.4/BA.5, and Comirnaty Original/Omicron BA.1 vaccines. This approach is in line with current clinical considerations for COVID-19 mRNA-based platforms which incorporate a change to the coding sequence related to the new variant of concern (Omicron XBB.1.5). Non-clinical and clinical data indicate that changes to the mRNA sequence do not impact the safety profile of the formulation, and Comirnaty Omicron XBB.1.5 is manufactured by the same process as the currently authorized Comirnaty vaccines. In addition, clinical information from a number of variant vaccine formulations used in the clinical development as well as post-market safety factored into the evaluation of safety for Comirnaty Omicron XBB.1.5. Therefore, extrapolation of data from other vaccines in the Comirnaty formulation portfolio is acceptable.

The analysis of the safety profile of Comirnaty Omicron XBB.1.5 was based on:

  • safety data accrued from the use of the original Comirnaty vaccine (administered as a primary series and as booster doses) in individuals 5 years of age and older;

  • safety data accrued from the use of a three-dose primary series of the original Comirnaty vaccine in individuals 6 months to less than 5 years of age;

  • the extrapolation of safety data for participants 5 to less than 12 years of age in Group 2 - Substudy D of Study C4591048 following the administration of Comirnaty Original & Omicron BA.4/BA.5 vaccine (10 mcg) as a booster (fourth dose);

  • preliminary safety data from participants in Cohort 2 (12 years of age and older) and Cohort 3 (18 years of age and older) of Study C4591044 following administration of Comirnaty Original & Omicron BA.4/BA.5 (30 or 60 mcg) as a booster (fourth dose);

  • preliminary safety data for a subset of participants 6 months to less than 5 years of age in Group 2 - Substudy B of Study C4591048 following administration of Comirnaty Original & Omicron BA.4/BA.5 (3 mcg) as a booster (fourth dose); and,

  • non-clinical data.

Information on the design and results of the studies carried out in the age‑specific age ranges mentioned above are described in the Clinical Efficacy section.

Overall, the collective safety data suggest that the safety profiles of the original Comirnaty vaccine, Comirnaty Original & Omicron BA.1, and Comirnaty Original & Omicron BA.4/ BA.5 are analogous dose per dose and vaccination scheme per vaccination scheme. The reactogenicity profiles of the monovalent and bivalent Comirnaty variant vaccines consistently displayed comparable local and systemic reactogenicity and mirrored the safety profile of the previously authorized monovalent original Comirnaty mRNA platform. The consistency of safety data across the mRNA platforms and studies suggests that the safety profile of Comirnaty Omicron XBB.1.5 is expected to be comparable to the safety profile of the previously authorized Comirnaty formulations encoding for variants of concern. Therefore, no new safety concerns are anticipated.

Summary of Safety Analysis

In conclusion, based on the totality of the data reviewed, the benefit-risk profile of Comirnaty Omicron XBB.1.5 is considered favourable for active immunization against COVID‑19 caused by SARS‑CoV‑2 in individuals 6 months of age and older. The safety of Comirnaty Omicron XBB.1.5 will be evaluated in studies C4591048 and Study C4591054. Additional supportive safety and reactogenicity data from clinical studies which evaluated primary and booster vaccination with the currently authorized Comirnaty vaccines, in addition to post‑marketing safety data for the original Comirnaty vaccine, Comirnaty Original & Omicron BA.4/BA.5, and Comirnaty Original/Omicron BA.1 were also considered as part of the safety evaluation.

At the time of authorization, several uncertainties remained, including: a lack of long-term safety data; possible waning of vaccine effectiveness; long-term antibody persistence; studies considering the coadministration of Comirnaty Omicron XBB.1.5 with other vaccines; limitations of study design and analysis including small sample size and descriptive immunogenicity across the clinical development programme and in ongoing and planned studies; and very rare cases of myocarditis and/or pericarditis following vaccination, particularly in young adult males, reported with the use of other Comirnaty formulations. These uncertainties will be managed through the terms and conditions associated with the authorization which require the submission of long-term safety data (from studies C4591048 and C4591054), the monitoring of the safety and effectiveness of all COVID-19 vaccines at the national and global level through post-market epidemiological studies, and the monitoring of neutralizing antibody titres in clinical studies (included in ongoing and/or planned studies subject to the herein terms and conditions) together with the evaluation of breakthrough infections to provide evidence for duration of immunity in immunized individuals.

Across the clinical development program, BioNTech Manufacturing GmbH has used the same base formulation, regardless of the mRNA content and coding sequence. Comirnaty Omicron XBB.1.5 is therefore chemically and physically highly similar to the currently authorized original Comirnaty vaccine, Comirnaty Original/Omicron BA.1, and Comirnaty Original and Omicron BA.4/BA.5.

Given the current epidemiological context, as well as the broadly similar safety and manufacturing profiles of Comirnaty Omicron XBB.1.5 to that of the other Comirnaty formulations, the results obtained across the clinical development program support an acceptable safety profile.

Risk Management Plan

A core (European Union [EU]) Risk Management Plan (RMP) and a Canadian RMP Addendum for Comirnaty Omicron XBB.1.5 were submitted by BioNTech Manufacturing GmbH 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 scheme, and to describe measures that will be put in place to minimize risks associated with the product, when needed.

The following information relates to the RMP submitted by BioNTech Manufacturing GmbH as part of the new drug submission for Comirnaty Omicron XBB.1.5. 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.

While clinical data for Comirnaty Omicron XBB.1.5 were not available at the time of authorization, the authorization was based on the extrapolation of clinical and post-market safety data for the original Comirnaty vaccine, Comirnaty Original/Omicron BA.1, and Comirnaty Original & Omicron BA.4/BA.5 to date. The RMP adequately captured the known and potential risks of this vaccine and included three important identified risks: anaphylaxis, myocarditis, and pericarditis. The RMP also listed eight areas of missing (limited/no clinical data) information: "use in pregnancy and while breastfeeding", "use in immunocompromised patients", "use in frail patients with comorbidities", "use in patients with autoimmune or inflammatory disorders", "interaction with other vaccines", "long-term safety", "vaccine effectiveness", and "use in paediatric individuals less than 6 months of age". An important limitation of the data for all approved age groups continues to be the long-term safety and effectiveness of the vaccine. This limitation is managed through labelling and the RMP.

The proposed routine and additional pharmacovigilance activities for the above safety concerns are considered to be acceptable and are consistent with those for currently authorized Comirnaty vaccines. Additional pharmacovigilance activities include continued safety surveillance of ongoing clinical and post-authorization studies undertaken for the currently Comirnaty vaccines and the addition of two clinical studies evaluating the safety of Comirnaty Omicron XBB.1.5 in healthy individuals 12 years of age and older, and 6 months to less than 5 years of age. Two additional post-market studies are planned to evaluate the real-world effectiveness of the vaccine. Routine risk minimization measures (i.e., Product Monograph and labelling) are also considered to be appropriate.

Clinical Summary

The benefit of the availability of an updated vaccine (Comirnaty Omicron XBB.1.5) in the current epidemiological context was determined to outweigh the uncertainty resulting from less comprehensive data. Based on updated post-market safety for the currently authorized Comirnaty vaccine formulations administered as a primary series and as a booster dose, it is anticipated that Comirnaty Omicron XBB.1.5 will have an acceptable safety profile. In consideration of the data provided, along with knowledge of other monovalent and bivalent mRNA vaccines, literature publications, market experiences from other formulations of Comirnaty and non-clinical data, as well as taking into context the risk of COVID-19 as a respiratory virus of ongoing public health concern, the totality of available evidence reasons that Comirnaty Omicron XBB.1.5 is expected to elicit an immune response that will confer protection against COVID-19. Immunogenicity and safety data will be provided as part of the terms and conditions to confirm these assumptions.

For more information, refer to the Comirnaty Omicron XBB.1.5 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 for Comirnaty Omicron XBB.1.5 (raxtozinameran) 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 was issued in relation to Comirnaty Omicron XBB.1.5, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug (described in the What follow-up measures will the company take? section).

Comirnaty Omicron XBB.1.5 is a messenger ribonucleic acid (mRNA)‑lipid complex dispersion that contains mRNA constructs encoding the pre‑fusion stabilized spike glycoprotein of the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) Omicron variant lineage XBB.1.5. The mRNA constructs are formulated (encapsulated) in a lipid nanoparticle (LNP) in order to protect and deliver the mRNA intracellularly. After intramuscular injection, cells take up the lipid nanoparticle, effectively delivering the mRNA sequences into cells for expression of the SARS‑CoV‑2 spike antigen. The delivered mRNA does not enter the cellular nucleus or interact with the genome, is non‑replicating, and is expressed transiently. The proteins undergo post‑translational modification and trafficking resulting in properly folded, fully functional spike proteins that are inserted into the cellular membrane of the expressing cell(s). 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 antigen, which may contribute to protection against coronavirus disease 2019 (COVID‑19).

Eleven primary pharmacodynamic studies, eleven pharmacokinetics studies, and three toxicology studies were submitted to support of the authorization of Comirnaty Omicron XBB.1.5. The majority of these studies were previously submitted in support of currently authorized Comirnaty formulations and had already been reviewed by Health Canada. The new data included in this submission were a murine biodistribution study and two murine pharmacodynamic studies.

The new pharmacodynamic studies evaluated the administration of XBB.1.5-modified vaccines. One study was conducted in naïve animals receiving a two-dose primary series while the second study used an XBB.1.5-modified vaccine as a fourth booster dose in vaccine‑experienced animals. The strongest neutralizing antibody response was observed with the monovalent Comirnaty Omicron XBB.1.5. This response was higher in naïve animals compared to vaccine‑experienced animals. The XBB.1.5-modified vaccines induced T‑cell responses that were similar against matched and unmatched strains. When used as boosters, both the XBB.1.5 monovalent and the XBB.1.5 + BA.4/BA.5 bivalent vaccines elicited neutralization activity that was either equivalent or better than Comirnaty Original & Omicron BA.4/BA.5 against all sub-lineages tested. As a primary series, the XBB.1.5-modified vaccines generated immune responses that followed similar trends as those observed in the booster study, although with a greater magnitude of difference between the XBB.1.5 variant-adapted vaccine and Comirnaty Original & Omicron BA.4/BA.5. Secondly, as a primary series, the XBB.1.5-modified vaccines elicited neutralization activity that was reduced against the reference and BA.4/BA.5 strains as compared to Comirnaty Original & Omicron BA.4/BA.5. The studies provide proof of concept that XBB.1.5-modified vaccines, administered in vaccine‑experienced or naïve animals, produce an immune response against matched and antigenically‑related strains including the current circulating EG.5 Omicron variant. This outcome/finding supports use in the clinical setting.

Collectively, the pharmacodynamic data suggest that when administered as a booster dose or a primary series in mice, Comirnaty Omicron XBB.1.5 is expected to elicit potent immune responses mediated by neutralizing antibodies, with high frequencies of antigen spike-specific T cells with a Th1-bias. The data also suggest that a more closely strain-matched formulation will generate the most potent immune responses which are expected to translate into improved effectiveness. The non-clinical data generated by the various Comirnaty-platform formulations have reliably predicted the immunological response trends in humans, and speak to the translatability of the above-mentioned non-clinical data as supportive to use in naïve and/or vaccine‑experienced humans.

No non-clinical safety studies were supplied specifically evaluating the Comirnaty Omicron XBB.1.5 vaccine. However, the non-clinical toxicity studies reviewed in earlier drug submissions for currently authorized Comirnaty vaccines supported the platform safety. Each of these four vaccines and the Comirnaty Omicron XBB.1.5 drug product utilizes the same mRNA-LNP platform. Therefore, no new safety concerns are expected with the use of this vaccine.

Collectively, the non-clinical data support the use of Comirnaty Omicron XBB.1.5 in the clinical setting. Whether administered as a booster dose or a primary series, the vaccine is anticipated to elicit potent immune responses, particularly those mediated by neutralizing antibodies, with high frequencies of T cells. Additionally, a more closely strain-matched vaccine formulation is anticipated to generate the most potent immune responses which are expected to translate into improved effectiveness, with no new safety concerns.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Comirnaty Omicron XBB.1.5 Product Monograph. In view of the intended use of Comirnaty Omicron XBB.1.5, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Comirnaty Omicron XBB.1.5 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 for Comirnaty Omicron XBB.1.5 (raxtozinameran) 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 was issued in relation to Comirnaty Omicron XBB.1.5.

Comirnaty XBB.1.5 is a monovalent prophylactic vaccine developed to prevent coronavirus disease 2019 (COVID‑19) caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2). This vaccine contains a messenger ribonucleic acid (mRNA) construct which encodes the prefusion‑stabilized spike protein of the XBB.1.5 variant of SARS-CoV-2. The mRNAs are encapsulated in lipid nanoparticles (LNPs) to enable their delivery into the host’s cells. Once inside the cell, the mRNA constructs enable the expression of the spike protein antigens. The vaccine elicits both neutralizing antibody and cellular immune responses which may contribute to protection against COVID‑19.

Characterization of the Drug Substance

Comirnaty Omicron XBB.1.5 contains the drug substance raxtozinameran. Raxtozinameran is a single‑stranded, 5’‑capped mRNA produced using cell‑free in vitro transcription from the corresponding deoxyribonucleic acid (DNA) templates, encoding for the viral spike protein of SARS-CoV-2 Omicron variant XBB.1.5. The resulting structure of the spike protein antigen includes a transmembrane‑anchored, full‑length spike with two point mutations within the central helix domain. This results in a stable prefusion conformation, which improves the production of neutralizing antibodies against the SARS‑CoV‑2 virus following immunization.

The mRNA drug substance is encapsulated in lipid nanoparticles (LNPs) stabilized in an aqueous cryoprotectant buffer. The LNPs are composed of four different lipids, each with a specific purpose, and when mixed with the mRNAs, bind together to produce the drug product.

Comirnaty Omicron XBB.1.5 utilizes a platform approach to new variant drug substances, which builds on the sponsor’s experience with the original Comirnaty vaccine and the development of other mRNA‑LNP vaccines.

Detailed characterization studies were performed to provide assurance that the drug substance, raxtozinameran, and the 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 Comirnaty Omicron XBB.1.5 is based on extensive platform knowledge from the original Comirnaty vaccine, Comirnaty Original & Omicron BA.4/BA.5, and Comirnaty Original/Omicron BA.1, sound scientific knowledge and prior experience with the development of other mRNA‑LNP vaccines, and pre‑established principles derived from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH; guideline Q8).

The manufacturing processes and control strategies for Comirnaty Omicron XBB.1.5 are considered equivalent to those which were previously approved for Comirnaty Original & Omicron BA.4/BA.5, with the exception of minor sequence changes to the plasmid used for in vitro transcription of the mRNA and to the primers used for identification tests, to match the Omicron XBB.1.5 variant.

The drug substance, raxtozinameran, is synthesized using in vitro transcription, which includes a linear DNA template produced via plasmid DNA from transformed Escherichia coli cells. Raxtozinameran encodes the spike protein for the Omicron variant XBB.1.5.

Once raxtozinameran is produced, it is combined with water for injection and the diluted drug substance is mixed until homogeneous using the same parameters and processes as those used in the manufacturing of the original Comirnaty vaccine.

The diluted drug substance is then processed for LNP production. The LNPs consist of four different lipids in a defined ratio. When mixed with the mRNA drug substance, the lipids bind together forming nanoparticles encapsulating the mRNA. The drug product solution is sterile filtered, aseptically filled into vials, stoppered and capped, visually inspected, labelled, and then frozen and stored between ‑90 °C to ‑60 °C. All above noted processes remained unchanged from those approved for the original Comirnaty vaccine.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits. The lot release tests for the drug substance and drug product are appropriately validated/qualified and are based on scientifically relevant assays and appropriate specifications that are in place 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 Comirnaty vaccine, is sufficient to support the issuance of a Notice of Compliance. Terms and conditions have been imposed related to the manufacturing process and process controls.

None of the non-medicinal ingredients (excipients) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of raxtozinameran with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The process parameters and controls, analytical methods, and release specifications for Comirnaty Omicron XBB.1.5 remain the same as those which were previously approved for Comirnaty Original & Omicron BA.4/BA.5. 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 similarity to the original Comirnaty vaccine. Minor changes to the mRNA sequence do not affect process performance or drug substance quality based on physicochemical characterization and batch release data, in addition to data from existing platform products.

Comirnaty Omicron XBB.1.5 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

The proposed shelf life of raxtozinameran, the drug substance, is 6 months when stored in ethylene vinyl acetate (EVA) bags at ‑20 °C ± 5 °C.

The proposed shelf life of Comirnaty Omicron XBB.1.5 is 18 months when formulated at 0.1 mg/mL or 12 months when formulated at 0.033 mg/mL when stored at ‑90 °C to ‑60 °C. Short‑term storage at 5 °C ± 3 °C for up to 10 weeks is also acceptable, as long as the storage does not exceed the expiry of the drug product. In addition, on the day of administration, the drug product may be stored at room temperature for up to 12 hours prior to use (first needle puncture). Following needle puncture, the vials can be stored at room temperature or refrigerated but must be discarded after 12 hours. Once thawed, the vaccine should not be re‑frozen.

Due to the expedited development of Comirnaty Omicron XBB.1.5, stability data for the drug substance and drug product were not available. However, based on extensive stability data for commercial-scale Comirnaty vaccines, minor sequence changes to the mRNA drug substance are not expected to impact the stability of the drug substance or drug product. Therefore, the proposed shelf lives for the drug substance and drug product are consistent with those of currently approved Comirnaty platform products. The aggregate data confirm that the stability profiles of the drug substance and drug product are highly similar, regardless of the sequence of the mRNA drug substance used.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

No new manufacturing sites are involved in the production of Comirnaty Omicron XBB.1.5 from a Canadian authorization perspective. All of the facilities have been previously authorized by Health Canada for the manufacture and testing of previous Comirnaty platform vaccines. All facilities used to manufacture Comirnaty vaccines have been issued Establishment Licenses by Health Canada. Other than minor changes to the plasmid sequence and the primers used for identity testing of the drug substance and drug product, the manufacturing and control remain the same. Therefore, an on‑site evaluation is not required for a currently approved facility.

Adventitious Agents Safety Evaluation

The raw materials used in the manufacturing process of Comirnaty Omicron XBB.1.5 are adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not of animal or human origin.