Summary Basis of Decision (SBD) for Spikevax (previously Spikevax XBB.1.5)

Summary Basis of Decision (SBD)

Contact: Office of Regulatory Affairs, Biologic and Radiopharmaceutical Drugs Directorate

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

Recent Activity for Spikevax (previously Spikevax 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 Spikevax (previously Spikevax XBB.1.5), a product which was initially authorized with andusomeran as the medicinal ingredient. Initial authorizations and previous strain variations of COVID-19 vaccines were authorized via a New Drug Submission with modified requirements for designated COVID-19 drugs. Given the more endemic state of COVID-19, and consistent with its approach to reviewing annual influenza vaccines, Health Canada has transitioned to reviewing COVID-19 vaccine updates in antigen composition as Supplements to New Drug Submissions. Therefore, Spikevax XBB.1.5 has been updated to reflect the currently authorized product name and medicinal ingredient, i.e., Spikevax (mRNA encoding SARS-CoV-2 spike protein, 5’[m7G-5’-ppp-5’-Gm] cap, 100‑nucleotide 3' poly[A] tail), as reflected in the PAAT below.

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.

Updated: 2024-09-20

Drug Identification Number (DIN):

DIN 02541270 - 0.1 mg/mL, mRNA encoding SARS-CoV-2 spike protein, 5’(m7G-5’-ppp-5’-Gm) cap, 100‑nucleotide 3' poly(A) tail (previously andusomeran), dispersion, intramuscular administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number	Date submitted	Decision and date	Summary of activities
SNDS # 287904	2024-06-20	Issued NOC (subject to terms and conditions) 2024-09-17	Submission filed as a Level I – Supplement to update the antigen composition (variant Omicron KP.2), product name (Spikevax), and medicinal ingredient name (mRNA encoding SARS-CoV-2 spike protein, 5’[m7G-5’-ppp-5’-Gm] cap, 100‑nucleotide 3' poly[A] tail). The submission was reviewed and considered acceptable, and an NOC was issued. Terms and conditions were imposed on the authorization.
NC # 288252	2024-06-27	Issued NOL 2024-08-26	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the shelf life for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 285161	2024-03-20	Issued NOC 2024-08-21	Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations, as a Level I – Supplement. Canadian-specific bilingual labelling was submitted. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 286213	2024-04-19	Cancellation Letter Received 2024-06-04	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the shelf life for the drug product. The sponsor cancelled the submission before Health Canada completed the review.
NC # 284961	2024-03-14	Issued NOL 2024-05-13	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the labelled storage conditions for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 280216	2023-10-24	Issued NOC 2024-03-12	Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Dosage Forms, Strengths, Composition and Packaging sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
NC # 281791	2023-12-05	Issued NOL 2024-02-23	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02541270) market notification	Not applicable	Date of first sale: 2023-09-18	The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 275936	2023-06-29	Issued NOC (subject to terms and conditions) 2023-09-12	NOC issued for New Drug Submission. Terms and conditions were imposed on the authorization.

Summary Basis of Decision (SBD) for Spikevax (previously Spikevax XBB.1.5)

Date SBD issued: 2023-10-31

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

Andusomeran

Drug Identification Number (DIN): DIN 02541270 - 0.1 mg/mL andusomeran, dispersion, intramuscular administration

Moderna Biopharma Canada Corporation

New Drug Submission Control Number: 275936

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

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

Date Filed: 2023-06-29

Authorization Date: 2023-09-12

On September 12, 2023, Health Canada issued a Notice of Compliance (NOC), subject to terms and conditions, to Moderna Biopharma Canada Corporation for Spikevax 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 Spikevax XBB.1.5 is favourable for active immunization against COVID‑19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) virus in individuals 6 months of age and older.

Spikevax 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?

Spikevax XBB.1.5, an active immunizing agent, was authorized for active immunization against coronavirus disease 2019 (COVID‑19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) virus in individuals 6 months of age and older.

The safety and effectiveness of Spikevax XBB.1.5 for individuals 6 months of age and older are inferred from several studies of a primary series and booster dose of the currently authorized Spikevax Bivalent in individuals 6 months to 5 years of age, a booster dose study of Spikevax Bivalent in individuals 18 years of age and older, a booster dose study of Spikevax XBB.1.5 in individuals 18 years of age and older, as well as data from studies which evaluated the primary series and booster vaccination with the currently authorized original monovalent Spikevax vaccine.

The safety and efficacy of Spikevax XBB.1.5 in individuals under 6 months of age has not yet been established.

Clinical studies of Spikevax Bivalent that included individuals 65 years of age and older and their data contributes to the overall assessment of safety and effectiveness of Spikevax XBB.1.5.

Spikevax XBB.1.5 (0.1 mg/mL andusomeran) is presented as a dispersion. In addition to the medicinal ingredient andusomeran, the dispersion contains the following non‑medicinal ingredients: 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 XBB.1.5 is contraindicated in individuals who are hypersensitive to the active ingredient 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 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 Spikevax (previously Spikevax XBB.1.5) approved?

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

Coronavirus disease 2019 is an 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 9, 2023 there were 4,722,099 confirmed cases of COVID‑19 and approximately 53,706 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 SARS‑CoV‑2 and are currently in a state of transition from 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), Covishield, Jcovden (previously Janssen COVID-19 Vaccine), Nuvaxovid, Covifenz, Spikevax Bivalent, Comirnaty Original & Omicron BA.4/BA.5, Comirnaty Original/Omicron BA.1, and Spikevax Bivalent Original / Omicron BA.4/5.

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. 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.

The evolving epidemiology of COVID‑19 calls for periodic updates to vaccine formulations to better 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. 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 Spikevax XBB.1.5 was developed to closely match the ongoing circulating variant, XBB.

Spikevax XBB.1.5 contains messenger ribonucleic acid (mRNA) with a genetic sequence that encodes the pre‑fusion stabilized spike protein of the SARS‑CoV‑2 Omicron subvariant XBB.1.5. The safety, reactogenicity, and immunogenicity of Spikevax XBB.1.5 was evaluated based on submitted components from the Phase II/III Study mRNA-1273-P205 (hereafter referred to as Study P205). This open-label study is ongoing and includes nine parts with multiple cohorts (i.e., Part A [1 and 2], Part B, Part C, Part D, Part E, Part F, Part G, Part H, and Part J) to evaluate different variant‑modified candidate vaccines.

The pivotal immunogenicity data in support of Spikevax XBB.1.5 was obtained from Part J of Study P205, which also evaluated the safety and reactogenicity of Spikevax XBB.1.5 by comparing Spikevax XBB.1.5 (containing 50 mcg Omicron XBB.1.5 mRNA) against an investigational bivalent vaccine (containing 25 mcg of Omicron XBB.1.5 and 25 mcg of BA.4/BA.5 mRNA). The study enrolled 101 participants 18 years of age and older who were randomized in a 1:1 ratio to receive either Spikevax XBB.1.5 (number of participants [n] = 50) or the investigational bivalent vaccine (n = 51).

The vaccines were administered as a fifth dose (third booster dose) to adults who previously received a two‑dose primary series, a first booster dose of an original COVID‑19 vaccine, and a second booster dose of a bivalent vaccine. Participants were followed for a median duration of 20 days. The median intervals from the fourth dose Spikevax Bivalent (Original / Omicron BA.4/5) and the fifth dose of Spikevax XBB.1.5 or the investigational bivalent vaccine (Omicron XBB.1.5 and Omicron BA.4/5 mRNA) were 8.2 and 8.3 months, respectively.

Given the complexity of designing a clinical study with an efficacy endpoint in the current epidemiological landscape, there was no pre‑specified hypothesis on the immune responses elicited by Spikevax XBB.1.5 and the investigational bivalent (XBB.1.5 and Omicron BA.4/5) vaccine. Also, no statistical testing was performed for an immunogenicity comparison between the two randomized groups. All analyses were descriptive, with the determination of the safety and reactogenicity of Spikevax XBB.1.5 being the primary objective. An evaluation of the immunogenicity at Day 15 and Day 29 against variants contained in the vaccine was also included as a primary objective. Note that the Day 29 immunogenicity results will be submitted at a later date as specified in the terms and conditions.

Based on the primary analysis submitted, it was shown that Spikevax XBB.1.5 elicited neutralizing responses at Day 15 against the SARS‑CoV‑2 variants assessed, including XBB.1.5, XBB.1.16, BA.4/5, BQ.1.1, and D614G. When assessed against XBB.1.5, the neutralizing antibody geometric mean titre (GMT) was 2,579.0 (95% confidence interval [CI]: 1,809.1, 3,676.7) and the geometric mean titre ratio (GMR) was 16.7 (95% CI: 12.8, 21.7), when measured 15 days after the Spikevax XBB.1.5 dose. At the same time point, when Spikevax XBB.1.5 was assessed against BA.4/5, the GMT was 9,673.4 (95% CI: 6,965.6, 13,433.8) and the GMR was 6.3 (95% CI: 4.8, 8.2).

The safety and effectiveness of Spikevax XBB.1.5 for children 6 months to 17 years of age was inferred from several studies. Firstly, for children 6 months to 11 years of age, data was inferred from studies of a primary series of Spikevax Bivalent in individuals 6 months to 5 years of age and older. Supportive safety data was also provided from studies of the original Spikevax vaccine as a primary series in individuals 18 years of age or older and studies of Spikevax Bivalent as a booster dose in individuals 18 years of age or older and individuals 6 months to 5 years of age. The safety and effectiveness of Spikevax XBB.1.5 for children 6 to 11 years of age and adolescents 12 to 17 years of age was also inferred from studies of a booster dose of Spikevax Bivalent in individuals 18 years of age and older, as well as data from studies which evaluated a primary series and booster vaccination with the original Spikevax vaccine. The safety of Spikevax XBB.1.5 in adolescents 12 to 17 years of age was also inferred from safety data from studies of a booster dose of the original Spikevax vaccine in adolescents 12 to 17 years of age and from the safety profile of the original Spikevax vaccine administered as a booster dose in children 6 to 11 years of age. Safety data from studies in individuals 18 years or age and older using Spikevax Bivalent were also considered supportive.

No new risks have been identified for Spikevax XBB.1.5 beyond those listed in the approved Product Monograph for the original Spikevax vaccine. The key safety concerns for Spikevax XBB.1.5 are documented adverse events which are recognized as class effects, including hypersensitivity and anaphylaxis, cardiovascular events, acute illness, hematologic events, immune‑related events, and syncope. The risks associated with Spikevax XBB.1.5 are listed in the Product Monograph. The potential risks posed by the administration of Spikevax XBB.1.5 are expected to be manageable through routine monitoring and standard medical practice.

An updated core European Union (EU) Risk Management Plan (RMP) and a Canadian Addendum for Spikevax XBB.1.5 were submitted by Moderna Biopharma Canada Corporation 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 XBB.1.5 includes three important identified risks (anaphylaxis, myocarditis, and pericarditis). The RMP also identified four areas of missing information (limited/no clinical data): “use in pregnancy and while breastfeeding”, “long‑term safety”, “long‑term effectiveness”, and “use in subjects less than 18 years 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.

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 Spikevax vaccine, Spikevax Bivalent, and Spikevax Bivalent (Original / Omicron BA.4/5). There were no significant outstanding issues identified during the review of the safety data to preclude the authorization of Spikevax XBB.1.5. These will continue to be investigated through planned and ongoing studies, including Study mRNA‑1273‑P205 (Part J). Post‑authorization commitments for monitoring the long‑term safety and effectiveness of Spikevax XBB.1.5 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 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.

Spikevax XBB.1.5 has been shown to have a favourable benefit‑risk profile and an acceptable safety profile based on non‑clinical data and clinical studies conducted with Spikevax Bivalent and the original Spikevax vaccine. Collectively, the results of the clinical efficacy and safety evaluation demonstrated that Spikevax XBB.1.5 met the requirements as specified in Health Canada's Guidance for Market Authorization Requirements for COVID‑19 Vaccines.. Furthermore, Study mRNA‑1273‑P205 (Part J) 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, as part of the terms and conditions.

At the time of authorization, important limitations of the data included limited information on the waning protection of the vaccine product, long‑term safety and efficacy of the vaccine, including in sub‑populations (e.g., pregnant or breastfeeding women, immunosuppressed patients, and children). These limitations are considered to be adequately managed through labelling, terms and conditions associated with the authorization of Spikevax XBB.1.5, the RMP, and adequate monitoring. Appropriate warnings and precautions are in place in the Spikevax 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 an NOC pursuant to section C.08.004 of the Food and Drug Regulations. The NOC in respect of Spikevax 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 Spikevax (previously Spikevax 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 Spikevax 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 Spikevax XBB.1.5, with imposed terms and conditions (described in the What follow-up measures will the company take? section), on September 12, 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: Spikevax XBB.1.5

Submission Milestone	Date
Initial New Drug Submission filed by sponsor	2023-06-29
Initial non-clinical data submitted by sponsor	2023-06-29
Initial quality data submitted by sponsor	2023-06-29
Screening Acceptance Letter issued	2023-07-12
Initial clinical data submitted by sponsor	2023-07-13
Health Canada quality evaluation completed	2023-08-02
Risk Management Plan submitted by sponsor	2023-08-16
Final Product Monograph (English) submitted by sponsor	2023-08-18
Final Product Monograph (French) submitted by sponsor	2023-08-24
Health Canada non-clinical evaluation completed	2023-09-05
Health Canada clinical/medical evaluation completed	2023-09-05
Health Canada labelling evaluation completed	2023-09-05
Terms and conditions finalized by Health Canada	2023-09-05
Health Canada Risk Management Plan evaluation completed	2023-09-06
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate	2023-09-12

4 What follow-up measures will the company take?

The Notice of Compliance issued in respect of Spikevax XBB.1.5 (andusomeran) is accompanied by terms and conditions imposed on the drug identification number assigned to Spikevax 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:

The interim analyses regarding primary and exploratory endpoints from Study mRNA-1273-P205 Part J.
The final Clinical Study Report for Study mRNA‑1273‑P205 Part J.
The data obtained from the pre-specified endpoints according to Protocol Amendment 6 from Study mRNA‑1273‑P203 Part 3 intended to infer effectiveness of the 50 mcg Spikevax Bivalent (Original / Omicron BA.4/5) vaccine in the Per‑Protocol Immunogenicity, Subset-Positive (PPIS-Pos).
The final Clinical Study Report for parts of Study mRNA‑1273‑P203 Part 3.

Additionally, the sponsor is required to:

Submit Periodic Safety Update Reports or Periodic Benefit‑Risk Evaluation Reports every 6 months for Spikevax 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 if a safety issue is identified that requires immediate regulatory action or 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 Spikevax 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 Spikevax (previously Spikevax 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 Spikevax 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:

See the Health Canada COVID-19 vaccines and treatments portal for information on vaccines and treatments authorized for COVID-19, as well as those currently under review.
See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Guidance Document: Notice of Compliance with Conditions (NOC/c), if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
See the Patent Register for patents associated with medicinal ingredients, if applicable.
See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.

7 What was the scientific rationale for Health Canada's decision?

7.1 Clinical Basis for Decision

The New Drug Submission for Spikevax XBB.1.5 (andusomeran) 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 Spikevax 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 assumed 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, Spikevax XBB.1.5 is a monovalent messenger ribonucleic acid (mRNA) vaccine that encodes the prefusion-stabilized spike protein of the SARS‑CoV‑2 Omicron subvariant XBB.1.5. Spikevax XBB.1.5 is manufactured by the same process as the currently authorized Spikevax Bivalent (Original / Omicron BA.4/5), Spikevax Bivalent, and original Spikevax vaccine.

Clinical Pharmacology

Spikevax XBB.1.5 contains the medicinal ingredient andusomeran, which is an mRNA construct. Andusomeran encodes the viral spike protein of the SARS‑CoV‑2 Omicron subvariant XBB.1.5. The mRNA construct is formulated in lipid nanoparticles (LNPs), which enable its delivery into host cells to allow expression of the SARS‑CoV‑2 spike antigen specific to the XBB.1.5 subvariant. The delivered mRNA does not enter the cellular nucleus or interact with the genome, is non‑replicating, and is expressed transiently. The proteins encoded by the mRNA 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 protein is membrane‑bound and mimics the presentation of natural infection. This elicits both neutralizing antibody and cellular immune responses (T‑cell and B‑cell) to the spike antigen, which may contribute to protection against COVID‑19.

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

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

At the time of authorization, there were no data on the use of Spikevax XBB.1.5 with other vaccines.

For further details, please refer to the Spikevax 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

The effectiveness of Spikevax XBB.1.5 was evaluated based on data submitted from the Phase II/III Study mRNA-1273-P205 (hereafter referred to as Study P205. This open‑label study is ongoing and includes nine parts with multiple cohorts (i.e., Part A [1 and 2], B, C, D, E, F, G, H, and J) to evaluate the immunogenicity and safety of different variant‑modified candidate vaccines. The pivotal immunogenicity data in support of Spikevax XBB.1.5 was obtained from Part J of Study P205.

Immunogenicity in Adults 18 Years of Age and Older

Study P205 (Part J)

In Study P205,participants 18 years of age and older were randomized in a 1:1 ratio to receive either a 50 mcg dose of Spikevax XBB.1.5 (containing 50 mcg of Omicron XBB.1.5 mRNA) or a 50 mcg dose of an investigational bivalent vaccine (containing 25 mcg of Omicron XBB.1.5 and 25 mcg of Omicron BA.4/5 mRNA). The vaccines were administered as a fifth dose (third booster dose) to adults who had previously received two doses of the original Spikevax vaccine (50 mcg each dose) as a primary series, a first dose booster dose of the original Spikevax vaccine (50 mcg), and a second booster dose of Spikevax Bivalent (Original / Omicron BA.4/5; 50 mcg).

In Part J of Study P205, 50 participants received a booster dose of Spikevax XBB.1.5 and 51 participants received an investigational bivalent vaccine (XBB.1.5 and Omicron BA.4/5). The median intervals from the fourth dose of Spikevax Bivalent (Original / Omicron BA.4/5) and the fifth dose of Spikevax XBB.1.5 or the investigational bivalent (XBB.1.5 and Omicron BA.4/5) vaccine were 8.2 and 8.3 months respectively.

Given the complexity of designing a clinical study with an efficacy endpoint in the current epidemiological landscape, there was no pre‑specified hypothesis on the immune responses elicited by Spikevax XBB.1.5 and the investigational bivalent (XBB.1.5 and Omicron BA.4/5) vaccine. No statistical testing was performed for an immunogenicity comparison between the two randomized groups, and all analyses were descriptive. The evaluation of the safety and reactogenicity of Spikevax XBB.1.5 was the primary objective, along with the evaluation of immunogenicity on days 15 and 29 against variants targeted by the vaccines. Note, that the Day 29 immunogenicity results will be submitted at a later date as specified the terms and conditions.

The submitted interim analysis had a median follow‑up time of 20 days with a data cut‑off date of May 16, 2023. Interim results showed that the primary immunogenicity objective was met at Day 15. Spikevax XBB.1.5 elicited neutralizing responses at Day 15 against the SARS‑CoV‑2 variants assessed, including XBB.1.5, XBB.1.16, BA.4/5, BQ.1.1 and D614G. When evaluating Spikevax XBB.1.5 against the Omicron XBB.1.5 variant, the neutralizing antibody geometric mean titre (GMT) was 2,579.0 (95% confidence interval [CI]: 1,809.1, 3,676.7) and the geometric mean ratio (GMR) was 16.7 (95% CI: 12.8, 21.7) when measured 15 days after the Spikevax XBB.1.5 dose. When evaluating Spikevax XBB.1.5 against the Omicron BA.4/5 variant, the GMT was 9,673.4 (95% CI: 6,965.6, 13,433.8) and the GMR was 6.3 (95% CI: 4.8, 8.2). Overall, these results indicate that Spikevax XBB.1.5 elicited potent neutralizing responses against variants of the Omicron XBB lineage (XBB.1.5, XBB.1.16, BA.4/5, BQ.1.1 and D614G). These results suggest that Spikevax XBB.1.5 has the potential to provide protection against these emerging variants.

Immunogenicity in Children and Adolescents 6 Months to 17 Years of Age

The effectiveness of Spikevax XBB.1.5 in children 6 months of age and older is inferred from several studies:

a booster dose of Spikevax Bivalent in adults 18 years of age and older;
a primary series and booster dose of Spikevax Bivalent in children 6 months to 5 years of age;
a booster dose of Spikevax XBB.1.5 (as described in the Clinical Efficacy section) in adults 18 years of age and older; and
a primary series and booster vaccination with the original Spikevax vaccine conducted in various age groups (adults 18 years of age and older, adolescents 12 to 17 years of age, children 6 to 11 years of age, and children 6 months to 11 years of age).

Spikevax Bivalent

Booster Dose, Adults 18 Years of Age and Older

The reactogenicity and immunogenicity of a Spikevax Bivalent booster dose were evaluated in an ongoing Phase II/III open‑label study conducted in participants 18 years of age and older (Study P205; Parts F and G). For further information on the study design and results refer to the Summary Basis of Decision documents for Spikevax Bivalent and Spikevax Bivalent (Original / Omicron BA.4/5) on the Health Canada COVID-19 vaccines and treatments portal

Children 6 Months to 5 Years of Age, Primary Series and Booster Dose

The reactogenicity and effectiveness of Spikevax Bivalent for use as a primary series (two doses of 25 mcg) were evaluated in an ongoing, Phase III, open‑label study in participants 6 months to 5 years of age (Study P306; Part 1). Spikevax Bivalent was administered as a primary series to 142 vaccine‑naïve children and compared with 179 recipients of at least one dose of a primary series of the original Spikevax vaccine in Study P204. The median age of participants in Study P306 Part 1 was three years.

In addition, the immunogenicity and effectiveness of the Spikevax Bivalent booster dose were evaluated in Part 2 of Study P306. In this part, Spikevax Bivalent was administered as a single 10 mcg booster dose to 539 participants who had received a two‑dose primary series of the original Spikevax vaccine at least four months prior. The median time between the second dose of the primary series and the Spikevax Bivalent booster dose was 7.85 months.

Overall, the primary immunogenicity analyses showed that the geometric mean concentration (GMC) ratios met the pre‑defined success criteria for superiority against Omicron BA.1 and non‑inferiority against the original Wuhan strain. The collected supportive immunogenicity data conducted with the Spikevax Bivalent in children 6 months to 5 years is suggestive that Spikevax XBB.1.5 may be at least as effective in protecting against the current dominant XBB.1.5 variant given that Spikevax XBB.1.5 is manufactured using the same process as that of the currently authorized Spikevax Bivalent.

The Original Spikevax Vaccine

Primary Series and Booster Dose, Adults 18 Years of Age and Older

The effectiveness and immunogenicity of the original Spikevax vaccine were evaluated in Study P301, also known as the COVE Study. Additionally, the effectiveness of a single booster dose of the original Spikevax vaccine in adults 18 years of age and older who previously received a two-dose primary series with the original Spikevax vaccine at least 6 months prior to the booster was inferred by comparing the antibody titres from Study P201 (part B) to Study P301. For further information on the study design and results, refer to the Summary Basis of Decision for the original Spikevax vaccine on the Health Canada COVID-19 vaccines and treatments portal.

Primary Series and Booster Dose, Adolescents 12 to 17 Years of Age

The efficacy and immunogenicity of the original Spikevax vaccine in participants 12 to 17 years of age were evaluated in Study P203, an ongoing Phase II/III randomized, placebo‑controlled, observer‑blind, clinical study. The design and results of this study are described in the Regulatory Decision Summary for the expansion of the indication for the original Spikevax vaccine to individuals 12 to 17 years of age.

The effectiveness of a booster dose of the original Spikevax vaccine in participants 12 through 17 years of age was inferred by comparing the post‑booster antibody titres from Study P203 to those following the primary series in adults 18 through 25 years of age in the pivotal Study P301. This comparison is described in the Regulatory Decision Summary for the expansion of the indication for the original Spikevax vaccine to a booster dose for individuals 12 to 17 years of age.

Primary Series and Booster Dose, Children 6 to 11 Years of Age

The efficacy and immunogenicity of the original Spikevax vaccine in participants 6 to 11 years of age were evaluated in Study P204 (Part 2), an ongoing Phase II/III randomized, placebo‑controlled, observer‑blind, clinical study. The design and results of this study are described in the Regulatory Decision Summary for the expansion of the indication for the original Spikevax vaccine to individuals 6 to 11 years of age.

The effectiveness of a booster dose of the original Spikevax vaccine in participants 6 to 11 years of age was inferred by comparing the post‑booster antibody titres from Study P204 to those following the primary series in adults 18 to 25 years of age in the pivotal Study P301. The design and results of this study are described in the Regulatory Decision Summary for the expansion of the indication for Spikevax Bivalent to individuals 6 to 11 years of age.

Primary Series, Children 6 Months to 5 Years of Age

Efficacy and immunogenicity data for the original Spikevax vaccine in children 6 months through 5 years of age were collected in an ongoing Phase II/III two‑part clinical study (Study P204). The design and results of this study are described in the Regulatory Decision Summary for the expansion of the indication for the original Spikevax vaccine to individuals 6 months to less than 6 years of age.

Booster Dose, Children 6 Months to 5 Years of Age

The effectiveness of a booster dose of 10 mcg of the original Spikevax vaccine in participants 6 months to 5 years of age is based on a comparison of immune responses. This was assessed based on the neutralizing antibody concentration against a pseudovirus expressing the SARS‑CoV‑2 spike protein of the ancestral (Wuhan‑1‑like) strain following the booster dose in participants 6 months to 5 years of age in Study P204 (n = 56), compared to the neutralizing antibody concentration following the primary series in adults 18 to 25 years of age in the pivotal adult Study 301 (n = 295). Among the 56 participants in the primary immunogenicity analysis population, the median age for receipt of the booster dose was 2.3 years (range: 1.4 to 5.6 years).

The primary immunogenicity analyses of the GMC ratio and difference in the seroresponse rates following the booster dose in Study P204, compared to the following primary series in Study P301, met the pre-defined immunobridging success criteria. Seroresponse for a participant was defined as achieving a ≥4‑fold rise of neutralizing antibody concentration from baseline (before the first dose of the primary series in Study P204 and Study P301).

In a descriptive analysis, the booster dose seroresponse rate among participants 17 months to 5 years of age was 94.6%. The difference in seroresponse rates (Study P204 participants minus Study P301 participants) in this post‑hoc analysis was ‑4.7% (95% CI: ‑14.0, ‑0.9). As a result, the success criterion was met.

Summary of Efficacy Analysis

The effectiveness of Spikevax XBB.1.5 was assessed in 50 participants in Study P205 (Part J), and was shown to elicit potent neutralizing responses against variants of the Omicron XBB lineage (XBB.1.5, XBB.1.16, BA.4/5, BQ.1.1 and D614G). The effectiveness of Spikevax XBB.1.5 was also established based on inferred data from supportive clinical studies conducted with the currently authorized Spikevax Bivalent and original Spikevax vaccine. While the encoded mRNA for the currently approved Spikevax Bivalent and original Spikevax vaccine used in the supportive studies contain different immunogens (i.e., ancestral SARS‑CoV‑2 strain, variants of interest), these two vaccines are chemically and physically highly similar to Spikevax XBB.1.5. Taking into account the current epidemiological context, the non-feasibility of conducting clinical studies rapidly enough to respond to the emergence of SARS‑CoV‑2 variants, and the need for a new COVID‑19 vaccine to protect against the current variant of concern, the totality of available evidence suggests that Spikevax XBB.1.5 is expected to elicit an immune response that will confer protection against COVID‑19.

The dosing interval approved by Health Canada for Spikevax XBB.1.5 reflects both the currently authorized dosing schedule for other Spikevax formulations (both monovalent and bivalent) and the intervals used in previous and ongoing clinical studies for all formulations.

Indication

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

Spikevax XBB.1.5 (andusomeran 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 6 months of age and older.

For more information, refer to the Spikevax 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

The clinical safety of Spikevax XBB.1.5 was primarily evaluated in Study P205 (see description in the Clinical Efficacy section). Additional supportive safety and reactogenicity data was provided from clinical trials which evaluated primary and booster vaccination with the currently authorized original Spikevax vaccine and Spikevax Bivalent. In addition, post‑marketing safety data for the original Spikevax vaccine, Spikevax Bivalent, and Spikevax Bivalent (Original / Omicron BA.4/5) were also considered as part of the evaluation.

Safety in Adults 18 Years of Age and Older

Study P205 (Part J)

This open‑label Phase II/III study assessed the safety and reactogenicity of Spikevax XBB.1.5 in participants 18 years of age and older (see description in the Clinical Efficacy section). In this study, 50 participants received a booster dose of Spikevax XBB.1.5, and 51 participants received a dose of an investigational bivalent vaccine (XBB.1.5 and Omicron BA.4/5). The vaccines were administered as a fifth dose (third booster) to adults who previously received a two‑dose primary series and a booster dose of an original COVID‑19 vaccine and a booster dose of a bivalent vaccine. Participants were followed for a median duration of 20 days (data cut‑off date of May16, 2023).

Based on the interim safety data submitted, Spikevax XBB.1.5 showed a reactogenicity profile similar to prior doses of the original Spikevax vaccine, Spikevax Bivalent, and Spikevax Bivalent (Original / Omicron BA.4/5). The most frequently reported adverse reactions after receiving the Spikevax XBB.1.5 booster dose were pain (68.0%), fatigue (44.0%), myalgia (38.0%), headache (34.0%), arthralgia (28.0%), axillary swelling or tenderness (16.0%), and chills (14.0%).

Solicited local reactions in the Spikevax XBB.1.5 group were reported in 68.0% of participants compared to 84.3% of participants in the investigational bivalent (XBB.1.5 and Omicron BA.4/5) group. Within 7 days after vaccination, solicited systemic reactions were reported in 58.0% of participants in the Spikevax XBB.1.5 group compared to 64.7% of participants in the investigational bivalent group. The majority of solicited adverse events were Grade 1 and Grade 2.

There were five unsolicited treatment‑emergent‑adverse events (TEAEs) within the mean 20 day follow‑up period reported in participants who received Spikevax XBB.1.5. Similar TEAE trends were observed in the investigational bivalent group. From Day 15 to Day 29, four unsolicited non‑serious adverse events were reported; three reports in the investigational bivalent group and one in the Spikevax XBB.1.5 group. All four reports were Grade 1 to 2 in severity.

While the safety data is currently limited by a small sample size, a limited duration of follow‑up, an assessed population of only adults 18 years of age and older, and use of Spikevax XBB.1.5 only administered as a fifth dose (third booster dose), overall Spikevax XBB.1.5 was well tolerated. Reactogenicity was similar to that observed with prior doses of the original Spikevax vaccine, Spikevax Bivalent, and Spikevax Bivalent (Original / Omicron BA.4/5). There were no Grade 4 local or systemic reactions and no fatal events or serious adverse events in the interim safety analysis. No adverse events of special interest were reported during the study period. Specifically, there were no reports of myocarditis, pericarditis, myopericarditis, or thrombosis.

Safety in Children and Adolescents 6 Months to 17 Years of Age

Safety data accrued with the original Spikevax vaccine and Spikevax Bivalent in individuals 18 years of age and older are relevant to Spikevax XBB.1.5 in individuals 6 through 17 years of age because these vaccines are manufactured using the same process.

The safety of Spikevax XBB.1.5 for individuals 6 months of age and older is inferred from several studies:

a booster dose study of Spikevax Bivalent in individuals 18 years of age and older;
a primary series and booster dose of Spikevax Bivalent in individuals 6 months to 5 years of age;
a booster dose study of Spikevax XBB.1.5 (see description in the Clinical Efficacy section) in individuals 18 years of age and older; and
data from studies that evaluated the original Spikevax vaccine as a primary series and a booster dose.

Adolescents 12 to 17 Years of Age

Safety data in adolescents 12 to 17 years of age were collected in Study P203, an ongoing Phase II/III randomized, placebo‑controlled, observer‑blind clinical study conducted in the United States involving 3,726 participants who received at least one dose of the original Spikevax vaccine (n = 2,486) or a placebo (n = 1,240).

Overall, solicited adverse reactions at any dose were reported more frequently among adolescents in the vaccine group than in the placebo group. The most frequently reported adverse reactions in adolescents were pain at the injection site (97.2%), headache (78.4%), fatigue (75.2%), myalgia (54.3%), and chills (49.1%).

This study then transitioned into an open‑label Phase II/III study in which 1,364 participants 12 to 17 years of age received a booster dose of the original Spikevax vaccine at least 5 months after the second dose of the primary series. The most common solicited local adverse reactions were pain (91%) and axillary swelling or tenderness (28%). The most common solicited systemic adverse reactions were fatigue (59%), headache (57%), myalgia (40%), chills (31%), and arthralgia (24%).

Children 6 to 11 Years of Age

Safety data in children 6 to 11 years of age were collected in Study P204, an ongoing Phase II/III two‑part clinical study conducted in the United States and Canada. Part 1 is an open‑label phase of the study for safety, dose selection, and immunogenicity involving 380 participants who received at least one dose of the original Spikevax vaccine (0.25 mL, 50 mcg). Part 2 is the placebo‑controlled phase for safety, immunogenicity and efficacy and it included 4,002 participants 6 to 11 years of age who received at least one dose (0.25 mL, 50 mcg) of the original Spikevax vaccine (n = 3,007) or a placebo (n = 995). Additionally, 2,988 participants had received the original Spikevax vaccine and 973 participants had received a placebo as a second dose.

Overall, solicited adverse reactions were reported more frequently among children in the original Spikevax vaccine group than in the placebo group. The most frequently reported adverse reactions in children 6 to 11 years of age in Part 2 following administration of the primary series were pain at the injection site (94.8%), fatigue (64.5%), headache (54.3%), chills (30.3%) and myalgia (28.2%).

Study P204 also had an amendment to the protocol to include an open‑label booster dose phase that included 1,294 participants (6 to 11 years of age) who received a booster dose of the original Spikevax vaccine at least 6 months after the second dose of the primary series. No additional adverse reactions were identified in the open‑label portion of the study.

Children 6 Months to 5 Years of Age

Safety data in children 6 months to 5 years of age were inferred from Study P306 where Spikevax Bivalent was evaluated for use as a two‑dose primary series vaccination (25 mcg per dose). Data were collected in an ongoing Phase III open‑label clinical study conducted in the United States. Part 1 included data in 179 participants 6 months to 5 years of age who received at least one dose of the original Spikevax vaccine. As of the data cut‑off date of December 5, 2022, the median duration of follow‑up for safety was 68 days after the second dose.

Safety data in children 6 months to 5 years of age were also collected in Study P204, an ongoing Phase II/III two‑part clinical study conducted in the United States and Canada. Part 1 was an open‑label phase evaluating safety, dose selection, and immunogenicity in 225 participants who received at least one dose of the original Spikevax vaccine (25 mcg). Part 2 was the placebo‑controlled phase evaluating safety, immunogenicity and efficacy. At the data cut‑off date of February 21, 2022, this study had enrolled 6,388 participants 6 months to 5 years of age who received at least one dose of the original Spikevax vaccine (n = 4,792) or a placebo (n = 1,596). Additionally, 4,560 participants had received the original Spikevax vaccine and 1,499 participants had received placebo as a second dose.

In Part 2, in participants 6 months to less than 2 years of age, the median follow‑up duration was 98 days after the first dose and 68 days after the second dose. A total of 1,470 (83.5%) participants in the original Spikevax vaccine group and 482 (81.8%) participants in the placebo group were followed for 28 days or more after the second dose. A total of 1,138 participants in the original Spikevax vaccine group (64.6%) and 368 participants in the placebo group (62.5%) have been followed for 56 days or more after the second dose. In participants 2 years to less than 6 years of age in Part 2, the median follow‑up duration was 103 days after the first dose and 71 days after the second dose. A total of 2,713 (89.5%) participants in the original Spikevax vaccine group and 892 (88.6%) participants in the placebo group have been followed for 28 days or more after the second dose. A total of 2,180 participants in the original Spikevax vaccine group (71.9%) and 710 participants in the placebo group (70.5%) have been followed for 56 days or more after the second dose.

Overall, solicited adverse reactions were reported more frequently among children in the vaccine group than in the placebo group. In Part 2, following the administration of the primary series the most frequently reported local and systemic adverse reactions in children 6 months to less than 24 months of age were irritability/crying (64.3%), pain (46.2%), sleepiness (35.1%) and loss of appetite (32.1%). The most frequently reported local adverse reaction in children 2 to 5 years of age was pain (71.4%). The most frequently reported systemic adverse reactions in children 24 months to 36 months of age were irritability/crying (54.3%), sleepiness (36.0%) and loss of appetite (30.5%). The most frequently reported systemic adverse reactions in children 37 months to 5 years of age was fatigue (48.8%).

Summary of Safety Analysis

In conclusion, based on the totality of the data reviewed, the benefit-risk profile of Spikevax 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 Spikevax XBB.1.5 was primarily evaluated in Study P205. Additional supportive safety and reactogenicity data from clinical studies which evaluated primary and booster vaccination based on the currently authorized original Spikevax vaccine and Spikevax Bivalent, in addition to post‑marketing safety data for the original Spikevax vaccine, Spikevax Bivalent, and Spikevax Bivalent (Original / Omicron BA.4/5) were also considered as part of the safety evaluation.

Across the clinical development program, Moderna Biopharma Canada Corporation has used the same base formulation, regardless of the mRNA content and coding sequence. Spikevax XBB.1.5 is therefore chemically and physically highly similar to the currently authorized original Spikevax vaccine, Spikevax Bivalent, and Spikevax Bivalent (Original / Omicron BA.4/5).

Given the current epidemiological context, as well as the broadly similar safety and manufacturing profiles of Spikevax XBB.1.5 to that of the original Spikevax vaccine, Spikevax Bivalent, and Spikevax Bivalent (Original / Omicron BA.4/5), 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 Spikevax XBB.1.5 were submitted by Moderna Biopharma Canada Corporation to Health Canada as part of the application 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 Moderna Biopharma Canada Corporation as part of the new drug submission for Spikevax 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 Spikevax XBB.1.5 is limited at this time, based on the extrapolation of clinical safety data for the original Spikevax vaccine and Spikevax Bivalent, and post‑market safety data for the original Spikevax vaccine, Spikevax Bivalent, and Spikevax Bivalent (Original / Omicron BA.4/5) to date, the RMP adequately captures the known and potential risks of this vaccine. The RMP includes three important identified risks: anaphylaxis, myocarditis, and pericarditis and also lists four areas of missing information (limited/no clinical data): “use in pregnancy and while breastfeeding”, “long-term safety”, “long-term effectiveness”, and “use in subjects less than 18 years of age (Spikevax XBB.1.5).” 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.

7.2 Non-Clinical Basis for Decision

Spikevax XBB.1.5 is a messenger ribonucleic acid (mRNA)‑lipid complex dispersion that contains mRNA constructs (50 mcg) 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).

To support the need for an updated Omicron XBB variant‑matched COVID‑19 vaccine, new non‑clinical immunogenicity studies conducted with monovalent (Omicron XBB.1.5) and bivalent (Omicron XBB.1.5 and Omicron BA.4/BA.5) formulations of vaccines containing mRNA encoding the SARS-CoV-2 spike protein of the XBB.1.5/XBB.1.9.1 (the spike protein of XBB.1.9.1 is identical to that of XBB.1.5) or XBB.1.16 subvariants of Omicron were submitted for evaluation.

The non‑clinical data builds from and is directly linked to the non‑clinical pharmacodynamic, pharmacokinetic, and toxicology data from currently authorized COVID‑19 mRNA vaccines in the Spikevax portfolio. When administered as a two‑dose primary series in naïve mice, both monovalent and bivalent formulations of the XBB.1.5‑variant matched vaccines elicited robust binding antibody titres against the spike protein as well as neutralizing antibody titres against both XBB.1.5 and XBB.1.16 strains. This data is consistent with non‑clinical immunogenicity data generated for currently authorized variant-matched vaccines against the Omicron BA.1 and BA.4/BA.5 strains. Moreover, no toxicity issues were identified in animals over the course of study. This data is considered supportive, as proof‑of‑concept, of the potential immunogenicity of Spikevax XBB.1.5 as a single dose or two‑dose series in naïve individuals. While acknowledging that animal models are not always predictive of immunogenicity in humans, previously generated non‑clinical immunogenicity data for the Spikevax platform has translated into similar findings in corresponding clinical studies.

7.3 Quality Basis for Decision

Spikevax XBB.1.5 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 nucleoside-modified messenger ribonucleic acid (mRNA) in the vaccine encodes the spike protein of the XBB.1.5 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 andusomeran drug substance is a single‑stranded, 5'‑capped mRNA that encodes the full‑length transmembrane protein with two point modifications, leading to an antigenically stable prefusion conformation. This conformation improves the stimulation of neutralizing antibodies against SARS‑CoV‑2.

Spikevax XBB.1.5 utilizes a ‘platform approach’, which is an mRNA‑based platform with SM‑102-containing LNPs, as well as knowledge from the sponsor’s vaccine development experience with three currently authorized mRNA platform vaccines (the original Spikevax vaccine, Spikevax Bivalent, and Spikevax [Original / Omicron BA.4/5]). Similar to the original Spikevax vaccine, only one strain, the XBB.1.5 variant, is represented in the formulation. As such, the mRNA drug substance is encapsulated in SM‑102-containing LNPs to produce a monovalent LNP intermediate. The LNPs, optimized for their biodegradable and mRNA delivery properties, consist of four distinct lipid types (SM‑102; PEG2000-DMG; 1,2-distearoyl-sn-glycero-3-phosphocholine; and cholesterol), each with a specific purpose.

Detailed characterization studies were performed to provide assurance that both the drug substance 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 Spikevax XBB.1.5 is based on ‘platform approach’ knowledge from the sponsor’s development experience with three currently authorized mRNA vaccines (the original Spikevax vaccine, Spikevax Bivalent, and Spikevax Original / Omicron BA.4/5), sound scientific knowledge, prior experience with the development of mRNA‑LNP vaccines, and principles described in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

The Spikevax XBB.1.5 drug substance, andusomeran, is manufactured through in vitro transcription reactions using a linearized plasmid DNA template. The resulting mRNAs are then mixed with SM‑102 LNPs to produce the mRNA LNP intermediate. The mRNA LNP intermediate is then buffered, filtered, and frozen between -60 ºC and -90 ºC.

The Spikevax XBB.1.5 drug product is a dispersion for intramuscular injection, supplied in a multi-dose vial (total volume 2.5 mL per vial, up to a maximum of 10 doses) 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 concentration of 0.10 mg/mL to produce the formulated drug product. The diluted drug product solution is then sterile filtered, aseptically filled into vials, stoppered and capped, visually inspected, labelled, and then frozen and stored between -50 ºC and -15 ºC.

The method of manufacturing and the controls used for the drug substance and the drug product were informed by the sponsor’s cumulative manufacturing history and experience with three currently authorized mRNA vaccines. These methods and controls are considered to be adequately controlled within justified limits and all analytical methods are considered appropriately validated and qualified. Continual process verification activities informed updates to in-process controls. The in-process controls and lot release tests for the Spikevax XBB.1.5 drug substance and drug product are based on scientifically justified assays, and appropriate specifications are in place to monitor key quality attributes.

Changes made throughout development are considered acceptable upon review and the sponsor provided sufficient information to support the consistency of production.

Supportive release and extended characterization data were provided for all variant-specific drug substance and drug product batches.

This information, along with the sponsor’s experience with the ‘platform approach’, is sufficient to support the authorization.

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

Control of the Drug Substance and Drug Product

The drug substance are tested against suitable reference standards to verify that they meet approved specifications, and that analytical procedures are validated and in compliance with ICH guidelines. The sponsor leveraged ‘platform approach’ information gained from development activities and cumulative manufacturing history from three currently authorized mRNA vaccines. This ‘platform approach’ strategy to validation was found to be satisfactory. Process validation studies demonstrated the consistency and robustness of the manufacturing process and provided sufficient analytical characterization data to assess any impacts of the mRNA sequence changes on drug substance critical quality attributes. Analytical methods (mRNA sequence and identity) were re‑validated for the drug substance and drug product. Sequence‑specific methods do not require a reference standard, therefore no new XBB.1.5‑specific references materials were produced.

Spikevax XBB.1.5 is the first monovalent (as opposed to bivalent) variant Spikevax vaccine. The formulation critical process parameters, critical in‑process controls, and analytical controls and specifications are therefore simplified relative to the bivalent formulations and more reflective of the original strain monovalent vaccine process. The Spikevax XBB.1.5 manufacturing process incorporates platform‑wide analytical improvements approved in submissions for the bivalent vaccines into the formulation process approved for the 0.10 mg/mL mRNA presentation.

Spikevax 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

Due to the review schedule and leveraging of platform information, real‑time stability data for Spikevax XBB.1.5 drug substance and drug product were not available. The proposed shelf lives are based on the extrapolation of aggregate stability data across the Spikevax platform, which demonstrates 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 statistical and real‑time basis for this extrapolation has been validated by ongoing stability studies for approved Spikevax platform products. Stability studies for Spikevax XBB.1.5 are ongoing, and the sponsor has committed to providing stability updates as data are generated in ongoing studies.

Based on the stability data available, when stored at ‑60 °C to ‑90 °C, the shelf lives of andusomeran, the SM‑102 LNP, and the mRNA‑LNP drug substance are 36 months, 6 months, and 12 months, respectively. The drug product, when stored in the commercial container closure system, is assigned a shelf life of 12 months when stored at ‑50 °C to ‑15 °C, including 30 days of storage at 2 °C to 8 °C. On the day of dose administration, the drug product is allowed an additional in‑use time of up to 24 hours at 8 °C to 25 °C. Spikevax XBB.1.5 is preservative‑free. Once a vial has been needle‑punctured, it can be stored at room temperature or refrigerated, but must be discarded after 24 hours.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

No new manufacturing sites are involved in the production of Spikevax 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 Spikevax platform vaccines. The drug product manufacturing site is a Health Canada‑accredited facility with a Canadian Establishment License, and is under the Moderna Global Quality Control framework which has upheld high quality manufacturing standards under the challenging conditions and pressures of the COVID‑19 pandemic. Additionally, successful on‑site evaluations have been previously completed for two of the manufacturing facilities, and both have maintained a compliant rating.

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.