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

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.

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.

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).

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.

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.

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.

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.