Summary Basis of Decision for Spikevax Bivalent (Original / Omicron BA.4/5)

The New Drug Submission (NDS) for Spikevax Bivalent (Original / Omicron BA.4/5) (0.05 mg/mL elasomeran and 0.05 mg/mL davesomeran) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. The amended regulations also permit an exemption from submitting detailed reports of tests made to establish the safety and substantial evidence of the clinical effectiveness of the new drug. The sponsor must provide sufficient evidence to support the conclusion that the benefits of the drug outweigh the risks, taking into account the uncertainties, as well as the public health need related to coronavirus disease 2019 (COVID-19). Following review of the provided information, a Notice of Compliance was issued in relation to Spikevax Bivalent (Original / Omicron BA.4/5), with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug.

The World Health Organization (WHO) and the WHO‑Strategic Advisory Group of Experts on Immunization (SAGE) advise that the composition of current and future vaccines for 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 (TAG‑CO‑VAC) 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 Bivalent (Original / Omicron BA.4/5) is a bivalent vaccine messenger ribonucleic acid (mRNA) that encodes the prefusion-stabilized spike protein of the ancestral (Wuhan-1-like) strain and the variant of concern (VOC), Omicron BA.4/5 (Omicron B.1.1.529, BA.4/5 sub-lineage). Spikevax Bivalent (Original / Omicron BA.4/5) vaccine is manufactured by the same process as the currently authorized Spikevax Bivalent (Original and Omicron BA.1) (hereafter referred to as Spikevax Bivalent) and the currently authorized original monovalent Spikevax vaccine (hereafter referred to as the original Spikevax vaccine).

No data were submitted from clinical studies using Spikevax Bivalent (Original / Omicron BA.4/5). Clinical data will be collected in the post‑market setting. The sponsor will also include Spikevax Bivalent (Original / Omicron BA.4/5) in ongoing and planned post-authorization studies. The outcomes of these clinical studies will be submitted to Health Canada, when available. The authorization of Spikevax Bivalent (Original / Omicron BA.4/5) was inferred from clinical data from the studies of a booster dose of Spikevax Bivalent, as well as the effectiveness of primary and booster vaccination with the original Spikevax vaccine.

Clinical Pharmacology

Spikevax Bivalent (Original / Omicron BA.4/5) contains the medicinal ingredients elasomeran and davesomeran, both of which are mRNA constructs. Elasomeran encodes the viral spike protein of the ancestral strain SARS‑CoV‑2. Davesomeran encodes the viral spike protein of the SARS-CoV-2 Omicron variant lineages BA.4 and BA.5. The mRNA constructs are formulated in lipid nanoparticles (LNPs), which enable their delivery into host cells to allow expression of the SARS-CoV-2 spike antigen. The delivered mRNAs do not enter the cellular nucleus or interact with the genome, are non‑replicating, and are expressed transiently. The proteins encoded by the mRNAs undergo post‑translational modification and trafficking resulting in properly folded and fully functional spike proteins that are inserted into the cellular membrane of the expressing cells. The spike proteins are membrane-bound and mimic the presentation of natural infection. This elicits both neutralizing antibody and cellular immune responses (T‑cell and B‑cell) to the spike antigens, which may contribute to protection against COVID‑19.

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

Immunogenicity was assessed as part of the clinical efficacy evaluation of Spikevax Bivalent (Original / Omicron BA.4/5).

At the time of authorization, there were no data regarding the co‑administration of Spikevax Bivalent (Original / Omicron BA.4/5) with other vaccines.

For further details, please refer to the Spikevax Bivalent (Original / Omicron BA.4/5) 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 Bivalent (Original / Omicron BA.4/5) as a second booster dose was established based on studies of a booster dose of the Spikevax Bivalent vaccine, as well as effectiveness data of the original Spikevax vaccine administered as a primary series and as a booster dose.

Data supporting the effectiveness of Spikevax Bivalent (Original / Omicron BA.4/5) as a second booster dose was inferred by immunogenicity bridging (immunobridging) between Study P205 and that of study mRNA-1237-P301 (hereafter referred to as Study P301), the pivotal study which provided the main evidence on which the authorization of the original Spikevax vaccine was based. In Study P205, the group that received the original Spikevax vaccine as a second booster (Part F, cohort 2) served as the within‑study comparator against Spikevax Bivalent as a second booster (Part G).

Immunogenicity

Spikevax Bivalent (Original and Omicron BA.1) booster dose immunogenicity

Clinical evidence of the immunogenicity of a booster dose of Spikevax Bivalent (Original / Omicron BA.4/5) was evaluated based on data submitted from a Phase II/III, open‑label clinical trial known as Study P205. This study is ongoing, with multiple cohorts designed to assess the immunogenicity, safety, and reactogenicity of mRNA‑based variant-modified candidate vaccines administered as booster doses. The pivotal immunogenicity data submitted in support of Spikevax Bivalent (Original / Omicron BA.4/5) were based on Part G and Part F (cohort 2, hereafter referred to as Part F) of this study. Part G and Part F included a total of 814 adult participants, 18 years of age and older, who had previously received two 100 mcg doses of the original Spikevax vaccine (50 mcg elasomeran) vaccine as a primary series and one 50 mcg dose of the original Spikevax vaccine as a first booster (third dose) at least three months prior to enrolment, for a total of three previous doses. All participants in Part G (total number of subjects [n] = 437) and Part F (n = 377) were then administered a second 50 mcg booster dose (fourth dose) of either Spikevax Bivalent (25 mcg elasomeran and 25 mcg davesomeran) or the original Spikevax vaccine (50 mcg elasomeran), respectively, on Day 1 of the study. Subjects in Part G (n = 437) who received a 50 mcg booster dose of Spikevax Bivalent were followed for a median of 43 days (range: 22 to 51 days). Subjects in Part F (n = 377) who received a 50 mcg dose of the original Spikevax vaccine were followed for a median of 57 days (range: 51 to 66 days). Approximately 40% of the participants were 65 years of age and older. No immunocompromised or pregnant women were included in the study. Additionally, all demographic and baseline characteristics were similar between the Spikevax Bivalent and the original Spikevax vaccine groups.

The co-primary objectives were to demonstrate superiority with respect to the level of neutralizing titre and non‑inferiority with respect to seroresponse rate of anti‑Omicron immune response after a second booster dose of Spikevax Bivalent compared to a second booster dose of the original Spikevax vaccine. The co‑primary endpoints were the geometric mean titres (GMTs) and seroresponse rates (SRRs) for the serum neutralizing antibody titres against the ancestral SARS-CoV-2 strain and Omicron BA.1 variant at Day 29 and Day 91. At the time of the analysis, only data corresponding to Day 29 was submitted. As per the terms and conditions imposed on the authorization of Spikevax Bivalent, the sponsor will submit Day 91 and Day 181 immunogenicity data as soon as it becomes available.

The primary efficacy analysis was conducted in the immunogenicity set, which included participants with no evidence of SARS‑CoV‑2 infection at baseline (presecond booster dose). The per‑protocol immunogenicity set with negative baseline SARS‑CoV‑2 status (PPSI‑Neg set) included 334 subjects from Part G and 260 subjects from Part F. At baseline, in the PPSI‑Neg set, there were no major imbalances between the two comparator groups. Neutralization against Omicron BA.1 and ancestral SARS‑CoV‑2 virus was measured using a validated pseudovirus neutralization assay.

Immunobridging analyses compared the neutralizing antibody titres (measured as the inhibitory dilutions at which 50% neutralization [ID₅₀] was attained) of subjects in Part G (n = 334; Spikevax Bivalent group) to the corresponding titres 29 days following the second booster dose of subjects in Part F (n = 260; original Spikevax vaccine group) against the SARS‑CoV‑2 ancestral strain and Omicron BA.1 strain after administration of the second booster dose.The analyses of the GMT were adjusted for age and baseline titres.

The results obtained at Day 29 showed that the co-primary objectives were met. At Day 29, the neutralizing antibody GMTs against the Omicron BA.1 variant were 2,479.9 (95% confidence interval [CI]: 2,264.5, 2,715.8) in the Spikevax Bivalent group, and 1,421.2 (95% CI: 1,283.0, 1,574.4) in the original Spikevax vaccine group. For neutralization against the Omicron BA.1 variant, Spikevax Bivalent was shown to be superior to the original Spikevax vaccine, as the GMT ratio (GMR) between the two groups was 1.75 (97.5% CI: 1.49, 2.04). The neutralizing antibody GMTs against the ancestral SARS‑CoV‑2 strain were 5,977.26 (95% CI: 5,321.90, 6,713.32) in the Spikevax Bivalent group, and 5,649.33 (95% CI: 5,056.85, 6,311.23) in the original Spikevax vaccine group. For neutralization against the ancestral SARS-CoV-2 strain, non-inferiority was demonstrated between Spikevax Bivalent and the original Spikevax vaccine, as the GMR was 1.22 (97.5% CI: 1.08, 1.37).

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

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

Observed neutralizing antibody titres for Omicron BA.4/5 variants

Neutralization against the Omicron BA.4/5 variants was measured as an exploratory endpoint using a research grade pseudovirus neutralization assay. Though the analyses are exploratory, results suggest that a second booster with Spikevax Bivalent would provide a superior neutralizing antibody response against the Omicron BA.4/5 variants compared to a second booster with the original Spikevax vaccine.

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

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

For subjects with prior SARS‑CoV‑2 infection, the estimated Day 29 neutralizing antibody GMTs against the Omicron BA.4/5 variants were 2,246.25 (95% CI: 1,975.52, 2,554.09) in the Spikevax Bivalent group and 1406.89 (95% CI: 1,227.88, 1,612.01) in the original Spikevax vaccine group. The GMR was 1.60 (95% CI: 1.34, 1.91).

Supportive Studies

Booster subset using variant‑modified vaccines

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

Exploratory data were also provided for neutralization titres against the Beta and Delta variants conducted in a convenience sample of the first 50 participants in Parts G and F of Study P205. These exploratory results suggest that Spikevax Bivalent may be at least as effective as the original Spikevax vaccine in protecting against variants that previously dominated. Immunoglobulin G binding antibody data up to Day 29 were provided from Parts G and Part F against Omicron, Ancestral, Alpha, Beta, Delta, and Gamma variants. Although there was no multiplicity adjustment due to the exploratory nature of these analyses, the binding antibody data suggest that Spikevax Bivalent could offer superior cross-protection compared to the original Spikevax vaccine against the ancestral SARS‑CoV‑2 strain and the variants that were previously dominant.

Summary of Efficacy

In conclusion, the clinical information provided for Spikevax Bivalent demonstrated a superior neutralizing antibody response against the Omicron BA.1 strain and a similar neutralizing antibody response against the SARS‑CoV‑2 ancestral strain when compared to the original Spikevax vaccine, it can be assumed, based on the results of exploratory analyses, that Spikevax Bivalent (Original / Omicron BA.4/5) will induce superior antibody responses to the Omicron BA.4/5 variants and a non‑inferior response to the SARS‑CoV‑2 ancestral strain when compared to the original Spikevax vaccine. Based on the collective evidence from the aforementioned data and experience with other bivalent mRNA vaccines, market experiences from the original Spikevax vaccine, and relevant non‑clinical data, as well as taking into context the current and evolving pandemic, the totality of available evidence reasons that a booster dose of Spikevax Bivalent (Original / Omicron BA.4/5) is expected to elicit an immune response that will confer protection against COVID‑19. Immunogenicity and safety data will be provided as part of the terms and conditions to confirm these assumptions.

Indication

The NDS for Spikevax Bivalent (Original / Omicron BA.4/5) was filed by the sponsor with the following indication, which Health Canada subsequently approved:

• Spikevax Bivalent (elasomeran/davesomeran) Original / Omicron BA.4/5 mRNA vaccine is indicated as a booster dose for active immunization against coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in individuals 18 years of age and older.

For more information, refer to the Spikevax Bivalent (Original / Omicron BA.4/5) Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

Clinical Safety

At the time of authorization, no clinical data were available to assess the safety profile of Spikevax Bivalent (Original / Omicron BA.4/5) as studies were ongoing. As such, its safety profile was evaluated primarily based on the established safety of, and cumulative experience with the authorized original Spikevax vaccine. This approach in assessing safety is in line with the current clinical considerations for COVID-19 mRNA-based formulations which incorporate the addition of a change to the coding sequence (active substance) related to the new variant of concern (Omicron BA.4/5) in addition to the current sequence (the original Spikevax vaccine). In addition to experience with the original Spikevax vaccine, both as a primary series vaccination and as a booster, clinical information from a number of variant vaccine formulations used in the clinical development program, post‑market safety data, and feedback from consultations with Canadian experts all factored into the extrapolation of safety information for Spikevax Bivalent (Original / Omicron BA.4/5). Notably, Spikevax Bivalent (Original / Omicron BA.4/5) is manufactured by the same process as the currently authorized original Spikevax vaccine and as such is expected to have a similar safety profile.

Primary and Booster Vaccination

Safety profile of the original Spikevax vaccine

The safety of the original Spikevax vaccine administered as a primary series was evaluated in participants, aged 12 years and older, in clinical studies conducted globally. Cumulative experience on the safety of the original Spikevax vaccine is derived from a large safety database comprising primary series and booster doses.

At the time of analysis, a total of 30,351 subjects received at least one dose of the original Spikevax vaccine (n = 15,181) or placebo (n = 15,170). Subjects were followed for a median of 92 days from first injection and 63 days from the second injection.

Overall, through the clinical development program and across the age strata, systemic adverse reactions were less frequent following a third dose (first booster) of the original Spikevax vaccine than were those following a second dose (primary series) of the original Spikevax vaccine. Across age groups, as is usually seen with other mRNA‑based formulations, reactogenicity was reported with slightly increased frequency in younger ages. Across the clinical development program, the safety of the original Spikevax vaccine was consistent with the post‑market safety data.

Spikevax bivalent variant vaccine formulations

Cumulative experience on the safety of Spikevax bivalent variant vaccine formulations, Spikevax Bivalent and a second bivalent vaccine (mRNA-1237.211; containing 25 mcg of the ancestral SARS-CoV-2 and Beta variant spike mRNA sequence) is derived from a database comprising primary series and booster vaccinations.

Study P205 Part G (Spikevax Bivalent as a second booster, n = 437), and Part F cohort 2 (original Spikevax vaccine as a second booster, n = 377) constituted the basis for the clinical safety review of Spikevax Bivalent as a booster dose in individuals 18 years of age and older. The data cut-off date was April 27, 2022 which provided a median follow-up duration of 43 days. 

Additional, long‑term supportive safety and reactogenicity data was also provided from a pre‑specified comparison between Part A in Study 205 and Part B in Study mRNA-1273-P201 (hereafter referred as Study P201). In Part A, a 50 mcg dose of a bivalent mRNA-1273.211 vaccine containing equal amounts of the ancestral SARS-CoV-2 and Beta spike mRNA sequences was administered as a third dose (first booster) to 300 subjects who had received two 100 mcg doses of the original Spikevax vaccine as a primary series. In Part B, 50 mcg of the original Spikevax vaccine was administered as a third dose (first booster) to 177 subjects who had received two 100 mcg doses of the original Spikevax vaccine as primary series. The long‑term safety data from this arm of the study had a median follow-up duration of 245 days.

Safety Analysis Results

A high frequency in reactogenicity was observed for both local and systemic adverse reactions with 380 (87%) subjects in the Spikevax Bivalent group and 301 (85%) subjects in the original Spikevax vaccine group experiencing any solicited adverse reactions. However, most of the events were Grade 1 or 2 in severity and resolved within a few days (median 1 to 3 days). The frequency and severity of the solicited adverse reactions was similar between the two groups. The most common local solicited adverse reactions (equal to or greater than 10%) were pain at the injection site (77.9% and 77.2%) and axillary swelling (17.1% and 19.6%) in the Spikevax Bivalent and original Spikevax vaccine groups, respectively. The most common (equal to or greater than 10%) solicited systemic adverse reactions were fatigue (54.9% and 51.4%), headache (43.9% and 41.1%), myalgia (39.6% and 38.6%), arthralgia (31.1% and 31.7%), chills (23.8% and 21.1%), and nausea/vomiting (10.3% and 10.0%) in the Spikevax Bivalent and the original Spikevax vaccine groups, respectively. The frequency of Grade 3 adverse reactions was 8.0% in both groups. There were no Grade 4 solicited adverse reactions in either group. In addition, no safety concerns or differences regarding solicited or unsolicited adverse reactions were identified between the two groups based on SARS‑CoV‑2 infection status prior to receiving the booster dose.

A great deal of similarity was noted between the reactogenicity profiles of the subjects who received Spikevax Bivalent as a second dose (50 mcg; Study P205 Part G), the original Spikevax vaccine as a first booster (50 mcg; Study P201 Part B), and the bivalent mRNA-1273.211 vaccine given as a first booster dose (50 mcg; Study P201 Part A, n = 300, with longer duration of follow-up [median of 245 days]). Corroborated, these data suggest that the reactogenicity profile of Spikevax Bivalent, when administered as a second booster (50 mcg), should be similar to the reactogenicity profile of the original Spikevax vaccine when used as a first or second booster in individuals who received the original Spikevax vaccine (100 mcg) as their primary series.

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

In general, no adverse events of special interest which could raise safety concerns were identified through the Standard Medical Dictionary for Regulatory Activities (MedDRA) Queries tools. An enhanced assessment of myocarditis and pericarditis events using custom MedDRA Queries confirmed that the myocarditis rates continue to appear to be lower following the third dose as compared to the second dose. This was reported for both sexes and across the age strata, including the age range reported to be at highest risk (12 to 39 years of age), with the caveat that the post‑marketing data for third vaccination are limited and estimates may change as the demographic characteristics of third vaccination recipients change over time. These data align with the historical data on the epidemiology of myocarditis and pericarditis following a booster dose of COVID‑19 vaccines. The safety data for the bivalent vaccines were consistent across study arms.

Overall, the safety and reactogenicity data from both bivalent vaccines indicated a similar safety profile to the original Spikevax vaccine, regardless of the number of prior booster doses and of the intervals between prior booster doses. The study conducted with the mRNA-1273.211 bivalent formulation provided more comprehensive safety data with a longer median follow-up duration of 245 days.

Based on the collective evidence from the aforementioned safety data and experience with other bivalent mRNA vaccines, market experiences from the original Spikevax vaccine, and relevant non‑clinical data, as well as taking into context the current and evolving pandemic, the totality of available evidence reasons that a booster dose of the Spikevax Bivalent (Original / Omicron BA.4/5) is expected to have a similar safety profile. Further safety data will be provided to confirm this assumption as part of the terms and conditions of authorization.

Overall, the emerging safety profile of Spikevax monovalent and bivalent variant vaccines is similar to that of the original Spikevax with the caveat that the size of the safety database for the variant vaccine formulations is not large enough to characterize the frequency of rare adverse events. This limitation will be addressed via post-market surveillance and fulfillment of the requirements set in the terms and conditions that were put in place at the time of authorization. Specifically, an open-label clinical study, Study P205 (Part H), was initiated on August 11, 2022. Part H is designed to assess the safety and immunogenicity of Spikevax Bivalent (Original / Omicron BA.4/5) as a second booster following primary series and booster with the original Spikevax vaccine, using a historical original Spikevax vaccine fourth dose comparator (Study P205 Part F, cohort 2). Day 181 safety and reactogenicity data from Study P205 (Part H) will be provided as soon as it becomes available, as part of the terms and conditions.

Summary of Safety Analysis

Across the clinical development program, ModernaTX, Inc. has used the same LNP‑based formulation, regardless of the mRNA content and coding sequence per dose. The mRNAs encoding different immunogens (i.e., ancestral SARS‑CoV‑2 strain, variants of interest [VOCs]) are chemically and physically highly similar, while the adjuvant used (LNPs) in the formulations is identical. The safety results are consistent across the clinical development program studies, and Spikevax Bivalent (Original / Omicron BA.4/5) is formulated and manufactured in the same way as the original Spikevax vaccine.

The inflammatory milieu induced by the LNPs is, at least in part, responsible for the reactogenicity of the mRNA-LNP platform. A marginally higher frequency of reactogenicity was noted for the formulations encoding VOC (Spikevax Bivalent and mRNA-1237.211) versus the formulations encoding for the ancestral strain alone (the original Spikevax vaccine). This marginal difference was not statistically significant and it is not deemed to be clinically meaningful. Overall, the reactogenicity profiles of the reviewed formulations were comparable dose per dose, regardless of the mRNA platform administered.

Input on the approach to evaluating the available data for Spikevax Bivalent (Original / Omicron BA.4/5) was sought from a panel of Canadian experts. Individual meetings took place with 6 experts between September 14 and 20, 2022. Overall, none of the experts that were consulted voiced major concerns regarding the proposed regulatory approach for the review of Spikevax Bivalent (Original / Omicron BA.4/5). Generally, they expressed confidence in the adverse monitoring system for authorized mRNA vaccines and emphasized the importance of monitoring real world evidence safety information and obtaining safety data from the ongoing studies required by the terms and conditions that were put in place at the time of authorization.

In conclusion, inference on the reactogenicity and safety of Spikevax Bivalent (Original / Omicron BA.4/5) is based on extrapolation from the very large safety database for the original Spikevax vaccine, as well as the broadly similar safety profiles of the original Spikevax vaccine and the Spikevax variant vaccines derived from cross‑comparisons (although not all compared in the same study). Given the current epidemiological context, the safety results obtained across the clinical development program support an acceptable safety profile for both monovalent and bivalent variant vaccines with divergent coding sequences. In addition, real-world evidence and Canadian expert opinions supported the regulatory decision. Taken together, these data do not raise concerns with respect to the safety profile of Spikevax Bivalent (Original / Omicron BA.4/5).

The size of the accrued pivotal safety database across the clinical development program is considered acceptable given the considerable safety experience accumulated via the mass vaccination setting with the monovalent mRNA-based COVID-19 platforms and given that the investigational product retains the ancestral SARS‑CoV‑2 spike protein mRNA sequence that is already authorized and with which there is experience in routine use.

Given that it is not feasible to conduct clinical studies rapidly enough to respond to the emergence of SARS-CoV-2 variants that may evade the immune response conferred by previously‑authorized vaccines, and in light of the need for a booster dose to protect against circulating VOCs, Spikevax Bivalent (Original / Omicron BA.4/5) was authorized subject to terms and conditions.

Risk Management Plan

A Core (European Union [EU]) Risk Management Plan (RMP) and a Canadian RMP Addendum for Spikevax Bivalent (Original / Omicron BA.4/5) were submitted by ModernaTX, Inc. 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 ModernaTX, Inc. as part of the NDS for Spikevax Bivalent (Original / Omicron BA.4/5). 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 for Spikevax Bivalent (Original / Omicron BA.4/5).

Clinical data for Spikevax Bivalent (Original / Omicron BA.4/5) were not yet available at the time of authorization. However, based on the extrapolation of clinical data from Spikevax Bivalent and clinical and post‑market data with the original Spikevax vaccine to date, including when used as a booster dose, the RMP included three important identified risks (anaphylaxis, myocarditis, and pericarditis) and two important potential risks (vaccine‑associated enhanced disease [VAED] and vaccine-associated enhanced respiratory disease [VAERD]). The RMP also identified nine areas of missing (limited/no clinical data) information: “use in pregnancy”, “use in breastfeeding”, “use in immunocompromised patients”, “use in subjects with autoimmune or inflammatory disorders”, “use in frail patients with unstable health conditions and co‑morbidities”, “potential interaction with other vaccines and other drug products”, “long‑term safety", “long‑term effectiveness”, and “use in subjects less than 18 years of age”.

The proposed routine and additional pharmacovigilance activities for the above safety concerns are considered to be acceptable. The sponsor confirmed that they would be applied in the Canadian context. Additional pharmacovigilance activities include continued safety surveillance of ongoing clinical and post‑authorization studies undertaken for the original Spikevax vaccine, Spikevax Bivalent (Original / Omicron BA.1) and Spikevax Bivalent (Original / Omicron BA.4/5) and one ongoing clinical study evaluating the immunogenicity and safety of Spikevax boosters for SARS‑CoV‑2 variants including Omicron BA.4/5 (Study P205; Part H). Routine risk minimization measures (i.e., product monograph and labelling) are also considered to be appropriate.

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

• Children: Children less than 18 years of age were not included in the clinical development program. This sub-population was identified as missing information in the Canadian Addendum. Studies of Spikevax Bivalent (Original / Omicron BA.4/5) in children are planned.

• Pregnant women: More information is needed about vaccine use in pregnant women. This sub-population was identified as missing information in the RMP. The sponsor will monitor and submit monthly safety reports to Health Canada. The sponsor will assess outcomes in pregnancy and lactation as part of ongoing and planned studies.

• Breastfeeding women: This sub‑population was identified as missing information in the RMP. The sponsor will monitor and submit monthly safety reports to Health Canada. The sponsor will assess outcomes in pregnancy and lactation as part of ongoing and planned studies.

• Immunocompromised individuals and patients with chronic or debilitating conditions: These individuals were not included in the clinical development program. This sub-population was identified as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada.

• Anaphylaxis: This was listed as an important identified risk in the Canadian Addendum. This risk will be assessed via routine pharmacovigilance activities and reported in monthly safety reports.

• Myocarditis and pericarditis: The risks of myocarditis and pericarditis were listed as important identified risks in the RMP. These risks will be assessed via routine pharmacovigilance activities and reported in monthly safety reports.

The sponsor will also provide prompt reporting of adverse reactions. The submission of post‑market safety summary reports has been adjusted to a monthly basis for enhanced monitoring.

In view of the limited clinical data available for Spikevax Bivalent (Original / Omicron BA.4/5), it is important that further safety data are collected in the post‑marketing setting. The sponsor is expected to include Spikevax Bivalent (Original / Omicron BA.4/5) in all ongoing post‑authorization safety studies. Results related to safety and effectiveness from ongoing and planned studies will be submitted for review as they become available. The sponsor is also expected to provide an updated RMP to discuss any additional pharmacovigilance activities for long‑term safety and effectiveness of Spikevax Bivalent (Original / Omicron BA.4/5).

There are no significant outstanding issues requiring risk management beyond labelling or that warrant consideration in addition to the outstanding safety requirements outlined in the terms and conditions and in the RMP that would preclude the approval of this submission for Spikevax Bivalent (Original / Omicron BA.4/5).

The benefit of the immediate availability of Spikevax Bivalent (Original / Omicron BA.4/5) was determined to outweigh the remaining uncertainties of the data provided. Based on updated post-market safety for the authorized original Spikevax vaccine administered as a primary series and as a booster dose, it can be concluded that Spikevax Bivalent (Original / Omicron BA.4/5) will have an acceptable safety profile. In consideration of the data provided, along with knowledge of other bivalent mRNA vaccines, market experiences from the original Spikevax vaccine, and non‑clinical data, as well as taking into context the current and evolving pandemic, the totality of available evidence reasons that a booster dose of Spikevax Bivalent (Original / Omicron BA.4/5) is expected to elicit an immune response that will confer protection against COVID-19. Immunogenicity and additional safety data will be provided as part of the terms and conditions to confirm these assumptions.

For more information, refer to the Spikevax Bivalent (Original / Omicron BA.4/5) Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.