Summary Basis of Decision for Spikevax Bivalent

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

Clinical Pharmacology

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

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

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

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

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

Clinical Efficacy

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

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

Immunogenicity

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

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

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

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

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

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

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

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

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

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

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

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

Indication

Sponsor's proposed indication	Health Canada-approved indication
Spikevax Bivalent (elasomeran/imelasomeran) Original/Omicron mRNA vaccine is indicated for active immunization against coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in individuals 12 years of age and older.	Spikevax Bivalent (elasomeran/imelasomeran) Original/Omicron mRNA vaccine is indicated as a booster dose for active immunization against coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in individuals 18 years of age and older.

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

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

Clinical Safety

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

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

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

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

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

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

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

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

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

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

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

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

Risk Management Plan

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

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

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

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

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

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

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

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

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

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

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