Regulatory Decision Summary for Spikevax XBB.1.5
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
Vaccines, for human use
Type of Submission:
New Drug Submission (New Active Substance) (COVID-19)
Authorized; issued a Notice of Compliance in accordance with the Food and Drug Regulations
What was the purpose of this submission?
The purpose of this submission was to seek authorization for a new messenger ribonucleic acid (mRNA) -based vaccine formulation Spikevax XBB.1.5 (andusomeran mRNA vaccine) 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.
The recommended dosing regimen is proposed to be 2 doses for children aged 6 months to 4 years who were not previously immunized and one dose in children who have been immunized. Individuals over 5 years receive one dose regardless of immunization status at an interval of at least 6 months following last dose.
Why was the decision issued?
Given the antigenic differences in currently circulating SARS-CoV-2 (XBB lineage) compared to the reference strain there are still uncertainties in the evolution of SARS-CoV-2 and the genetic and antigenic characteristics of future variants. Therefore, an updated vaccine composition that contains an updated construct encoding the spike protein for the prominent variants of concern may provide a better antibody response against these circulating and emerging variants. The dose and dosing regimen for Spikevax XBB.1.5 has been updated to reflect an internationally agreed upon simplified schedule. The recommended dosing regimen is proposed to be 2 doses for children aged 6 months to 4 years who were not previously immunized and one dose in children who have been immunized. Individuals over 5 years receive one dose regardless of immunization status at an interval of at least 6 months following last dose.
The Sponsor submitted non-clinical immunogenicity studies conducted with monovalent (XBB.1.5) and bivalent (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. The non-clinical data described builds from and is directly linked to non-clinical pharmacodynamic, pharmacokinetic, and toxicology data from the following previously submitted and reviewed COVID-19 mRNA vaccines in the Spikevax portfolio. When administered as a two-dose primary series in naïve mice, both the monovalent and bivalent formulations of the XBB.1.5-variant matched vaccines elicited robust binding antibody titers against the spike protein as well as neutralizing antibody titers against both XBB.1.5 and XBB.1.16 strains. This data is consistent with non-clinical immunogenicity data generated by the Sponsor for previously reviewed and approved variant-matched vaccines against the Omicron BA.1 and BA.4/BA.5 strains. Moreover, no toxicity issues were identified in the animals over the course of this 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.
The safety, reactogenicity, and immunogenicity of Spikevax XBB.1.5 are evaluated in an ongoing Phase 2/3 open-label study in participants 18 years of age and older (study mRNA-1273-P205, Part J). In addition, the safety and effectiveness of Spikevax XBB.1.5 for individuals 6 months of age and older is inferred from studies of a primary series and booster dose of Spikevax Bivalent (Original/Omicron BA.1) in individuals 6 months to 5 years of age, a booster dose of Spikevax Bivalent (Original/Omicron BA.1) in individuals >18 years of age, as well as data from studies which evaluated the primary series and booster vaccination with Spikevax (original).
In study mRNA-1273-P205 Part J, 50 participants received a 50 mcg dose of Spikevax XBB.1.5, and 51 participants received a dose of an investigational bivalent vaccine (XBB.1.5/Omicron BA.4/5). Overall, of the Spikevax XBB.1.5 group 60.0% were female and 40.0% were male. The mean age was 51.6 years (range: 21 to 84 years) and 22.0% of participants were ≥65 years of age. The interval between the fourth dose (Spikevax Bivalent Original/Omicron BA.4/5) and the fifth dose of Spikevax XBB.1.5 was a median of 8.2 months. Spikevax XBB.1.5 elicited neutralizing responses at Day 15 against the SARS-CoV-2 variants assessed, including XBB.1.5, XBB.1.16, BA.4/5, BQ.1.1 and D614G. When assessed against XBB.1.5 the neutralising antibody geometric mean titre (GMT) and corresponding 95% CI was 2,579.0 (1,809.1, 3,676.7) 15 days after the Spikevax XBB.1.5 dose, and the GMR (95% confidence interval [CI]) was 16.7 (12.8, 21.7). When Spikevax XBB.1.5 was assessed against BA.4/5, the GMT (95% CI) was 9,673.4 (6,965.6, 13,433.8) and the GMR was 6.3 (4.8, 8.2). Data on Day 29 will be submitted at a later time as a Term and Condition for authorization. The immunogenicity results suggest that a dose of Spikevax XBB.1.5 could provide superior protection against antigen-matched and related Omicron variants.
Regarding safety, the median follow-up time in the interim analysis was 20 days (data cutoff date of 16 May 2023). Reactogenicity was similar to prior doses of the original Spikevax vaccine and Spikevax Bivalent Original/Omicron BA.4/5. The percentage of participants reporting any solicited local (68% Spikevax XBB.1.5, 84.3% Spikevax XBB.1.5 + BA.4/5) and systemic adverse reactions (58% Spikevax XBB.1.5, 64.7% Spikevax XBB.1.5 + BA.4/5) within seven days after vaccination. The XBB.1.5-containing vaccines (monovalent Spikevax XBB.1.5, bivalent Spikevax XBB.1.5 + BA.4/5) given as a fifth dose were well tolerated. There were no Grade 4 local or systemic reactions and no fatal events or serious adverse events in this interim analysis. No adverse events of special interest (AESI) were reported during the study period. Specifically, there were no reports of myocarditis, pericarditis, myopericarditis, or thrombosis.
Given the aforementioned immunogenicity data from the Spikevax XBB.1.5 vaccine administered as booster dose in individuals 18 years of age and older, combined with accumulated experience with the primary series of the Spikevax monovalent formulation, and a booster dose of Spikevax Original/Omicron BA.1 or Spikevax Original/Omicron BA.4/BA.5, along with the understanding that the Spikevax XBB.1.5 vaccine is manufactured by the same process as the currently approved Spikevax formulations, it is reasonable to generalize the inferred effectiveness of Spikevax XBB.1.5 administered under the new simplified schedule in individuals 6 months and older.
Variant-containing vaccine studies to date suggest that a variant-containing primary series should also induce superior nAb responses against circulating variants, translating to enhanced vaccine effectiveness. More effective COVID-19 vaccine primary series will be particularly relevant to children in each new birth cohort who may lack prior natural infection or vaccine-induced immunity. The two dose regimen is considered because this young population is more likely immune naïve against COVID-19, and in order to ensure that the efficacy will be the similar clinically to that of the 2 dose primary series achieved with original trials.
The current context encompasses, the state of the pandemic transitioning towards an ongoing health issue, the need for vaccines that are more targeted to currently circulating strains, and the overall impact on public health systems and incorporation into future immunization programs within Canada. This context has been taken into account when deciding the level of clinical evidence required to support approval of the Spikevax XBB.1.5 vaccine in individuals 6 months and older. Based on the totality of data reviewed, the safety profile of Spikevax XBB.1.5, administered as a 5th booster dose in individuals 18 years of age and older is expected to be comparable with the safety profile of other formulation of Spikevax formulations.
An updated core Risk Management Plan (RMP) and a Canadian RMP Addendum were included in the submission for Spikevax XBB.1.5. 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. Upon review, the RMP was considered to be acceptable and identified appropriate monitoring (pharmacovigilance) activities and risk minimization measures for Spikevax XBB.1.5 based on the known safety profile of Spikevax, Spikevax Original/Omicron BA.1 and Spikevax Original/Omicron BA.4/5. This included providing information in the product monograph and identifying populations where more data are needed. The RMP will be updated to reflect additional safety information as this is collected. In addition to regulatory requirements for post-market monitoring, Terms and Conditions have imposed for the submission of periodic safety update reports/periodic benefit risk evaluation reports and RMPs to Health Canada. Results related to safety and effectiveness from ongoing and planned studies will be submitted as they become available.
Based on the totality of the information, the benefit-risk profile for a dose of Spikevax XBB.1.5 is considered favourable in individuals 6 months of age and older.
For further details about Spikevax XBB.1.5, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.
Date of Decision:
Manufacturer / Sponsor:
Drug Identification Number Issued:
Schedule D drug