Regulatory Decision Summary for Comirnaty Original & Omicron BA.4/BA.5

The purpose of this submission was to seek authorization for an extension for the use of a messenger ribonucleic acid (mRNA)-based vaccine formulation Comirnaty Original & Omicron BA.4/BA.5, containing two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA components (Original strain [Comirnaty] and Omicron BA.4/BA.5 strain) in equal amounts in a 3 mcg (1.5 mcg/1.5mcg) formulation as a 3-dose primary series in individuals 6 months to 4 years of age. The dosing regimen was proposed to be administered as a primary series of 3 doses (3 mcg each) with the initial two doses given 3 weeks apart followed by a third dose given at least 8 weeks after the second dose.

After evaluation of the submitted data package, Health Canada authorized that a 3-dose primary series of Comirnaty Original & Omicron BA.4/BA.5 at 3 mcg per dose may be administered in individuals 6 months through 4 years of age.

The safety and effectiveness of a 3-dose primary series of Comirnaty Original & Omicron BA.4/BA.5 in individuals 6 months to <5 years of age (YOA) is supported largely by safety and effectiveness data accrued with the monovalent formulation (Comirnaty) administered as a 3-dose primary series currently authorized for the 6 months to <5 years age bracket. Preliminary clinical data from studies of a booster (fourth) dose of Comirnaty Original & Omicron BA.4/BA.5 in this age bracket, and a booster (fourth) dose in children ≥5 years to <12 YOA, along with a booster (fourth) dose in adolescents ≥12 YOA and adults ≥18 YOA is considered marginally supportive as proof of concept.

Given the antigenic differences in currently circulating SARS-CoV-2 compared to the reference strain there are uncertainties in the evolution of SARS-CoV-2 and the genetic and antigenic characteristics of future variants. Therefore, an updated vaccine composition that contains constructs encoding the spike protein for both, the reference and Omicron (the most antigenically distinct SARS-CoV-2 variant of concern to date), may provide a broader antibody response against circulating and emerging variants, while retaining cross-protective immunity against severe disease. The dose and dosing regimen for Comirnaty Original & Omicron BA.4/BA.5 is the same as currently on label for Comirnaty for this age bracket and consists of a 3-dose primary series where the second dose is administered 3 weeks after the first dose, followed by a third dose administered at least 8 weeks after the second dose.

Pre-clinical data indicate that while the polyclonal T-cell response is not affected by variant-specific mutations, the bivalent formulations induce a broader immune response against all strains tested in comparison with the monovalent variant-matched formulations. Overall, pre-clinical data supports the improved antibody response of bivalent vaccines over the monovalent formulations against Omicron variants when used in naïve animals as primary series. Across the data generated to date, including evaluation of bivalent Omicron BA.4/5, preclinical data have reliably predicted the responses trends in humans, and this speaks to the translatability of the provided non-clinical data as supportive to use in naïve humans.

The Sponsor provided data from a Phase 1/2/3 Study C4591048 of a booster (fourth) dose of the bivalent Comirnaty Original & Omicron BA.4/BA.5 at 3 mcg in children 6 months to less than 5 years of age at 1-month post-dose. Neutralizing antibodies against the SARS-CoV-2 Omicron BA.4/BA.5 were numerically higher by approximately 2.7-fold in children 1 month following the booster (fourth) dose of the Comirnaty Original & Omicron BA.4/BA.5 vaccine (N = 58) as compared to children that had received 3 doses of the monovalent original Comirnaty vaccine (N = 54) 1-month post-dose. Neutralizing antibodies against the SARS-CoV-2 ancestral strain were numerically similar in the same children. This 1-month post dose-4 immunogenicity data is considered marginally supportive as proof of concept for the Comirnaty Original & Omicron BA.4/BA.5 3-dose primary series indication requested for authorization.

Regarding safety, 1-month post-dose safety data in 163 children were provided with a data cutoff date of November 30, 2022, representing a median follow-up time of 1.8 months (1.3-2.5). The pattern of local and systemic reactions reported within 7 days after the Comirnaty Original & Omicron BA.4/BA.5 vaccine was generally comparable to that previously observed in association with the original Comirnaty monovalent formulation. Most local and systemic reactions were mild or moderate in severity. No severe or Grade 4 local or systemic reactions were reported. The onset for all local reactions was 1 to 2 days, and all events resolved within 1 to 3 days after onset. The median onset for most systemic reactions was 1 to 6 days, and most events resolved within a median duration of 1 to 3 days after onset. Overall, adverse events (AEs) were reported by 6 (15.4%) and 6 (4.8%) participants in the ≥6 months to <2 years of age group and ≥2 to <5 years of age group, respectively. Related AEs were consistent with reactogenicity events. No severe AEs, life-threatening AEs, serious AEs, AEs leading to withdrawal, or death were reported from study vaccination to 1 month after study vaccination. Additionally, no AEs of lymphadenopathy, rash, anaphylaxis/hypersensitivity, appendicitis, Bell’s palsy, and myocarditis/pericarditis were reported. Although these one-month post-dose reactogenicity and AE data are following a booster (fourth) dose of the Comirnaty Original & Omicron BA.4/BA.5 and are not data from administration as part of the primary series being sought as part of this authorization, they represent the first time this formulation has been administered in this age bracket and are thus considered valuable for safety of the formulation. Overall, no new safety concerns were raised; however, the safety database is too small to draw conclusions on more uncommon, rare, or very rare AEs and the follow-up is of short duration. Additionally, in the absence of a placebo group, it is difficult to ascertain causality of certain local and systemic events in this age group. The reactogenicity profile within (within 7 days post-dose) was generally consistent and comparable between formulations.

A Comirnaty Original & Omicron BA.4/BA.5 3-dose primary series is considered particularly important for infants who age into vaccine eligibility at 6 months and are less likely to be previously infected than older children and adults. The Sponsor’s ongoing Study C4591048, Substudy A evaluates the safety, tolerability, and immunogenicity of a 3-dose primary series of Comirnaty Original & Omicron BA.4/BA.5 at 3, 6 or 10 mcg in a group of subjects 6 months to less than 5 years of age who have not received a previous coronavirus vaccination. Data outcomes from this substudy will be required as a Terms and Conditions for this authorization.

Given the aforementioned immunogenicity data from the Comirnaty Original & Omicron BA.4/BA.5 administered as booster doses in individuals 6 months of age and older, combined with accumulated experience with the primary series of the Comirnaty monovalent formulation, along with the understanding that the Comirnaty Original & Omicron BA.4/BA.5 vaccine is manufactured by the same process as the currently approved monovalent formulation, it is reasonable to generalize the inferred effectiveness of Comirnaty Original & Omicron BA.4/BA.5 administered as a 3-dose primary series in children 6 months to less than 5 years of age. Although, there is uncertainty as to whether the investigational product would present as statistically superior with respect to the neutralizing antibodies geometric mean ratios compared to the prototype against the circulating variants of concern in general and the currently circulation Omicron sub-lineages, in particular in individuals 6 months to less than 5 years of age, when administered as a 3-dose primary series, from a clinical perspective, it can be reasonably anticipated to have potential to offer a greater magnitude and breadth of protection with respect to the overall immune response.

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 Comirnaty Original & Omicron BA.4/BA.5 vaccine as a primary series in children 6 months to less than 5 years of age. Based on the totality of data reviewed, the safety profile of the Comirnaty Bivalent Original & Omicron BA.4/ BA.5, administered as a 3-dose primary series in individuals 6 month to less than 5 years of age is expected to be comparable with the safety profile of the monovalent formulation administered as a 3-dose primary series in this age bracket.

An updated Core Risk Management Plan (RMP) and a Canadian RMP Addendum were included in the submission to expand the currently approved indication for Comirnaty Original & Omicron BA.4/BA.5 vaccine to include a three-dose primary series in individuals 6 months to <5 years of age. 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 based on the known safety profile of Comirnaty (original) vaccine as a primary series and Comirnaty Original & Omicron BA.4/BA.5 vaccine as a booster dose. 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 been included to submit periodic safety update reports/periodic benefit risk evaluation reports (PSURs/PBRERs) and updated RMP to Health Canada. Results related to safety and effectiveness from ongoing and planned studies will be submitted as they become available.

Conclusion

Based on the totality of the information, the benefit-risk profile for a 3-dose primary series of Comirnaty Original & Omicron BA.4/BA.5 of Comirnaty is considered favourable in children 6 months to <5 years of age.

For further details about Comirnaty Original & Omicron BA.4/BA.5, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.