Regulatory Decision Summary for Comirnaty Original & Omicron BA.4/BA.5 (tozinameran / famtozinameran)

The purpose of this submission was to seek authorization for an extension for the use of an mRNA-based vaccine formulation Comirnaty Original & Omicron BA.4/BA.5, containing two SARS-CoV2 mRNA components (Original strain [Comirnaty] and Omicron BA.4/BA.5 strain) in equal amounts in a 10 mcg [5 through 11 years old] and 30 mcg [in >12 years old] dose as a 2-dose primary series. The dosing regimen was proposed to be an interval of 3 weeks between the two doses.

The safety and effectiveness of a 2-dose primary series of Comirnaty Original & Omicron BA.4/BA.5 in individuals 5 years of age and older is based on the following considerations taken within the context of the current epidemiological context:

• Safety and effectiveness of primary series of Comirnaty in individuals 5 years of age and older.

• Preliminary safety data for participants ≥5 years to <12 years of age in Group 2 - Substudy D of Study C4591048 following administration of Comirnaty Original & Omicron BA.4/BA.5 vaccine at 10 mcg as a booster (fourth dose).

• Preliminary immunogenicity and safety data from participants in Cohort 2 (≥12 years of age) and Cohort 3 (≥18 years of age) of Study C4591044 following administration of Comirnaty Original & Omicron BA.4/BA.5 vaccine at 30 or 60 mcg as a booster (fourth dose).

• Clinical data from the studies of a booster dose of Comirnaty Original/Omicron BA.1 vaccine at 30 mcg in adults >55 years of age.

• Estimates of current seroprevalence rates

• Preclinical data

Comirnaty Original

The safety and immunogenicity of the primary series of Comirnaty Original in participants 5 years of age and older has been extensively characterized in several clinical studies conducted globally. These data were previously supplied to Health Canada to support the authorization of Comirnaty Original as a 2-sdose primary series. For further details, refer to see the Regulatory Decision Summary (Food and Drug Regulations) document dated 2021-09-16 for Comirnaty Original.

Comirnaty Original & Omicron BA.4/BA.5

Study C4591044

Interim 1-month post dose safety and immunogenicity clinical data from Study C4591044 (Cohorts 2 and 3) of a booster dose of Comirnaty Original & Omicron BA.4/BA.5 was provided in response to Clinical Term and Condition No. 5 a and b issued on October 7, 2022. Study C4591044 is an ongoing, interventional, randomized, active-controlled, Phase 2/3 study to investigate the safety, tolerability, and immunogenicity of bivalent BNT162b RNA-based vaccine candidates as a booster dose in COVID-19 vaccine–experienced healthy individuals, which includes evaluation of the safety, tolerability, and immunogenicity of Comirnaty Original & Omicron BA.4/BA.5 vaccine in individuals ≥12 years of age.

Analysis of immunogenicity data from Study C4591044 Cohort 2 and Cohort 2 and Cohort 3 combined for Comirnaty-experienced subjects who received a booster (Dose 4) of Comirnaty Original & Omicron BA.4/BA.5 at 30 or 60 mcg demonstrated a relatively robust immune response against Omicron BA.4/BA.5. Omicron BA.4/BA.5 geometric mean titres (GMT)s (95% confidence interval [CI]) in the evaluable immunogenicity population (at 30 mcg and 60 mcg dose) were significantly lower pre-vaccination versus 1-month post-dose 4. Sensitivity analyses demonstrated that pre- and post-vaccination Omicron BA.4/BA.5 GMTs were higher in subjects who were baseline positive compared with those were baseline negative in all age and vaccine groups. Subgroup analyses revealed that Comirnaty Original & Omicron BA.4/BA.5 elicited robust immune response against Omicron BA.4/BA.5 in all age groups and the response was higher than the corresponding Comirnaty Original/Omicron BA.1 dose groups (GMT [95% CI]). Immune responses against Omicron sublineages (BA.4.6, BA.2.75.2 and BQ.1.1) were also higher compared to Comirnaty vaccine while immune responses against Omicron XBB were limited.

Superiority of Comirnaty Original & Omicron BA.4/BA.5 30 mcg to Comirnaty Original 30 mcg in the >55 year age group from Study C4591031, Substudy E was met with respect to anti-Omicron BA.4/BA.5 neutralizing titers. Noninferiority based on Omicron BA.4/BA.5 seroresponse and anti-reference strain immune response based on geometric mean ratios (GMRs) was also met in the >55 years of age group. Noninferiority of the anti-Omicron BA.4/BA.5 response based on GMR and seroresponse for Comirnaty Original & Omicron BA.4/BA.5 30 mcg in subjects 18 through 55 years of age to subjects >55 years of age in the Comirnaty Original & Omicron BA.4/BA.5 30 mcg were also met. These clinical data support the effectiveness of the BA.4/5 variant-matched bivalent formulation.

These preliminary data show that a booster (Dose 4) dose of 30 mcg of Comirnaty Original & Omicron BA.4/BA.5 vaccine elicited higher Omicron BA.4/BA.5 specific neutralization titers and numerically higher reference strain neutralization titers 1-month post-vaccination in both age groups of 18 to 55 and >55 years compared to an adult comparator group from Study C4591031, Substudy E (>55 years of age) who received a booster dose of Comirnaty Original at the 30 mcg dose level. There is currently no immunological correlate of protection established for COVID-19, thus, the relevance of numerical titre differences, in terms of impact on protection against severe disease or any clinical disease, cannot be determined. This 1-month post Dose-4 immunogenicity data is considered marginally supportive at best as proof of concept for the indication sought after.

A review of the 7 days post-dose reactogenicity and 1 month adverse events (AEs) data for subjects enrolled in Cohort 2 has been conducted. Generally, the reactogenicity pattern (including the frequency and severity) of a booster dose of Comirnaty Original & Omicron BA.4/ BA.5 was similar to the reactogenicity profile of Comirnaty Original/Omicron BA.1 bivalent vaccine and to the Comirnaty Original within the respective age bracket as previously reported, reactogenicity was higher in younger individuals.

Interim 1-month post dose safety clinical data from study C4591044 (Cohorts 2 [cut-off date October 12, 2022] and 3 [cutoff date October 31, 2022]) of a booster dose of Comirnaty Original & Omicron BA.4/BA.5 was provided in response to Clinical Term and Condition No. 5 a and b issued on 7 October 2022.

Cohort 2

Overall, the reactogenicity profile within 7 days after administration of the Comirnaty Original & Omicron BA.4/BA.5 vaccine was generally similar to that previously observed in association with booster doses of an Comirnaty Original/Omicron BA.1 and Comirnaty Original within the respective age groups at the same dose. There was an observed dose-dependency for reactogenicity. A single serious adverse event (SAE) of dyspnea was reported in a >55 years of age subject who received the 30 mcg dose.

The following adverse events of special interest (AESI) were reported: lymphadenopathy (n = 2), rash (n = 1) dyspnea (n = 2), contusion (n = 1), arthralgia (n = 1). No AESI of myo-/pericarditis were reported.

Combined Cohort 2 (Group 2 and Group 4) and Cohort 3

The pattern of the local and systemic reactogenicity reported within 7 days following the administration of the Comirnaty Original & Omicron BA.4/BA.5 was generally similar to that previously observed in association with an Comirnaty Original/Omicron BA.1 and Comirnaty Original within the respective age groups at the 30 mcg dose level. The frequency of reactions tended to be lower in the participants >55 years of age. Only two AESI were reported: arthralgia (n = 1) and lymphadenopathy (n = 1). Overall, no new safety signals have been identified; however, the small sample size and the short duration of the follow-up (1 month) do not allow for quantification of the frequency of AEs. Thus, causality cannot be established; safety data from a longer Follow-up period is subject to the outstanding Terms and Conditions and post-market surveillance needs to be further conducted.

Study C4591048

One-month post-dose safety data for participants ≥5 years to <12 years of age in Group 2 - Substudy D of Study C4591048 following administration of Comirnaty Original & Omicron BA.4/BA.5 vaccine at 10 mcg as a booster (Dose 4) was provided in response to Clinical No. 1 issued on December 9, 2022.

Study C4591048 is a Phase 1/2/3 study that investigates the safety, tolerability, and immunogenicity of a bivalent BNT162b2 RNA-based vaccine candidate. One-month post-dose reactogenicity and AE data (n = 113; data cutoff date: November 25, 2022) in the ≥5 to <12 years of age in Group 2 of Substudy D who received a second booster (dose 4; median time since last prior dose was 5.5 months) of the Comirnaty Original & Omicron BA.4/BA.5 at 10 mcg was provided and partly satisfies the Terms and Conditions No. 1 issued on 9 December 2022. The pattern of local and systemic reactions reported within 7 days after the administration of Comirnaty Original & Omicron BA.4/BA.5 vaccine was generally comparable to that previously observed in association with a booster dose (Dose 3) of Comirnaty Original. The median onset for local adverse reactions (ARs) was 1 to 2 days for the local ARs and 2 to 4 days for the systemic ARs; most reactions were mild or moderate in severity and no Grade 4 ARs were reported. A total of 4 (3.5%) subjects reported an adverse event (AE) from vaccination to 1-month post-dose. No SAEs or life-threatening AEs were reported. No withdrawals due to AEs, or deaths were reported. A single AESI (lymphadenopathy) was reported. Overall, no new safety concerns were raised; however, it should be noted that the sample size is too small to detect any safety pattern.

The reactogenicity profile within (within 7 days post-dose) was generally consistent and comparable between formulations.

Study C4591031, Substudy D Cohort 2 and Substudy E

Reference data from an ongoing clinical trial, C4591031 (Substudy E) was also provided. Study C4591031, Substudy E is a randomized, observer-blinded designed to evaluate the safety, tolerability, and immunogenicity of high-dose of Comirnaty Original (60 mcg), high-dose Comirnaty Original / Omicron BA.1 (60 mcg), and a high-dose combination of Comirnaty Original and Comirnaty Original & Omicron BA.4/BA.5 at 60 mcg (30 mcg each), given as a booster (Dose 4). Approximately 1,920 subjects >55 years of age and 990 subjects 18 to 55 years of age who have received 3 prior doses of BNT162b2 (30-mcg doses), with the most recent dose being 5 to 12 months prior to randomization were enrolled. Only interim data for participants >55 years of age were provided.

Marginally supportive data from subjects 18 to ≤55 years of age (n = 640) in Study C4591031, Substudy D, Cohort 2 who had a median of 1.4 months of follow-up after a booster dose (Dose 4) demonstrated that the safety profile of a monovalent Comirnaty encoding for the Omicron strain at 30 mcg and Comirnaty Original at 30 mcg up to 1 month post-Dose 4 vaccination was acceptable and consistent with results previously reported in clinical trials for Comirnaty Original 30 mcg in this age group. Additional supportive data from subjects >55 years of age (n = 1,840) who received Comirnaty Original, monovalent Comirnaty encoding for the Omicron strain or Comirnaty Original & Omicron BA.4/BA.5 30 mcg or 60 mcg dose level as a booster (Dose 4) did not identify any new safety-related concerns.

Cumulative safety data with mono- and bivalent formulations administered as booster doses in individuals >12 years of age has shown a marginally higher frequency of reactogenicity for the formulations encoding VOC vs. the formulations encoding for the ancestral strain alone (Comirnaty); notwithstanding, this marginal difference is not statistically significant, and it is not deemed to be clinically meaningful. Overall, safety data accrued with Comirnaty mono- and bivalent formulations suggests that the safety profiles of Comirnaty, Comirnaty Original/Omicron BA.1 and Comirnaty Original & Omicron BA.4/ BA.5 (primary series or booster doses) are comparable dose per dose and vaccination scheme per vaccination scheme.

Overall, the findings indicated that the Comirnaty Original & Omicron BA.4/BA.5 provides better immune response to the Omicron BA.4/5 strain. Planned post-market studies are expected to provide additional validation of the immune response when the vaccine is used as a primary series. No new safety concerns were identified in these studies when compared to the currently approved original Comirnaty Original vaccine. No deaths or AESI including cases of myocarditis or pericarditis occurred. Safety concerns remain as those captured in the Comirnaty Original label.

Estimates of current seroprevalence rates

Cumulative data on comparative protection of immunity relative to previous infection only, vaccination only, and hybrid immunity suggests that individuals with hybrid immunity have the highest magnitude and durability of protection against all outcomes. Overall, rapidly accumulating epidemiologic and immunogenetic evidence pertaining to hybrid protection against Omicron infection suggests that vaccination among individuals with prior heterologous SARS-CoV-2 infection provides the greatest protection against severe outcomes as a result of reinfection with Omicron sub-lineages.

Preclinical data

Preclinical studies associated with the authorization of Comirnaty Original are considered supportive as proof of concept for the herein authorization. Additionally, the Sponsor has provided updated data for two preclinical studies which assess the immunogenicity of Omicron variant-matched vaccines as a two-dose primary series in naïve mice. These data indicate that two intramuscular doses of monovalent Omicron variant-matched formulation elicit a strong neutralizing antibody response against Omicron sublineages, with the greatest response observed in the variant-matched target and reduced response to the reference strain. The bivalent BA.4/BA.5 variant-matched formulations elicited a strong broad neutralizing antibody response to all Omicron variants, as well as the reference strain. Both the monovalent and bivalent formulations of the variant-matched formulation produced a high frequency of spike-specific CD8+ and CD4+ T cells, as assessed by flow cytometry, with intracellular cytokine staining indicating a TH1-based response. The magnitude of the polyclonal T cell response was similar for both reference and Omicron BA.4/BA.5 strains, indicating that this response is not affected by variant-specific mutations. These data are consistent with the current literature.

Taken together, this preclinical data indicates that the bivalent BA.4/BA.5 variant-matched formulations provides a broader scope of neutralizing antibody response in naïve animals as compared to monovalent formulations when used as a two dose primary series, as well as a greater spike-specific and cross-reactive B cell response when used as a booster in prototype vaccine-experienced mice. The updated preclinical data submitted here does not identify any new safety concerns and is supportive of the use of the bivalent BA.4/BA.5 variant-specific vaccine as a two dose primary series.

Risk Management Plan (RMP)

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 two-dose primary series in individuals 5 years and older. 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 Comirnaty Original & Omicron BA.4/BA.5 as a 2-dose primary series is considered favorable in individuals >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.