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

The safety and effectiveness of a booster dose of Comirnaty Original & Omicron BA.4/BA.5 at 10mcg in children 5 to <12 years of age is inferred from:

• preliminary supportive descriptive clinical data from studies of a booster dose of Comirnaty Original & Omicron BA.4/BA.5 at 30mcg in adults,
• clinical data from the studies of a booster dose of Comirnaty Original & Omicron BA.1 vaccine at 30mcg in adults >55 years of age,
• effectiveness of primary series and booster vaccination with Comirnaty at 10mcg in children 5 to <12 years of age currently authorized for this age bracket.
• post-market safety data/ real-world evidence and clinical safety data from studies of a booster dose of Comirnaty at 10mcg in children 5 to <12 years of age

Comirnaty ^® Original & Omicron BA.4/BA.5

Preliminary descriptive 7-day and 1-month post (fourth) dose safety and immunogenicity data were provided for a subset of participants 18 to 55 and >55 years of age in Study C4591044 Cohort 2 who received Comirnaty Original & Omicron BA.4/BA.5 30 mcg as a booster (fourth) dose compared to participants >55 years of age from Study C4591031 Substudy E who received Comirnaty 30 mcg as a booster (fourth) dose.

The data showed a numerical increase in the Omicron BA.4/BA.5 neutralizing antibody response above pre-booster levels in individuals 18 to 55 and over 55 years of age. Neutralizing GMTs against Omicron BA.4/BA.5 1 month post-boost were higher for participants 18 to 55 (N = 38) and >55 years (N = 36) of age in the Comirnaty Original & Omicron BA.4/BA.5 groups (605.9 and 896.4, respectively) compared to participants >55 years of age (N = 40) in the Comirnaty group (236.3). Neutralizing GMTs against reference strain 1 month post-boost were numerically higher than pre-vaccination levels for all vaccine groups. This immunogenicity data is valuable in that it provides for the first time, preliminary human data with the Comirnaty Original & Omicron BA.4/BA.5 vaccine. However, the sample size is too small to draw immunogenicity conclusions. Moreover, the analysis is descriptive, and the data is only in adults at a dose of 30 mcg, thus providing only supportive evidence of proof of concept for the 5 to <12 years of age bracket at a dose of 10 mcg.

In the 7-day post-dose (four) reactogenicity and adverse events (AE) data safety analyses set for Cohort 2 in (n=503), subjects received either a 30mcg (12-17 years [n=97], 18-55 years [n=100], > 55 years [n=101]) or a 60mcg (18-55 years [n=106], >55 years [n= 99]) dose of Comirnaty Original & Omicron BA.4/BA.5. All subjects received 3 prior doses (30mcg) of Comirnaty, with the most recent dose being 150 to 365 days prior to Day 1 and have received a single dose of Comirnaty Original & Omicron BA.4/BA.5 as a booster (Dose 4) dose (subjects 12-17, 30mcg, open label and subjects 18-55 and >55 either 30 or 60mcg, observer-blind, randomized 1:1). As of the data cutoff date (September 12, 2022), the overall median time since last prior dose of Comirnaty before study vaccination was 10.5 months for subjects >18 years of age. Participants in the 12-17 years of age group had shorter median time (8.3 months) since last dose of Comirnaty (received prior to the study) to the study vaccination.

Across the age groups and vaccine doses, pain at injection site was the most frequently reported local AR within 7 days after booster dose, with swelling and redness at the injection site reported much less frequently. Most local ARs were mild or moderate in severity. Severe local ARs were reported by 1 (1.0%) subject in the 12-17 years of age group. The median onset for all local ARs was 1 to 2.5 days, and all events resolved within a median duration of 1 to 3 days after onset. Fatigue was the most frequently reported systemic ARs within 7 days after booster dose, followed by headache, muscle pain and less frequently by chills, joint pain, diarrhea, or fever. Most systemic ARs were mild or moderate in severity. In the Comirnaty Original & Omicron BA.4/BA.5 30 mcg dose group, severe systemic ARs of fever (n=1), fatigue (n=3) and diarrhea (n=1) were reported. In the BNT162b2 bivalent 60mcg dose group, severe systemic ARs of fever (n=4), fatigue (n=5), headache (n=2), chills (n=1), muscle pain (n=2) and joint pain (n=2) were reported. The median onset for all systemic ARs was 2 to 4 days, and all ARs resolved within a median duration of 1 to 2 days.

No Grade 4 systemic or local ARs events were reported in any group. The incidence of local and systemic ARs was higher in subjects who received the 60mcg dose of Comirnaty Original & Omicron BA.4/BA.5 within each age group. Analysis of specific AEs reported from study vaccination through 7 days after study vaccination found a total of 9 AEs; most were consistent with reactogenicity events and most were reported in the 12-17 years of age bracket (n=5). No SAEs, withdrawals due to AEs, or deaths were reported. A single AESI of lymphadenopathy was reported on the study up until the data cutoff date.

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 that of Comirnaty within the respective age bracket.

No new safety signals have been identified; however, the small sample size and the short duration of the follow-up (7 days) 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 Terms and Conditions and post-market surveillance needs to be further conducted. The data is only in adults at a dose of 30 mcg, thus providing only marginally supportive generalized evidence for safety in the 5 to <12 years of age bracket at a dose of 10 mcg.

Comirnaty ^® Original & Omicron BA.1

These data were previously supplied to HC to support the authorization of both Comirnaty Original & Omicron BA.4/BA.5 and Comirnaty Original & Omicron BA.1 in individuals ≥12 years of age. For further details, refer to see the Regulatory Decision Summary (Food and Drug Regulations) document dated 2022-10-07 for Comirnaty Original & Omicron (BA.4/BA.5) on HCs COVID-19 vaccines and treatments portal.

Overall, the findings indicated that the Comirnaty Original & Omicron BA.1 provides better immune response to the Omicron BA.1. Planned post-market studies are expected to provide additional validation of the immune response. No new safety concerns were identified in these studies when compared to the currently approved original Comirnaty vaccine. No deaths or Adverse Events of Special Interest (AESI) including cases of myocarditis or pericarditis occurred. Safety concerns remain as those captured in the original Comirnaty label. The data are considered supportive in speaking to the prospective breadth of protection conferred by the investigational product, however, the data are only in an elderly population at a dose of 30mcg, thus providing only supportive evidence of proof of concept for the 5 to <12 years of age bracket at a dose of 10 mcg.

Comirnaty ^® (originally authorized vaccine)

These data were previously supplied to HC to support authorization of the original Comirnaty booster dose, the immune response and safety data were provided from a subset of subjects from an ongoing study in children 5 to <12 years of age evaluating the safety, tolerability, and immunogenicity of the Comirnaty vaccine. These subjects received a booster dose of 10 mcg of Comirnaty approximately 6 months after the second dose of Comirnaty. For further details, refer to see the Regulatory Decision Summary (booster, ages 5-11) document dated 2022-08-19 for Comirnaty on HCs COVID-19 vaccines and treatments portal.

The immune response one month after a Comirnaty booster dose compared to one month after completion of the primary 2-dose series was assessed in subjects who had no evidence of past SARS-CoV-2 infection up to one month after the booster vaccination. Overall, the antibody levels were 2.17-fold higher after the booster dose relative to levels after the second dose.

At the time of analysis, participants were followed-up for safety for 1 month after receiving the booster. Safety and immune response data from 6-months and 12-months of follow-up will be provided to Health Canada when available. The number of participants with any Adverse Events (AE) was 36/401 (9.0%). No AE or serious AEs leading to withdrawal from the study were reported and no study participants died. The most common adverse reaction (AR) after Dose 3 included pain at the injection site (73.9%), fatigue (45.6%), headache (34.0%), myalgia (18.3%), chills (10.5%), injection site redness (15.6%), and swelling (16.4%). These ARs were similar to what was reported following the primary series. The most frequently reported unsolicited AE was lymphadenopathy (2.5%) which was reported at a higher frequency compared to the primary series (0.9%) but with similar onset timing, severity levels, and duration.

At the time of analysis, there were no AEs of special interest (AESI) reported of anaphylaxis, myocarditis, pericarditis, Bell’s palsy (or facial paralysis/paresis), or appendicitis. No cases of arthritis, thrombocytopenic events, thromboembolic or intravascular coagulation events, autoimmune or demyelination events, meningitis, encephalitis, neuritis, peripheral neuropathy, vasculitis, Kawasaki disease, MIS-C, or acute respiratory distress syndrome were reported following Dose 3 in this population.

Alongside safety data provided in Study C4591007, post-market-safety data/ real-world evidence represents the pivotal data for the herein safety approval. Preliminary analyses of post-market data following administration of booster doses of Comirnaty in children 5 to <12 years of age suggests that although reports of local and systemic ARs reported post-Dose 3, are similar in frequency to those reported after Dose 2, some reactions are more frequently reported as moderate or severe after Dose 3 than after Dose 2. This reporting pattern is consistent with clinical trial (Study C4591007) results.

The sequential pattern of reactogenicity in children 5 to <12 years of age vs. individuals ≥ 12 years of age bears some differences; a higher reactogenicity is recorded in children 5 to <12 years of age following Dose 3 in comparison with post-Dose 2 while in individuals ≥12 years of age the vice versa applies. Cumulative safety data with mono- and bivalent formulations 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.

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 to children 5 to <12 years of age for Comirnaty Original and Omicron BA.4/BA.5 vaccine. 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 and Comirnaty Original/Omicron BA.1 vaccine. 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 and prioritized reporting of adverse events following immunization, monthly summary safety reports on the vaccine will be provided 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 10 mcg booster dose of Comirnaty^® Original & Omicron BA.4/BA.5 is considered favorable in individuals 5 to <12 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.

For more information on Health Canadas decision, please view the Summary Basis of Decision.