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

The New Drug Submission (NDS) for Comirnaty Original & Omicron BA.4/BA.5 (15 mcg/0.3 mL tozinameran and 15 mcg/0.3 mL famtozinameran) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. The amended regulations also permit an exemption from submitting detailed reports of tests made to establish the safety and substantial evidence of the clinical effectiveness of the new drug. The sponsor must provide sufficient evidence to support the conclusion that the benefits of the drug outweigh the risks, taking into account the uncertainties, as well as the public health need related to coronavirus disease 2019 (COVID-19). Following review of the provided information, a Notice of Compliance was issued in relation to Comirnaty Original & Omicron BA.4/BA.5, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug.

As described above, the clinical review of the NDS for Comirnaty Original & Omicron BA.4/BA.5 was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .

The World Health Organization (WHO) and the WHO‑Strategic Advisory Group of Experts on Immunization (SAGE) advise that the composition of current and future COVID-19 vaccines be based on strains that are genetically and antigenically close to circulating SARS-CoV-2 variants. In the interim, the Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) encourages COVID-19 vaccine manufacturers to generate and provide data on the performance of current and Omicron-specific COVID-19 vaccines, including the breadth, magnitude and durability of humoral and cell mediated immune responses to variants through monovalent and/or multivalent vaccines. It is assumed that the safety, reactogenicity and immunogenicity of the updated vaccine composition will be comparable to those of the currently authorized vaccines based on the index virus. To that aim, Comirnaty Original & Omicron BA.4/BA.5 is a bivalent vaccine containing messenger ribonucleic acid (mRNA) encoding for the antigen from the ancestral strain of SARS-CoV-2 and from the variant of concern (VOC) Omicron BA.4/BA. Strain. Comirnaty Original & Omicron BA.4/BA.5 vaccine is manufactured by the same process as the currently authorized monovalent Comirnaty vaccine (herein referred to as the original Comirnaty vaccine).

No data were submitted from clinical studies using Comirnaty Original & Omicron BA.4/BA.5. Clinical trials with Comirnaty Original & Omicron BA.4/BA.5 in the age brackets associated with the indication were ongoing at the time of authorization. The outcomes of these clinical trials have been requested as terms and conditions associated with the submission approval. The authorization of Comirnaty Original & Omicron BA.4/BA.5 was supported largely by data from the original Comirnaty vaccine and related submissions filed post-approval. In addition, data from studies evaluating the bivalent Comirnaty Original/Omicron BA.1 (under review at the time of Comirnaty BA.4/BA.5 authorization) were submitted for review.

Clinical Pharmacology

Comirnaty Original & Omicron BA.4/BA.5 contains the medicinal ingredients tozinameran and famtozinameran, both of which are messenger ribonucleic acid (mRNA) constructs. Tozinameran encodes the viral spike protein of the ancestral strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Famtozinameran encodes the viral spike protein of the SARS-CoV-2 Omicron variant lineages BA.4 and BA.5. The mRNA constructs are formulated in lipid nanoparticles, which enable their delivery into host cells to allow expression of the SARS-CoV-2 spike antigen. The vaccine elicits both neutralizing antibody and cellular immune responses to the spike antigen, which may contribute to protection against COVID-19.

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

Immunogenicity was assessed as part of the clinical efficacy evaluation of Comirnaty Original & Omicron BA.4/BA.5.

At the time of authorization, there were no data regarding the co‑administration of Comirnaty Original & Omicron BA.4/BA.5 with other vaccines.

For further details, please refer to the Comirnaty Original & Omicron BA.4/BA.5 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

The effectiveness of a booster dose of Comirnaty Original & Omicron BA.4/BA.5 was inferred using clinical data from studies of a booster dose of the bivalent Comirnaty Original/Omicron BA.1 (under review at the time of Comirnaty Original & Omicron BA.4/BA.5 authorization), as well as effectiveness data of primary and booster vaccination with the original Comirnaty vaccine. Supportive data were also provided for of a booster dose of a monovalent Omicron BA.1 vaccine in individuals 18 to 55 years of age.

Data supporting the bivalent Comirnaty Original/Omicron BA.1 as a booster dose were evaluated from two ongoing clinical studies: Study C4591031 (Substudy E and Substudy D) and Study C4591001, both conducted in the United States. The Phase III Study C4591031 was designed to evaluate Comirnaty boosting strategies across different age group populations.

Furthermore, as requested in the terms and conditions, the results of Study C4591044 (Cohorts 2 & 3) will be provided when available. This study is an ongoing interventional, randomized, active-controlled, observer-blind, Phase II study investigating the safety, tolerability, and immunogenicity of bivalent Comirnaty vaccine candidates in COVID-19 vaccine‑experienced healthy individuals. One of the vaccines used in the study is Comirnaty Original & Omicron BA.4/BA.5.

Immunogenicity

Study C4591031 - Substudy E – Participants over 55 years of age

Study C4591031 is an ongoing Phase III, randomized, observer-blind, placebo-controlled study conducted in healthy individuals 16 years of age and older. Substudy E was designed to evaluate the safety, tolerability, and immunogenicity of a high dose (60 mcg) or a standard adult dose (30 mcg) of various monovalent and bivalent formulations of Comirnaty vaccines when given as booster (fourth) doses. Participants over 55 years of age were enrolled at investigator sites in the United States. All participants had received three previous doses of the original Comirnaty vaccine (30 mcg doses), with the most recent dose being 5 to 12 months prior to randomization. Only interim data for participants over the age of 55 were submitted with this submission.

In Substudy E, participants in the vaccine test group (bivalent vaccine) received the bivalent Comirnaty Original/Omicron BA.1 (15 mcg tozinameran/15 mcg riltozinameran, for a total of 30 mcg) as a second booster dose (fourth overall). Participants in the comparator group (monovalent vaccine) received the original Comirnaty vaccine (30 mcg tozinameran) as a second booster dose (fourth overall).

The inferred effectiveness of the bivalent Comirnaty Original/Omicron BA.1 as a second booster dose was determined through immunobridging analyses comparing the SARS-CoV-2 neutralizing antibody titres against the Omicron BA.1 subvariant and the ancestral strain 1 month following the second booster dose with the bivalent Comirnaty Original/Omicron BA.1 (total number of participants [n] = 177) to the corresponding titres 1 month following the second booster dose with the original Comirnaty vaccine (n = 167).

The co-primary objectives were to demonstrate superiority with respect to the level of neutralizing titre and non-inferiority with respect to seroresponse rate of anti-Omicron immune response. Values were compared after the second booster (fourth dose overall) with the bivalent Comirnaty Original/Omicron BA.1 to those after a second booster (fourth dose overall) with the original Comirnaty vaccine. All participants evaluated were over 55 years of age, had previously received three doses of the original Comirnaty vaccine, and were without evidence of SARS-CoV-2 infection up to 1 month after study vaccination.

In the expanded cohort, the evaluable immunogenicity population without evidence of infection up to 1 month after the fourth dose included 186 participants in the bivalent Comirnaty Original/Omicron BA.1 group and 182 participants in the original Comirnaty vaccine group. Demographic characteristics were well balanced between the groups and the median time from the third dose of the original Comirnaty vaccine was 6.3 months (range: 5 to 12 months).

The co-primary objectives of Substudy E were met as the lower bound of the two-sided 95% confidence interval (CI) for the geometric mean ratio (GMR) was >1 and the lower limit of the two-sided 95% CI for the difference in percentages of participants with seroresponse rate (SRR) was >‑5%. The estimated 1 month neutralizing antibody geometric mean titres (GMTs) against Omicron BA.1 were 711.0 (95% CI: 588.3, 859.2) and 455.8 (95% CI: 365.9, 567.6) in the bivalent Comirnaty Original/Omicron BA.1 and the original Comirnaty second booster groups, respectively. The GMR was 1.56 (two-sided 95% CI: 1.17, 2.08). Non-inferiority of the bivalent Comirnaty Original/Omicron BA.1 to the original Comirnaty vaccine with respect to SRR was also met, as the lower bound of the two-sided 95% CI for the difference in SRRs was greater than the prespecified non-inferiority margin of -5%. The Omicron BA.1 SRRs were 71.6% (95% CI: 64.2, 78.3) and 57.0% (95% CI: 48.7, 65.1) 1 month post vaccination in the bivalent Comirnaty Original/Omicron BA.1 and the original Comirnaty vaccine groups, respectively. The difference in SRR was 14.6% (95% CI: 4.0, 24.9).

In a sentinel cohort of participants over 55 years of age without evidence of prior SARS-CoV-2 infection, the observed GMT at 1 month after the fourth dose against Omicron variants (BA.1, BA.2, BA.2.12.1, and BA.4/BA.5) for the bivalent Comirnaty Original/Omicron BA.1 group showed, in general, higher neutralization titers to Omicron variants compared to the original Comirnaty group. A total of 100 participants were randomly selected from each vaccine group in the expanded cohort for the evaluable immunogenicity population Omicron BA.4/BA.5 neutralization assay subset. Demographic characteristics were similar between the two vaccine groups.

The observed Omicron BA.4/BA.5 neutralizing GMTs at 1 month after the fourth dose were numerically slightly higher for the bivalent Comirnaty Original/Omicron BA.1 group (n = 100) compared to the original Comirnaty vaccine group (n = 100) (167.4 and 155.1, respectively). The proportion of participants who achieved seroresponse in Omicron BA.4/BA.5 50% neutralizing titres at 1 month after the fourth dose was higher for the bivalent Comirnaty Original/Omicron BA.1 group compared to the original Comirnaty vaccine group (56% versus 42%). These data should be interpreted with caution given their exploratory nature, the non-validated assays used for the analysis, and the very small number of subjects enrolled in the sentinel cohort. Nonetheless, the data is considered supportive in speaking to the prospective breadth of protection conferred by the bivalent Comirnaty Original/Omicron BA.1.

Study C4591031 - Substudy D – Participants 18 to 55 years of age

Study C4591031 - Substudy D provided supportive immunogenicity data for a second booster (fourth dose overall) of the original Comirnaty vaccine (30 mcg) or a monovalent Omicron BA.1 variant‑specific vaccine (30 mcg) in participants who had received three prior doses of the original Comirnaty vaccine. A total of 600 individuals 18 to 55 years of age were randomized 1:1 to receive a second booster (fourth dose overall) of either vaccine. Fourth doses were administered a median of 3.9 months (range: 3.3 to 6.5 months) following the administration of the first booster (third dose overall) of the original Comirnaty vaccine.

The primary immunogenicity evaluable population included 132 participants in the monovalent Omicron BA.1 group and 141 in the original Comirnaty vaccine group. All participants had no evidence of infection prior to 1 month after the fourth dose. Demographic characteristics were well balanced and the median age was 43.5 years (range: 20 to 55 years) in the monovalent Omicron BA.1 group and 42 years (range: 19 to 55 years) in the original Comirnaty vaccine group.

When administered as a booster (fourth) dose, the monovalent Omicron BA.1 met the pre-specified criteria for simple superiority with respect to GMR and non-inferiority with respect to seroresponse rate when compared to the original Comirnaty vaccine. In the primary immunogenicity subset of participants without prior evidence of infection up to 1 month after first study (Dose 4) vaccination, the ratio of GMTs for the monovalent Omicron BA.1 group to the original Comirnaty vaccine group (GMR) was 1.75 (two-sided 95% CI: 1.39, 2.22). The difference in seroresponse rate to the Omicron variant between the two vaccine groups was 23.0% (two-sided 95% CI: 11.1%, 34.3%). These data are only considered supportive from an immunogenicity perspective as they pertain to an investigational monovalent SARS-CoV-2 Omicron-targeting vaccine at a higher dose than what is included in Comirnaty Original & Omicron BA.4/BA.5.

Supportive Studies

Supportive Information for Effectiveness in other age groups

The effectiveness of the bivalent Comirnaty Original/Omicron BA.1 (15 mcg tozinameran/15 mcg riltozinameran) vaccine in individuals 18 to 55 years of age one month after the fourth dose is being evaluated as part of the ongoing Study C4591031. The data will be submitted when it becomes available. However, as has been observed with other vaccines, immunocompetent younger adults are anticipated to mount a more robust overall immune response to the target strains contained in the vaccine as compared to older adults. Moreover, the investigational product targets both the ancestral strain and the Omicron BA.1 strain which should confer a greater breadth of immune response against SARS-CoV-2 variants and is anticipated to translate into more clinically meaningful protection compared to the original Comirnaty vaccine. Based on the totality of the scientific evidence available, including the data above and previously submitted data on the effectiveness of primary and booster vaccination with the original Comirnaty vaccine, it is reasonable to believe that the bivalent Comirnaty Original/Omicron BA.1 may be effective as a booster dose in individuals 18 years of age and older. Therefore, given the understanding of the overall complexity of the immune response to SARS‑CoV‑2 induced by booster vaccinations in this age bracket, and in the context of the ongoing pandemic, the lack of data for effectiveness in the 18 to 55 years population was deemed to not preclude the inclusion of individuals 18 to 55 years in the proposed indicated population. Consequently, these data are required as a term and condition for authorization of Comirnaty Original & Omicron BA.4/BA.5.

At the time of authorization of Comirnaty Original & Omicron BA.4/BA.5, a booster dose (third overall) for patients 12 to 15 years of age was not included as part of the authorized indication of the original Comirnaty vaccine (30 mcg tozinameran). However, on January 28, 2022, the National Advisory Committee on Immunization (NACI) in Canada approved recommendations for the use of booster doses of COVID-19 vaccines in adolescents 12 to 17 years of age who may be at higher risk of severe COVID-19 disease. Moreover, since early 2022, many other regulators have authorized this booster for this age group based on published data from the Israeli Ministry of Health database which documented experience with boosters in approximately 4.7 million individuals in Israel, 1,129,585 of whom were 16 to 29 years of age. In addition, the real-world effectiveness of booster doses of the original Comirnaty vaccine administered to individuals 16 years of age or older, at least 5 months after completion of the primary series, was documented during a Delta wave. Overall, those receiving booster doses appeared to be better protected against COVID-19, and this effect was observed throughout the age ranges in the publication.

The sponsor also provided four published studies documenting the administration of the original Comirnaty vaccine as a booster dose to adolescents in the United States, Italy, and Canada. No systematic review or meta-analysis was conducted for these literature publications and market experiences and these publications are considered only supportive in nature. However, Health Canada considered there was enough evidence to support the inferred clinical vaccine effectiveness of the currently authorized original Comirnaty vaccine in adolescents as a booster (third) dose. This was based on literature publications and market experience data forming this part of the submission that mirror the proposed indication for use in terms of dosing, population, intervention, and outcome measures. These publications also collectively reinforce the current unmet medical need for a first booster dose that is more broadly protective against currently circulating strains and potential future strains.

In addition, Health Canada has also reviewed an interim report for Study C4591031 which provides evidence of efficacy in patients aged 16 years and older who received the original Comirnaty vaccine as a booster (third) dose.

The ongoing Study C4591031 is designed to evaluate Comirnaty boosting strategies in healthy individuals previously vaccinated with the original Comirnaty vaccine. Substudy B and Substudy C include the evaluation of booster dosing in individuals over the age of 12 years. Substudy B is an ongoing randomized, placebo-controlled, observer-blind, crossover, designed to evaluate the safety and tolerability of a third dose of the original Comirnaty vaccine. Participants are between the ages of 12 and 30 years who have completed a two-dose primary series of the original Comirnaty vaccine (30 mcg) at least 6 months prior to randomization. Substudy C is an ongoing randomized, observer-blinded study, designed to evaluate the safety, tolerability, and immunogenicity of a third dose of the original Comirnaty vaccine at 10 mcg and 30 mcg. Participants are 12 years of age and older who have completed a two-dose primary series of the original Comirnaty vaccine prior to randomization. Data outcomes from Study C4591031 Substudy B and Substudy C are required as part of the terms and conditions of authorization for Comirnaty Original & Omicron BA.4/BA.5.

Health Canada considers that there is sufficient evidence to reasonably infer efficacy of the currently approved original Comirnaty vaccine as a booster in adolescents 12 to 15 years based on the demonstrated efficacy from those aged 16 and older. This was determined based on the supportive published studies which include real world evidence from the Ministry of Health of Israel database on booster doses, along with clinical study data in individuals 16 years of age and older. It is understood that immunocompetent younger individuals generate more robust immune responses compared to immunocompetent older adults. The sponsor's rationale was considered, along with the inference of efficacy of the original Comirnaty vaccine (30 mcg) as a booster in adolescents 12 to 15 years based on published literature studies and demonstrated efficacy in a clinical study conducted in patients 16 years of age and older. Health Canada reasons that the same rationale for the inferring of immunogenicity of the bivalent Comirnaty Original/Omicron BA.1 (15 mcg/15 mcg) in the 18 to 55 years of age bracket can be applied to infer immunogenicity in the younger age bracket of 12 to 17 years, with the same limitations and unknowns. There is some uncertainty as to whether the bivalent Comirnaty Original/Omicron BA.1 would present as statistically superior to the original Comirnaty vaccine with respect to GMR against the Omicron variant in the 12 to 17 age bracket. However, from a clinical perspective, it can be reasonably anticipated to have the potential to offer a greater magnitude and breadth of protection as it would for the 18 to 55 years age bracket.

Summary of Efficacy

Immunogenicity data for the bivalent Comirnaty Original/Omicron BA.1 were limited to adults over the age of 55 years from Study C4591031 Substudy E. This sample size was relatively small and the duration of follow-up was relatively short. Due to the urgency to develop this and other bivalent formulations, limited information was provided in this submission. However, ongoing studies are expected to provide additional immunogenicity information, including long-term data on populations as young as 12 years of age. Additional post-market studies will provide information on the impact of monovalent and bivalent vaccines when administered as a first booster (third dose overall), their ability to protect against novel circulating Omicron subvariants, responses in people with immune deficiency or in those taking immune suppressive medications, as well as individuals with comorbidities (including those with severe cardiovascular or respiratory illness), immunogenicity in pregnant women, and their ability to protect against future variants of SARS-CoV-2.

Risks will be mitigated through compliance with the terms and conditions, accurate labelling in the Comirnaty Original & Omicron BA.4/BA.5 Product Monograph, and through the Risk Management Plan (RMP).

In addition, all currently ongoing post-authorization safety studies will be updated to include the bivalent Comirnaty Original/Omicron BA.1 as well as Comirnaty Original & Omicron BA.4/BA.5, to further monitor the safety and real-world effectiveness profile of each.

In conclusion, from the clinical information provided with the bivalent Comirnaty Original/Omicron BA.1, it can be assumed that Comirnaty Original & Omicron BA.4/BA.5 will induce superior antibody responses to the Omicron BA.4 and BA.5 virus strains and non-inferior responses to the ancestral strain when compared to the original Comirnaty vaccine. Based on the collective evidence from the aforementioned data and experience with other bivalent mRNA vaccines, literature publications, market experiences from the original Comirnaty vaccine, and relevant non-clinical data, as well as taking into context the current and evolving pandemic, the totality of available evidence reasons that a booster dose of Comirnaty Original & Omicron BA.4/BA.5 is expected to elicit an immune response that will confer protection against COVID-19. Immunogenicity and safety data will be provided as part of the terms and conditions to confirm these assumptions.

Indication

The NDS for Comirnaty Original & Omicron BA.4/BA.5 was filed by the sponsor with the following indication:

• Comirnaty Original and Omicron BA.4/BA.5 (COVID-19 mRNA Vaccine, Bivalent [Original and Omicron BA.4/BA.5]) is indicated for active immunization as a booster dose to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 12 years of age and older.

Health Canada approved the following indication:

• Comirnaty Original & Omicron BA.4/BA.5 (COVID-19 mRNA Vaccine, Bivalent [Original and Omicron BA.4/BA.5]) is indicated as a booster dose for active immunization against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 12 years of age and older.

The sponsor requested a three-month interval between the second dose of the primary series and the booster dose, and a four-month interval between the first and second booster dose. In the clinical Study C4591031, the majority of subjects received second booster doses 5 to 12 months (median: 6.3 months) following the first booster dose. The first booster dose time period authorized in Canada for the original Comirnaty vaccine for individuals 16 years of age and older is 6 months. In the Product Monograph for Comirnaty Original & Omicron BA.4/BA.5, Health Canada approved a recommended booster dose 3- to 6‑months after completing a primary course with the original Comirnaty vaccine and/or a previous booster dose of the original Comirnaty vaccine in individuals 12 years of age and older. There is no reason to believe that the immune response to the booster administration Comirnaty Original & Omicron BA.4/BA.5 would be different from the currently authorized monovalent vaccine when administered as a first booster. Given that the Omicron variants are the dominant circulating variants at the time of market authorization, it is expected to increase the breadth of the immune response. Additionally, the exact timing of booster doses and appropriate populations to target will depend on a variety of factors including local epidemiological contexts which are constantly evolving and may vary between provinces and territories. As such, standardized timing is not currently recommended and the decision for when and for whom to implement a booster dose should be made considering relevant vaccine effectiveness data (e.g., evidence of waning effectiveness) taking into account the available safety and immunogenicity data.

For more information, refer to the Comirnaty Original & Omicron BA.4/BA.5 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

At the time of authorization, no clinical data were available to assess the safety profile of Comirnaty Original & Omicron BA.4/BA.5 as studies were ongoing. As such, its safety profile was evaluated based on the established safety of, and cumulative experience with the authorized original Comirnaty vaccine. This approach is in line with current clinical considerations for COVID-19 mRNA-based platforms which incorporate a change to the coding sequence (active substance) related to the new variant of concern (Omicron BA.4/5) in addition to the current sequence (original Comirnaty vaccine). In addition to experience with the original Comirnaty vaccine, both as a primary series vaccination and as a booster, clinical information from a number of variant vaccine formulations used in the clinical development program, post-market safety data, and feedback from consultations with Canadian experts, all factored into the extrapolation of safety information for Comirnaty Original & Omicron BA.4/BA.5. Notably, Comirnaty Original & Omicron BA.4/BA.5 is manufactured by the same process as the currently authorized original Comirnaty vaccine and as such is expected to have a similar safety profile.

Across the clinical development program, clinical safety profiles were comparable dose per dose, regardless of the mRNA platform administered. The reactogenicity profiles of the monovalent and bivalent Comirnaty variant vaccines consistently displayed comparable local and systemic reactogenicity and mirrored the safety profile of the previously authorized monovalent original Comirnaty mRNA platform. The consistency of safety data across the mRNA platforms and studies suggests that Comirnaty Original & Omicron BA.4/BA.5 should elicit a similar safety profile when administered as a booster dose. Therefore, no new safety concerns are anticipated.

Safety profile of the original Comirnaty vaccine & Comirnaty variant vaccines

The safety of a primary series of the original Comirnaty vaccine was evaluated in subjects 12 years of age and older in Phase I/II and I/II/III studies conducted globally. Cumulative experience on the safety of the original Comirnaty vaccine is derived from a large safety database comprising primary series and booster doses.

Overall, through the clinical development program and across the age strata, systemic adverse reactions following the administration of the original Comirnaty vaccine were less frequent following the first booster (third overall dose) than following second dose of the primary series. Across age groups, as typically seen with other vaccines, reactogenicity was reported with slightly increased frequency in younger ages. Across the clinical development program, the safety of the original Comirnaty vaccine was consistent with the post-market safety data.

With respect to the safety profile of Comirnaty variant vaccine formulations, cumulative experience was derived from a database comprising primary series and booster dose data which included Study C4591031 (substudies D and E) and Study C4591001, each described in the Clinical Efficacy section. Additional safety data on variant vaccine formulations were provided from Study BNT162-17 (Part B Cohort 1 and Cohort 4).

Study C4591031 – Substudy E – Participants over 55 years of age

Study C4591031 evaluated several different doses of monovalent and bivalent vaccine formulations containing different amounts of antigen. The results below discuss the observations for the groups who received the original Comirnaty vaccine (30 mcg tozinameran) or the bivalent Comirnaty Original/Omicron BA.1 (15 mcg of the ancestral strain and 15 mcg of Omicron BA.1, for a total of 30 mcg). All participants were older than 55 years of age.

Pronounced reactogenicity was observed for both local and systemic adverse reactions (ARs) within the first 7 days following vaccine administration. In the original Comirnaty vaccine and the bivalent Comirnaty Original/Omicron BA.1 groups, the percentages of subjects experiencing any local AR were 61.1%, and 59.5%, respectively, while the percentages experiencing any systemic AR were 56% and 60.5%, respectively.

The most common solicited local ARs were pain at injection site, followed by redness and swelling. The most common solicited systemic AR was fatigue, followed by headache, chills and muscle and joint pain.

Severe local or systemic ARs were reported infrequently. No Grade 4 local ARs were reported in any arm of the substudy. A marginal increase in the frequency of both local and systemic ARs was noted in other treatment groups where the amount of the formulation/mRNA in a single dose was the greatest (60 mcg).

From study vaccination to the data cut-off date (May 16, 2022), a total of 6.6% and 6.2% of subjects in the original Comirnaty vaccine and the bivalent Comirnaty Original/Omicron BA.1 groups, respectively, experienced any adverse event. Overall, eight serious adverse events were reported from study vaccination up to the data cut-off date, six of which occurred within the first month following administration. Serious AEs included cases of pneumonia and ischaemic stroke in the original Comirnaty vaccine group, gastroesophageal reflux in the bivalent Comirnaty Original/Omicron BA.1 group, as well as dehydration, prostate cancer, and nephrolithiasis in a group receiving a different monovalent BA.1 formulation under study. A life-threatening (Grade 4) AR and a mild (Grade 1) event of atrial fibrillation in a group receiving a higher dose formulation of the bivalent Comirnaty Original/Omicron BA.1 were also reported. There were no AEs that led to study discontinuation or death. Most of the reported AEs were consistent with reactogenicity. A few cases of adverse events of special interest including eight cases of lymphadenopathy and four cases of rash were reported across the study arms. There were no reports of myocarditis or pericarditis.

Study C4591031 – Substudy D – Participants 18 to 55 years of age

Substudy D provided supportive safety analyses for the 18 to 55 years of age bracket (Cohort 2). At the time of data cut-off (March, 11, 2022), 640 subjects had received a second booster (fourth dose) of either a monovalent Omicron BA.1 variant vaccine (30 mcg; n = 315) or the original Comirnaty vaccine (30 mcg; n = 325). The median follow-up time after first study (fourth dose) vaccination was 1.4 months.

Severe local or systemic ARs were reported infrequently. Reactogenicity observed for both local and systemic ARs within the first 7 days following vaccine administration was comparable between the two arms of the substudy (78.6% versus [vs.] 79.4% for any local ARs and 77.6% vs. 72.9% for any systemic ARs in the monovalent Omicron BA.1 variant vaccine group vs. the original Comirnaty vaccine group, respectively). Most local or systemic ARs were mild or moderate in severity and short-lived, with the majority arising within 1 to 2 days following administration. No Grade 4 local or systemic ARs were reported. Pain at the injection site was the most frequently reported local AR in both groups (77.9% vs. 78.4% in the monovalent Omicron BA.1 group vs. the original Comirnaty vaccine group). The most common solicited systemic AR was fatigue (64.3% in the monovalent Omicron BA.1 group vs. 72.9% in the original Comirnaty vaccine group), followed by headache, myalgia, chills and arthralgia.

Adverse events from the second booster (fourth dose) to 1 month after its administration were reported at slightly higher rates in the monovalent Omicron BA.1 group vs. the original Comirnaty group (5.7% vs. 3.7%, respectively). Serious adverse events were also reported at higher frequencies in the monovalent Omicron BA.1 group vs. the original Comirnaty group (1.3% versus 0.6%, respectively). Most of the reported AEs were consistent with reactogenicity. No life-threatening AEs (Grade 4), AEs leading to withdrawal, or deaths were reported in either group. No additional AEs were reported up to the data cut-off date. Adverse events of special interest were reported at low rates (five in the monovalent Omicron BA.1 group vs. four in the original Comirnaty group). There were no cases of anaphylaxis, hypersensitivity, myocarditis, pericarditis, appendicitis, Bell’s palsy, or rash in either group.

Supportive Study C4591001 – Booster Subset using a Beta-modified Vaccine

A Beta-modified vaccine (30 mcg) was administered as two doses to subjects who had not previously received the monovalent original Comirnaty vaccine, or as one or two booster doses in patients who had received a primary series of the original Comirnaty vaccine. The reactogenicity profile was consistent with the reactogenicity profile of the original Comirnaty vaccine (30 mcg).

The overall frequency of solicited local ARs in the original Comirnaty vaccine-experienced subjects who were assigned to receive one booster dose of the Beta-modified vaccine was slightly lower than the frequency reported following a primary series with either the original Comirnaty vaccine or the Beta-modified vaccine. The frequency of local and systemic ARs in the original Comirnaty vaccine-experienced subjects who were assigned to receive two booster doses (30 mcg) of Beta-modified vaccine were generally similar or lower after the second booster (fourth dose) than after the first booster (third dose). The local reactogenicity profile of the Beta-modified vaccine when administered as a primary series was similar to that of the original Comirnaty vaccine when administered as a primary series.

Long-term safety data beyond 6 months following two doses of the original Comirnaty vaccine (30 mcg), a first booster dose of the original Comirnaty vaccine (30 mcg) or the Beta-modified vaccine (30 mcg), and beyond 5 months after the second booster dose of the Beta-modified vaccine (30 mcg) did not reveal any new safety concerns. These data provide for a longer follow-up on the safety of a monovalent mRNA against a variant of concern (VOC; in this particular case the Beta variant) that, within the above-mentioned similar reactogenicity profile, given the nearly identical formulations (variation only within the coding sequence) may be extrapolated to Comirnaty Original & Omicron BA.4/BA.5.

Study BNT162-17

Study BNT162-17 is an ongoing Phase II study investigating the safety and immunogenicity of a monovalent Delta variant-modified vaccine (30 mcg) and a bivalent Alpha and Delta variant-modified vaccine (15 mcg of each for a total of 30 mcg).

Safety data up to 1-month post-booster dose (third dose) from certain cohorts in the study provided supportive data in predicting the overall safety profile of Comirnaty Original & Omicron BA.4/BA.5. Overall, the analysis of AEs 1 month post booster did not suggest any new safety concerns. The reactogenicity profile of the monovalent Delta variant-modified vaccine and the bivalent Alpha and Delta variant-modified vaccine when administered as a booster dose (third dose) was consistent with the safety profile of a booster (third dose) of the Beta variant-modified vaccine.

Overall, the emerging safety profile of Comirnaty monovalent and bivalent variant vaccines is similar to that of the original Comirnaty vaccine (30 mcg) with the caveat that the size of the safety database for the variant vaccine formulations is not large enough to characterize the frequency of rare adverse events. This limitation will be addressed via post-market surveillance and fulfillment of the requirements set in the terms and conditions.

Summary of Safety Analysis

Across the clinical development program, the same lipid nanoparticle (LNP)-based formulation has been used, regardless of the mRNA content and coding sequence per dose. The mRNAs encoding different immunogens (i.e., ancestral strain, VOCs) are chemically and physically highly similar, while the adjuvant used (LNPs) in the formulations is identical. The safety results are consistent across the clinical development program studies, and Comirnaty Original & Omicron BA.4/BA.5 is formulated and manufactured in the same way as the original Comirnaty vaccine.

The inflammatory milieu induced by the LNPs is, at least in part, responsible for the reactogenicity of the mRNA-LNP platform. A marginally higher frequency of reactogenicity was noted for the formulations encoding VOC versus the formulations encoding for the ancestral strain alone. This marginal difference was not statistically significant and it is not deemed to be clinically meaningful. Overall, the reactogenicity profiles of the reviewed formulations were comparable dose per dose, regardless of the mRNA platform administered.

Input on the approach to evaluating the available data for Comirnaty Original & Omicron BA.4/BA.5 was sought from a panel of Canadian experts. Individual meetings took place between September 14 and 20, 2022, with six out of the nine solicited experts. Overall, none of the experts consulted voiced major concerns regarding the proposed regulatory approach for the review of Comirnaty Original & Omicron BA.4/BA.5. Generally, they expressed confidence in the adverse monitoring system for authorized mRNA vaccines and emphasized the importance of monitoring real world evidence safety information and obtaining safety data from the ongoing studies required by the terms and conditions.

In conclusion, the inference of reactogenicity and safety of Comirnaty Original & Omicron BA.4/BA.5 is based on extrapolated data from the very large safety database for the original Comirnaty vaccine, as well as the broadly similar safety profiles of the original Comirnaty vaccine and the Comirnaty variant vaccines derived from cross-comparisons (although not all compared in the same study). Given the current epidemiological context, the safety results obtained across the clinical development program support an acceptable safety profile for both monovalent and bivalent variant vaccines with divergent encoding sequences, at a total dose of 30 mcg. In addition, real-world evidence and Canadian expert opinions supported the regulatory decision. Taken together, these data raise no anticipated concerns with respect to the safety profile of Comirnaty Original & Omicron BA.4/BA.5.

Given that it is not feasible to conduct clinical studies rapidly enough to respond to the emergence of SARS-CoV-2 variants that may evade the immune response conferred by previously‑authorized vaccines, and in light the need for a booster dose to protect against circulating VOCs, Comirnaty Original & Omicron BA.4/BA.5 was authorized subject to terms and conditions.

Risk Management Plan

A Core (European Union [EU]) Risk Management Plan (RMP) and a Canadian RMP Addendum for Comirnaty Original & Omicron BA.4/BA.5 were submitted by BioNTech Manufacturing GmbH 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 scheme and to describe measures that will be put in place to minimize risks associated with the product, when needed.

The following information relates to the RMP submitted by BioNTech Manufacturing GmbH as part of the New Drug Submission for Comirnaty Original & Omicron BA.4/BA.5. 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 PAAT for Comirnaty Original & Omicron BA.4/BA.5.

While clinical data for Comirnaty Original & Omicron BA.4/BA.5 were not available at the time of authorization, the authorization was based on the extrapolation of clinical data from the bivalent Comirnaty Original/Omicron BA.1, clinical data obtained from the original Comirnaty vaccine used as a primary series and as a booster dose, as well as post-market safety data. The RMP included three important identified risks (anaphylaxis, myocarditis, and pericarditis) and two important potential risks (vaccine-associated enhanced disease [VAED] and vaccine-associated enhanced respiratory disease [VAERD]). The RMP also identified eight areas of missing (limited/no clinical data) information: “use in pregnancy and while breastfeeding”, “use in immunocompromised patients”, “use in frail patients with unstable health conditions and comorbidities”, “use in patients with autoimmune or inflammatory disorders”, “interaction with other vaccines”, “long-term safety”, “long-term vaccine effectiveness”, and “use in the population <12 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 in ongoing clinical and post-authorization studies undertaken for the original Comirnaty vaccine and the addition of two ongoing clinical studies evaluating the immunogenicity and safety of Comirnaty boosters for SARS-CoV-2 Omicron variants including BA.4/BA.5 and BA.1 (studies C4591044 and C4591031). 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 EU RMP and Canadian Addendum in a timely manner if a signal for 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 subpopulations listed below in the post‑market period:

• Children: Children less than 12 years old were not included in the clinical development program. This subpopulation was identified as missing information in the Canadian Addendum. Studies of Comirnaty Original & Omicron BA.4/BA.5 in children are planned.
• Pregnant women: More information is needed about vaccine use in pregnant women. This subpopulation was identified as missing information in the RMP. The sponsor will assess outcomes of the effect of the vaccine on pregnancy and lactation as part of ongoing and planned studies, including a pregnancy exposure registry.
• Breastfeeding women: This subpopulation was identified as missing information in the RMP. The sponsor will assess outcomes of the effect of the vaccine on pregnancy and lactation as part of ongoing and planned studies, including a pregnancy exposure registry.
• Immunocompromised individuals and patients with chronic or debilitating conditions: These individuals were not included in the clinical development program. This subpopulation was identified as missing information in the RMP.
• Anaphylaxis: This was identified as an important identified risk in the Canadian Addendum. This risk will be assessed via routine pharmacovigilance activities and reported in monthly safety reports.
• Myocarditis and pericarditis: These were identified as important identified risks in the RMP. These risks will be assessed via routine pharmacovigilance activities and reported in monthly safety reports.

The sponsor will also provide prompt reporting of adverse reactions. The submission of the post-market safety reports has been adjusted to a monthly basis for enhanced monitoring of Comirnaty Original & Omicron BA.4/BA.5.

In view of the limited clinical data available for Comirnaty Original & Omicron BA.4/BA.5, it is important that further safety data is collected in the post-market setting. If possible, the sponsor will include Comirnaty Original & Omicron BA.4/BA.5 in all ongoing post-authorization safety studies. Results related to safety and effectiveness from ongoing and planned studies will be submitted for review as they become available. The sponsor is also expected to provide an updated RMP to discuss any additional pharmacovigilance activities for long-term safety and effectiveness for Comirnaty Original & Omicron BA.4/BA.5.

Real-world use of this vaccine may provide additional data related to the administration of this vaccine in the population under 12 years of age, pregnant and lactating women, immunocompromised individuals, frail individuals with comorbidities, individuals with autoimmune disease or inflammatory disorders, interaction with other vaccines, and long-term safety and efficacy of this vaccine.

Appropriate warnings and precautions are in place in the approved Comirnaty Original & Omicron BA.4/BA.5 Product Monograph to address the identified safety concerns.

The benefit of the immediate availability of Comirnaty Original & Omicron BA.4/BA.5 in the context of the pandemic was determined to outweigh the uncertanty resulting from less comprehensive data than are normally required. Based on updated post-market safety for the authorized original Comirnaty vaccine administered as a primary series and as a booster dose, it can be assumed that Comirnaty Original & Omicron BA.4/BA.5 will have an acceptable safety profile. In consideration of the data provided, along with knowledge of other bivalent mRNA vaccines, literature publications, and market experiences from the original Comirnaty vaccine and non-clinical data, as well as taking into context the current and evolving pandemic, the totality of available evidence reasons that a booster dose of Comirnaty Original & Omicron BA.4/BA.5 is expected to elicit an immune response that will confer protection against COVID-19. Immunogenicity and safety data will be provided as part of the terms and conditions to confirm these assumptions.

For more information, refer to the Comirnaty Original & Omicron BA.4/BA.5 Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.