Regulatory Decision Summary for Spikevax Bivalent (Original / Omicron BA.4/5)

The purpose of this submission was to request the expansion of booster indication in individuals 6 to 17 years of age with variant-modified bivalent mRNA-1273.222 (original strain and Omicron BA.4/5) vaccines, for the prevention of (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The dosing regimen is proposed to be an interval of at least 6 months following a primary series and/or previous booster dose, with the proposed dosage of 25 mcg for individuals 6 to 11 years of age, and 50 mcg for 12 to 17 years of age.

The safety and effectiveness of a booster dose of Spikevax Bivalent (Original / Omicron BA.4/5) in individuals 6 to <17 years of age is inferred from:

The safety and effectiveness of a booster dose of Spikevax Bivalent (elasomeran/imelasomeran) Original / Omicron mRNA vaccine at 25 mcg in children 6 to <12 years of age and 50 mcg in children 12 to <18 years of age is inferred from:

• Preliminary supportive clinical data from studies of a booster dose of Spikevax Bivalent (Original and Omicron BA.1) at 50 mcg in adults (approved September 1, 2022).

• Clinical data from the studies of a booster dose of Spikevax monovalent (Original) vaccine at 25 mcg in children 6 to <12 years of age (Study P204), data submitted in this Supplement to a New Drug Submission (SNDS).

• Clinical data from the studies of a booster dose of Spikevax monovalent (Original) vaccine at 50 mcg in children 12 to <18 years of age (Study P203; approved Jan 12, 2023).

Spikevax Bivalent (Original / Omicron BA.1) vaccine:

Eligible adults over 18 years of age (814 individuals both male and female) were included in the study, a total of 437 individuals received the Spikevax Bivalent and 377 individuals received the comparator vaccine Spikevax Original. The immune responses were evaluated in these two groups against the Original SARS-CoV-2 virus or against the Omicron BA.1 virus. The results presented indicate that the new Spikevax Bivalent vaccine induces similar responses to the Original virus and significantly higher responses to the Omicron BA.1 virus when compared to the Spikevax Original approved vaccine.

Overall, the findings indicate that the Spikevax Bivalent provides better immune response to the Omicron BA.1. Results of exploratory analyses suggest that a second booster with Spikevax Bivalent would provide a superior neutralizing antibody response against BA.4/5 compared to a second booster with Spikevax Original. Planned post-market studies are expected to provide additional validation of the immune response.

At the time of analysis, participants were followed-up for safety for approximately 6 weeks after receiving the booster. Safety and immune response data from 3-months and 6-months of follow-up will be provided to Health Canada when available and were requested as part of the Terms and Conditions required for marketing authorization. The frequency and severity of the solicited adverse reactions (ARs) was similar between the two groups; the most common local solicited ARs (≥10%) were pain at the injection site (77.9% and 77.2%) and axillary swelling (17.1% and 19.6%) in the Spikevax Bivalent and Spikevax Original groups, respectively. The commonest (≥10%) solicited systemic ARs were fatigue (54.9% and 51.4%), headache (43.9% and 41.1%), myalgia (39.6% and 38.6%), arthralgia (31.1% and 31.7%), chills (23.8% and 21.1%) and nausea/vomiting (10.3% and 10.0%) in the Spikevax Bivalent and Spikevax Original groups, respectively.

No new safety concerns have been identified in studies when compared to the currently approved Spikevax mRNA 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 Spikevax Original label.

A Core Risk Management Plan (RMP) and a Canadian RMP Addendum was included in the submission for Spikevax Bivalent. 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 Spikevax (original). 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 safety summary reports on the vaccine will be provided to Health Canada.

Spikevax (original approved vaccine):

6 to 11 years of age:

Study P204 (data cutoff of May 23, 2023) provides the primary evidence to support the use of the booster dose of Spikevax in adolescents. Study P204 (Part 1C-1) involved 1,294 participants 6 years through 11 years of age who received 25 mcg booster dose of Spikevax at least 6 months after the second dose of the primary series (two doses 28 days apart).

Effectiveness of a booster dose of Spikevax in participants 6 years through 11 years of age was inferred by comparing the post-booster antibody titers from Study P204 to those following the primary series in adults 18 through 25 years in the pivotal adult Study P301 for which vaccine efficacy in preventing COVID-19 has been demonstrated. The study shows that the immune response to the booster dose of Spikevax in the 6 through 11 years age group (n = 95) was comparable to the immune response to the two-dose primary series in the young adult participants (n = 295).

The safety of a single booster dose of Spikevax was evaluated in 1,294 participants 6 through 11 years of age. As of the 23 May 2022 data cut off, the median follow-up duration was 29 days after the booster dose. The reported solicited local ARs were pain (90%), axillary swelling or tenderness (28%), swelling (hardness) (11%) and erythema (redness) (11%). The reported solicited systemic ARs were fatigue (49%), headache (38%), myalgia (21%), chills (14%), arthralgia (13%), nausea/vomiting (13%) and fever (9%). The median duration of solicited local and systemic adverse reactions was 3 days and 2 days, respectively. There were no cases of myocarditis or pericarditis and one SAE (abdominal pain) reported among booster recipients. The investigator considered the SAE not related to study vaccination.

12 to 17 years of age:

Study P203 (Part 1C-1, data cutoff of May 16, 2022) provides the primary evidence to support the use of the booster dose of Spikevax in adolescents. Study P203 (Part 1C-1) involved 1,364 participants 12 years through 17 years of age who received a 50 mcg booster dose of Spikevax at least 5 months after the second dose of the primary series (two doses 28 days apart).

Effectiveness of a booster dose of Spikevax in participants 12 years through 17 years of age was inferred by comparing the post-booster antibody titers from Study P203 to those following the primary series in adults 18 through 25 years in the pivotal adult Study P301 for which vaccine efficacy in preventing COVID-19 has been demonstrated. The study shows that the immune response to the booster dose of Spikevax in the 12 through 17 years age group (n = 257) was comparable to the immune response to the two-dose primary series in the young adult participants (n = 295).

The safety of a single booster dose of Spikevax was evaluated in 1,364 participants 12 through 17 years of age, with a median follow-up duration of 116 days after the booster dose. The reported solicited local adverse reactions (ARs) were pain (91%), axillary swelling or tenderness (28%), swelling (hardness) (14%) and erythema (redness) (9%). The reported solicited systemic ARs were fatigue (59%), headache (57%), myalgia (40%), chills (31%), arthralgia (24%), nausea/vomiting (18%) and fever (6%). The median duration of solicited local and systemic adverse reactions was 3 days. There were no cases of myocarditis or pericarditis and no SAEs reported among booster recipients. In addition, no new risks have been identified from the available post-market safety data for Spikevax.

Conclusion

No emergent safety concerns have been identified in Study P204 or P203, nor from the available post-market safety data for Spikevax vaccine portfolio. There are some uncertainties or limitations with the available data, including unavailable longer-term safety, immunogenicity/efficacy data; the uncertainty around the risk of very rare events such as myocarditis and pericarditis post-vaccination; unavailable safety and immunogenicity data in subjects with severe comorbidities or who are immunocompromised. The limitations are mitigated by Terms and Conditions and by presenting the information in the product monograph. In addition, active and passive safety surveillance will continue during the post authorization period to monitor the vaccine safety.

Based on the totality of the information, the benefit-risk profile for a 50 mcg booster dose of Spikevax Bivalent (Original / Omicron BA.4/5) is considered favourable in individuals 6 through 17 years of age. The Sponsor will provide Health Canada the safety and immunogenicity data of the ongoing Spikevax Bivalent (Original / Omicron BA.4/5) clinical studies (see Terms and Conditions).

For further details about Spikevax (elasomeran), Spikevax Bivalent (elasomeran/imelasomeran), and Spikevax Bivalent (Original / Omicron BA.4/5), please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.