Regulatory Decision Summary for Nuvaxovid XBB.1.5

The purpose of this submission was to obtain market authorization under the New Drug Submission (NDS) with flexibilities for designated COVID-19 drugs (NDS-CV) framework which seeks approval on the basis of the requirements in subsections C.08.002(2.1), C.08.002(2.2) or C.08.002(2.3) of the Regulations for a vaccine formulation containing 5 mcg of a SARS-CoV-2 protein from the Omicron (XBB.1.5) strain that is co-formulated with Matrix-M adjuvant as a single dose (0.5 mL) for individuals 12 years of age and older regardless of previous vaccination status.

After evaluation of the submitted data package, Health Canada authorized a single dose of Nuvaxovid XBB.1.5 at 5 mcg per dose may be administered in individuals 12 years of age and older who have been vaccinated with a previously or currently marketed Canadian COVID-19 vaccine primary series 6 months after the most recent dose. Additionally, Health Canada authorized a two-dose series of Nuvaxovid XBB.1.5 at 5 mcg per dose may be administered in individuals 12 years of age and older who have not been vaccinated with a previously or currently marketed Canadian COVID-19 vaccine primary series.

Given the antigenic differences in currently circulating SARS-CoV-2 compared to the reference strain, members of the International Coalition of Medicines Regulatory Authorities (of which Health Canada is a member) along with the World Health Organization (WHO) concluded that there is a need to update the COVID-19 vaccine composition to enhance vaccine-induced immune responses to circulating SARS-CoV-2 variants with the use of a monovalent XBB.1 descendent lineage, such as XBB.1.5.

The safety and effectiveness of Nuvaxovid XBB.1.5 for individuals 12 years of age and older is inferred from studies which evaluated the primary series and booster vaccination with Nuvaxovid administered as a primary series and booster vaccination in the same age bracket. Additional supportive data was provided by a study of a heterologous booster dose of an investigational vaccine targeting the Omicron BA.5 variant of SARS-CoV-2 vaccine in individuals 18 years of age and older, and by a study of a heterologous booster dose of an investigational vaccine targeting the Omicron BA.1 variant of SARS-CoV-2 in individuals 18 to 64 years of age.

The dose for Nuvaxovid XBB.1.5 is the same as currently on label for Nuvaxovid for this age bracket. The dosing regimen for Nuvaxovid XBB.1.5 in individuals who have been vaccinated with a previously or currently marketed Canadian COVID-19 vaccine primary series consists of a single dose administration 6 months following the most recent dose. The dosing regimen for Nuvaxovid XBB.1.5 in individuals who have not been vaccinated with a previously or currently marketed Canadian COVID-19 vaccine primary series is the same as currently on label for Nuvaxovid for this age bracket where the second dose is administered 3 weeks after the first dose.

Pre-clinical data submitted for this product demonstrated that the Omicron XBB.1.5 variant-specific vaccine induced a strong immune response against the XBB.1.5 strain as well as against antigenically similar strains, such as the currently circulating EG.5 variant, when administered as either a two-dose series in vaccine naïve animals or as a third-dose in vaccine-experienced animals. This suggests that a more closely strain-matched vaccine is anticipated to induce a more potent immune response than one with less antigenic similarity to the currently circulating variants, which is likely to translate into improved effectiveness. While acknowledging that animal models are not always directly predictive of response in humans, previously generated non-clinical immunogenicity data generated for the Nuvaxovid platform has translated into similar findings in corresponding clinical trials. No new safety concerns were identified in the new non-clinical data, which builds off of previous non-clinical safety data from the original Nuvaxovid vaccine. Collectively, this data is considered supportive, as proof-of-concept, of the potential immunogenicity of Nuvaxovid XBB.1.5 as a two-dose series in naïve individuals or as a single dose in previously vaccinated individuals in a clinical setting.

The Sponsor provided data from a new 2-part clinical trial 2019nCoV-311 with investigational drug products NVX-CoV2515 and NVX-CoV2540 targeting the BA.1 and BA.5 strains of SARS-CoV-2 Omicron respectively. These investigational drug products are formulated and manufactured in the same way as the currently marketed Nuvaxovid vaccine (NVX-CoV2373) and the drug product Nuvaxovid XBB.1.5 proposed for market authorization in the herein submission with the exception of the active substance being SARS-CoV-2 recombinant spike protein of the respective strains.

In study 2019nCoV-311 Part 1, a total of 831 randomized participants 18 to 64 years of age, were evaluated for immunogenicity and previously received 2 or 3 doses of the Pfizer-BioNTech COVID-19 Vaccine or the Moderna COVID-19 vaccine received 1 of the following as a booster dose: Nuvaxovid, monovalent NVX-CoV2515 or bivalent vaccine NVX-CoV2373 + NVX-CoV2515. The booster doses were administered a median of approximately 6 months after the last vaccination. The study met the primary objective, achieving both co-primary endpoints needed to demonstrate that NVX-CoV2515 produced a superior antibody response to the Omicron BA.1 subvariant when compared to Nuvaxovid at Day 14 using a partially validated assay. Neutralizing antibodies against the Omicron BA.1 subvariant were 1.6-fold higher with NVX-CoV2515 compared with Nuvaxovid and the difference in seroresponse rates was 22.5%. The descriptive Day 28 analysis followed the same trend as the Day 14 analysis of the co-primary endpoints. Approximately 80% of participants experienced a solicited adverse events in each of the vaccine groups. The median day of onset for solicited adverse events was on Day 1 with a median duration of 2 days. There were no serious or severe unsolicited treatment emergent adverse events considered related to the study vaccination.

In study 2019nCoV-311 Part 2, a total of 694 participants 18 years of age and older, who were evaluated for immunogenicity and previously received 3 or more doses of the Pfizer-BioNTech COVID-19 Vaccine or the Moderna COVID-19 vaccine received 1 of the following as a booster dose: Nuvaxovid, NVX-CoV2540, or bivalent vaccine NVX-CoV2373 + NVX-CoV2540. The booster doses were administered a median of 12.8, 10.9, and 11.8 months after the last vaccination, respectively. As an exploratory endpoint, neutralizing antibody responses induced by NVX-CoV2540 were evaluated through Day 28 post-dose. The NVX-CoV2540 vaccine induced titers for the Omicron BA.5 subvariant 2.5-fold higher than that of the Nuvaxovid vaccine and that also would have been 1.3-fold higher than those induced by the bivalent vaccine. Moreover, the NVX-CoV2540 vaccine would have met all three co-primary endpoints compared to the Nuvaxovid vaccine demonstrating a superior neutralizing antibody titer for the Omicron BA.5 subvariant, a non-inferior seroresponse rate for the Omicron BA.5 subvariant and noninferior neutralizing antibody titer against the Original strain. Approximately 77% of participants experienced a solicited adverse event. The median day of onset for solicited adverse events was on Day 1 with a median duration of 2 days. There was 1 severe unsolicited treatment emergent adverse event in the group that received NVX-CoV2540 classified as an immunization reaction to the influenza vaccine. There were 3 severe unsolicited treatment emergent adverse events in the bivalent NVX-CoV2373/2540 group namely, diarrhea, limb injury, and pelvic pain. Only the event of diarrhea was considered related to the study vaccination and the participants is said to be recovered and the event resolved without medical treatment. Two participants reported serious adverse events of cranial nerve palsy, including a serious adverse event of fourth nerve cranial palsy with onset of symptoms 7 days post vaccination and a serious adverse event of sixth nerve palsy with onset of symptoms 14 days post vaccination. Both participants had predisposing risk factors, including diabetes, hypertension, hypercholesterolemia. Currently available information on cranial palsies is insufficient to determine a causal relationship with the vaccine.

Immunogenicity and safety data accrued with the original monovalent formulation Nuvaxovid administered as a primary series and a booster (homologous and heterologous) alongside preliminary data accrued with the aforementioned monovalent investigational drug product formulations administered as heterologous booster doses suggest that Nuvaxovid XBB.1.5 will safely induce neutralizing antibodies against the currently circulating Omicron sub-lineages; no new safety signals are anticipated. Individually, the aforementioned data cannot be used as basis for regulatory decision, but collectively, they are supportive for evidence that Nuvaxovid XBB.1.5 will induce a safe, targeted immune response against the currently circulating Omicron sub-lineages. Furthermore, through inference, it is expected that this updated formulation will induce superior antibody responses to Omicron XBB.1.5 virus and non-inferior responses to the reference strain when compared to the previously approved formulations as well as it is expected to provide broader antibody response against circulating and emerging variants as compared to the currently authorized Nuvaxovid, while retaining cross-reactive immunity and cross-protection from severe illness caused by the reference strain and other variants.

Access to Nuvaxovid XBB.1.5 vaccination is considered important for individuals 12 years of age (YOA) and older for whom another Health Canada authorized COVID-19 booster vaccine is not accessible or clinically appropriate, and those who choose to receive the Nuvaxovid XBB.1.5 vaccine because they would otherwise not receive a booster dose of a COVID-19 vaccine.

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 Nuvaxovid XBB.1.5 vaccine in individual 12 YOA and older. Based on the totality of data reviewed, the safety profile of the Nuvaxovid XBB.1.5 formulation in individual 12 YOA and older is expected to be comparable with the safety profile of the monovalent formulation administered as a primary series and booster in this age bracket.

Risk Management Plan (RMP)

An updated core Risk Management Plan (RMP) and a Canadian RMP Addendum were included in the submission for Nuvaxovid XBB.1.5. 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 for Nuvaxovid XBB.1.5 based on the safety profile of Nuvaxovid as well as investigational drug products NVX-CoV2515 and NVX-CoV2540. 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 imposed for the submission of periodic safety update reports/periodic benefit risk evaluation reports, RMPs, and post-authorization safety study reports 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 Nuvaxovid XBB.1.5 is considered favorable in individuals 12 years of age and older.

For further details about Nuvaxovid XBB.1.5, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.