Summary Basis of Decision (SBD) for Nuvaxovid (previously Nuvaxovid XBB.1.5)

The New Drug Submission for Nuvaxovid XBB.1.5 (severe acute respiratory syndrome coronavirus 2 [SARS‑CoV‑2] recombinant spike protein [Omicron XBB.1.5]) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance was issued in relation to Nuvaxovid XBB.1.5, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug (described in the What follow-up measures will the company take? section).

The World Health Organization (WHO) and the WHO Strategic Advisory Group of Experts on Immunization advise that the composition of current and future vaccines for coronavirus disease 2019 (COVID‑19) caused by SARS‑CoV‑2 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 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 anticipated 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, Nuvaxovid XBB.1.5 is a monovalent vaccine containing the recombinant spike protein of the SARS-CoV-2 Omicron variant lineage XBB.1.5. Nuvaxovid XBB.1.5 is manufactured by the same process as the original Nuvaxovid vaccine.

Clinical Pharmacology

Nuvaxovid XBB.1.5 is a sterile, preservative‑free, aqueous buffered suspension of the SARS‑CoV‑2 recombinant spike protein. It is co‑formulated with Matrix‑M adjuvant and a formulation buffer. The SARS‑CoV‑2 recombinant spike protein in Nuvaxovid XBB.1.5 is produced in the Spodoptera frugiperda insect cell line infected with a baculovirus that encodes full‑length SARS‑CoV‑2 spike gene‑producing trimeric spike proteins from the Omicron XBB.1.5 variant. The Matrix‑M adjuvant contains Quillaja saponari saponin fractions A and C. The addition of the saponin‑based Matrix‑M adjuvant facilitates activation of the cells of the innate immune system, which enhances the magnitude of the spike protein‑specific immune response. The vaccine elicits both humoral and cellular immune responses via B‑ and T‑cell immune responses to the spike protein, including neutralizing antibodies, which may contribute to protection against COVID‑19.

Pharmacokinetic studies to demonstrate absorption, distribution, metabolism, and excretion of SARS‑CoV‑2 recombinant spike protein were not conducted and are typically not required for vaccines.

Immunogenicity was assessed as part of the clinical efficacy evaluation of Nuvaxovid XBB.1.5.

For further details, please refer to the Nuvaxovid XBB.1.5 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

No clinical study data were submitted using the Nuvaxovid XBB.1.5 drug product, as studies were ongoing at the time of authorization. The outcomes of these studies have been requested as terms and conditions imposed. The authorization of Nuvaxovid XBB.1.5 was largely supported by clinical data from the original Nuvaxovid vaccine.

The inferred clinical effectiveness (immunogenicity) of Nuvaxovid XBB.1.5 is based on the following considerations, within the context of the current epidemiological landscape of SARS-CoV-2 variants of concern in Canada and globally:

• clinical effectiveness of the original Nuvaxovid vaccine (administered as a primary series and as booster doses) in individuals 12 years of age and older;

• the extrapolation of clinical effectiveness data from participants 18 to 64 years of age in Study 2019nCoV‑311 Part 1 following administration of an investigational Nuvaxovid platform vaccine targeting the Omicron BA.1 variant (NVX‑CoV2515) as a heterologous booster (third or fourth dose);

• the extrapolation of clinical effectiveness data from participants 18 years of age and older in Study 2019nCoV‑311 Part 2 following administration of an investigational Nuvaxovid platform vaccine targeting the Omicron BA.5 variant (NVX‑CoV2540) as a heterologous booster (fourth dose or greater);

• estimates of current seroprevalence rates; and

• non‑clinical data.

Immunogenicity

The Original Nuvaxovid Vaccine

Clinical effectiveness of Nuvaxovid (administered as a primary series and booster doses) in individuals 12 years of age and older

The immunogenicity of a primary series and booster doses of the original Nuvaxovid vaccine has been previously characterized in several clinical studies conducted globally. These studies were reviewed by Health Canada and supported the authorization of the original Nuvaxovid vaccine in individuals 12 years of age and older.

The original Nuvaxovid vaccine was first authorized for individuals 18 years of age and older based on data from six clinical studies which were ongoing at the time of authorization. Two of these studies, 2019nCoV-301 and -302, were considered pivotal and established the efficacy of the original Nuvaxovid vaccine. The primary efficacy analysis set for 2019nCoV-301 included 25,452 participants who received either Nuvaxovid (number of participants [n] = 17,312) or placebo (n = 8,140). The vaccine efficacy of Nuvaxovid to prevent the onset of COVID-19 from 7 days after the second dose was 90.4% (95% CI: 82.9, 94.6), meeting the pre-specified criterion for success. The primary efficacy analysis set for 2019nCoV-302 included 14,039 participants who received either Nuvaxovid (n = 7,020) or placebo (n = 7,019). The vaccine efficacy of Nuvaxovid to prevent the onset of COVID-19 from 7 days after the second dose was 89.7% (95% CI: 80.2, 94.6), meeting the pre-specified criterion for success. For more information on the designs of these studies and their results, refer to the Summary Basis of Decision for the original Nuvaxovid vaccine.

A third (booster) dose of the original Nuvaxovid vaccine, administered at least 6 months after the primary series, was shown to induce a robust immune response during a Phase II and a Phase III study including 866 healthy adult participants. Neutralizing antibody titers were approximately 3‑fold higher following the booster dose compared to the values observed after the primary series of vaccination. The immune response observed is expected to enhance protection against COVID-19 in vaccinated individuals. For more information on the designs of these studies and their results, refer to the Regulatory Decision Summary for the authorization of the booster dose of the original Nuvaxovid vaccine in adults.

The original Nuvaxovid vaccine was authorized as a primary series for adolescents 12 to 17 years of age based on a comparison between a subset of COVID‑19‑naïve adolescents (12 to 17 years of age) and a similar subset of young adults (18 to 25 years of age) from the original phase of Study 2019nCoV-301. Non-inferiority was demonstrated with respect to the neutralizing antibodies against the SARS‑CoV‑2 wild type virus 14 days after a completed two‑dose series of the original Nuvaxovid vaccine. For more information on the designs of these studies and their results, refer to the Regulatory Decision Summary for the authorization of the original Nuvaxovid vaccine in adolescents.

At the time of review of the New Drug Submission (NDS) for Nuvaxovid XBB.1.5, Health Canada had not authorized a booster dose of the original Nuvaxovid vaccine in adolescents. An ad hoc analysis was conducted as part of a pediatric expansion of Study 2019nCoV‑301 (a Phase III pivotal study initiated to evaluate the efficacy of the original Nuvaxovid vaccine). Participants 12 to 17 years of age were randomized in a 2:1 ratio to receive the original Nuvaxovid vaccine as a primary series or placebo. As part of a blinded crossover design, after sufficient safety data were collected, participants who had received placebo were invited to receive two injections of the original Nuvaxovid vaccine 21 days apart. All participants were offered the opportunity to continue being followed in the study. Within 5 months after the administration of the second dose of the original Nuvaxovid vaccine (initial or crossover), participants who remained in the study received a booster dose of the original Nuvaxovid vaccine in an open-label manner. Immunogenicity and safety data were collected from 220 participants immediately prior to the booster vaccination, through 28 days after the booster vaccination.

Thirty‑five (35) days after the second dose, an analysis of the SARS-CoV-2 neutralizing antibody response was conducted in a subset of adolescent participants 12 through 17 years of age and a subset of participants 18 through 25 years of age from the adult main study. Non-inferior immune responses were demonstrated in a comparison of adolescents 12 through 17 years of age to participants 18 through 25 years of age, as assessed by geometric mean titers (GMTs) and seroconversion rates (SCRs).

The immunogenicity analysis population (referred to as the Per‑Protocol Immunogenicity [PP‑IMM] analysis set) included the 220 participants who received two doses of the original Nuvaxovid vaccine as their primary series and a single dose of the original Nuvaxovid vaccine as a booster dose. These participants were divided into two cohorts:

• Cohort 1, in which 110 participants received a single booster dose of the original Nuvaxovid vaccine after receiving placebo during the initial (pre‑crossover) period, followed by active vaccination during the blinded crossover period, and

• Cohort 2, in which 110 participants received a single booster dose of the original Nuvaxovid vaccine after receiving active vaccination during the initial (pre‑crossover) period, followed by placebo during the blinded crossover period.

Only participants from Cohort 2 were included in the immunogenicity analysis. Immune responses were measured by a validated microneutralization assay against the ancestral Wuhan strain that defined the titer as the concentration that yielded over 50% viral inhibition (MN₅₀).

In Cohort 2, a single booster dose of the original Nuvaxovid vaccine elicited a robust MN₅₀ response. A 27.7‑fold increase in neutralizing antibodies was shown, from a GMT of 426.7 prior to receiving the booster to a GMT of 11,824.4 (95% confidence interval [CI]: 8,993.1, 15,546.9) measured 28 days after the booster vaccination. The post‑booster GMT observed in this analysis was 2.7‑fold higher than that reported at 14 days after the second dose of the original Nuvaxovid vaccine in the primary vaccination series, which was 4,434 (95% CI: 3,658.0, 5,374.5). The ratio of MN₅₀ titers measured 28 days after the booster dose versus at 14 days after the primary series vaccination was 2.7 (95% CI: 2.0, 3.5). A comparison of the neutralizing antibody responses against the SARS‑CoV‑2 wild type virus (ancestral Wuhan strain) at 28 days after booster administration and at 14 days after the second dose of the original Nuvaxovid vaccine in the primary vaccination series showed a geometric mean fold rise (GMFR) of 2.7 (95% CI: 2.0, 3.5) (number of participants [n] = 53). This finding meets the non‑inferiority criterion of a lower bound of the 95% CI greater than 1.0. The difference in SCRs was 0.0% (95% CI: ‑6.8, 6.8) for neutralizing antibodies against the SARS‑CoV‑2 wild type virus at 28 days after the third (booster) dose compared to 14 days after the second dose in the primary series. Both are relative to the first dose of the original Nuvaxovid vaccine. This finding supports non‑inferiority, with a lower bound of the 95% CI greater than ‑10%. The median duration between the time of the second dose and the time of the third (booster) dose in Cohort 2 was 10.6 months (range: 10 to 12 months).

Overall, a single booster dose of the original Nuvaxovid vaccine administered to adolescent participants 12 to less than 18 years of age elicited increased immune responses against the ancestral Wuhan strain. The responses measured at 28 days after the booster vaccination were higher than those reported at 14 days after the second dose in the primary vaccination series. Non‑inferiority was demonstrated for GMFRs and for the differences in SCRs using the first dose of the original Nuvaxovid vaccine in the pre‑crossover period (Cohort 2) as a baseline. The observed GMFR was attributed to the higher neutralizing antibody GMTs prior to booster administration relative to the neutralizing antibody GMTs prior to the first dose of the original Nuvaxovid vaccine. These data support a homologous boosting effect of Nuvaxovid in adolescents similar to what was observed from adult participants.

Data from Published Studies

The sponsor submitted various publications from scientific literature (not sponsored by Novavax Inc.) as supportive evidence of the effectiveness of a heterologous booster dose of the original Nuvaxovid vaccine in individuals whose primary vaccination series consisted of other COVID‑19 vaccines.

The Phase II COV‑BOOST study was independently randomized and controlled. Delivered by a network of study sites across the United Kingdom, this study was led by the University Hospital Southampton National Health Service (NHS) Foundation Trust. It was designed to assess the effectiveness of the original Nuvaxovid vaccine as a heterologous booster dose in individuals whose primary vaccination series consisted of other COVID‑19 vaccines. The participants were adults 30 years of age and older who completed their primary vaccination series at least 10 weeks before the beginning of the study, and who had no history of laboratory‑confirmed SARS‑CoV‑2 infection.

A booster response to Nuvaxovid was demonstrated, regardless of the vaccine used for the primary vaccination series. A follow‑up was conducted on Day 84 of the study. At all timepoints, no significant differences were observed in decay rates of cellular responses between vaccines. These data contributed to the authorization of the original Nuvaxovid vaccine as a heterologous booster in various regulatory jurisdictions worldwide.

Other publications were also submitted which corroborate the trends observed in the COV‑BOOST study, indicating that heterologous protein‑based booster vaccines are expected to have a boosting effect immunologically. Although the clinical significance of this is unknown, a protein‑based vaccine is expected to be an acceptable alternative to mRNA or adenoviral‑based COVID‑19 vaccines for use as a booster.

Investigational Nuvaxovid Platform Vaccines

With the current submission, data was submitted from two clinical studies conducted with the investigational Nuvaxovid platform vaccines targeting the SARS‑CoV‑2 Omicron BA.1 and BA.5 strains (NVX‑CoV2515 and NVX‑CoV2540, respectively). With the exception of the active substance being the SARS‑CoV‑2 recombinant spike protein of the respective strains, both investigational vaccines are formulated and manufactured using the same process as the original Nuvaxovid vaccine and Nuvaxovid XBB.1.5.

Investigational Nuvaxovid platform vaccine targeting the Omicron BA.1 variant (NVX‑CoV2515)

Part 1 of Study 2019nCoV‑311 included 831 participants 18 to 64 years of age who had previously received 2 or 3 doses of either the original Comirnaty or Spikevax vaccines. Participants were randomized to receive one of the following as a booster dose: NVX‑CoV2515 (targeting the Omicron BA.1 variant; Group C; number of participants [n] = 279), NVX‑CoV2373 (the original Nuvaxovid vaccine; Group D; n = 274), or a bivalent vaccine targeting the ancestral and Omicron BA.1 strains (NVX‑CoV2373 + NVX‑CoV2515; Group E; n = 278). The median time between the administration of the last vaccination and the booster dose was approximately 6 months (177 to 182 days).

The median age of the population was 42.5 to 44.5 years (range: 18 to 64 years). The majority of participants in each group were female (55.9% to 62.7%) and white (82.4% to 85.7%). Demographic characteristics were similar across the three groups.

The primary objective was to determine whether NVX‑CoV2515 induces antibody responses to the Omicron BA.1 variant that are superior to those induced by Nuvaxovid (NVX‑CoV2373) in participants previously vaccinated with three doses of the original Spikevax and/or Comirnaty vaccines. The co‑primary endpoints, the GMT ratio and seroresponse (defined as a 4‑fold or greater increase from baseline values) were evaluated 14 days post‑booster dose using a partially validated assay. Statistical significance would be achieved if the lower bound of the two‑sided 95% CI was above unity (i.e., greater than 1). Non‑inferiority would be established if the lower bound of the two‑sided 95% CI was above ‑5%. The per‑protocol neutralization assay analysis subset included 119, 126, and 188 participants in the NVX‑CoV2373, NVX‑CoV2515 group, and bivalent vaccine groups, respectively. The median age of the population was 42.5 to 44.5 years (range: 18 to 64 years). The majority of participants in each group were female (55.9% to 62.7%) and white (82.4% to 85.7%). Demographic characteristics were similar across the three groups.

Both co‑primary endpoints were achieved, demonstrating that NVX‑CoV2515 produces a superior antibody response to the Omicron BA.1 variant than the original Nuvaxovid vaccine (NVX‑CoV2373) at Day 14. The neutralizing antibody titers (MN₅₀) were 130.8 and 83.9 in the NVX‑CoV2515 and NVX‑CoV2373 groups, respectively (GMT ratio of 1.6 [95% CI: 1.33, 2.03]). The seroresponse rates (SRRs) were 73.4% for the NVX‑CoV2515 group and 50.9% for the NVX‑CoV2373 group (difference in SRR of 22.5% [95% CI: 10.3, 34.2]). When compared with seronegative participants, baseline neutralization titers were approximately 4‑fold higher in previously infected participants who were anti‑nucleocapsid‑positive at screening.

The descriptive Day 28 analysis followed the same trend as the Day 14 analysis of the co‑primary endpoints. At Day 28, neutralizing antibody responses to the Omicron BA.1 variant and the ancestral strain were generally similar to, or slightly lower than, those seen at Day 14 for all three study groups. At Day 28, neutralizing antibody GMTs against the Omicron BA.1 variant increased 4.8‑fold in the NVX‑CoV2515 group (122.3), 2.9‑fold in the NVX‑CoV2373 group (77.5), and 3.3‑fold in the bivalent vaccine group (87.4). The SRRs were 74.1%, 47.3%, and 54.9%, respectively. At Day 28, neutralizing antibody GMTs against the ancestral strain increased 2.0‑fold in the NVX‑CoV2515 group (960.8), 3.0‑fold in the NVX‑CoV2373 group (1,442.8), and 2.4‑fold in the bivalent vaccine group (1,087.4). The SRRs were 31.9%, 49.1%, and 41.2%, respectively.

Overall, the responses observed with the NVX‑CoV2515 investigational vaccine are considered marginally supportive for the authorization of Nuvaxovid XBB.1.5 given that it is not the exact same vaccine. However, these data support the expectation and biological plausibility that Nuvaxovid XBB.1.5 would induce strain‑targeted immune responses.

Investigational Nuvaxovid platform vaccine targeting the Omicron BA.5 variant (NVX‑CoV2540)

Part 2 of Study 2019nCoV‑311 included 694 participants 18 years of age and older who had previously received 3 or more doses of either the original Comirnaty or Spikevax vaccines. Participants were randomized to receive one of the following as a booster dose: NVX‑CoV2540 (targeting the Omicron BA.5 variant; Group F; n = 255), NVX‑CoV2373 (the original Nuvaxovid vaccine; Group G; n = 252), or the bivalent vaccine targeting the ancestral and Omicron BA.5 strains (NVX‑CoV2373 + NVX‑CoV2540; Group H; n = 259). The median times between the administration of the last vaccination and the administration of the booster dose were 12.8, 10.9, and 11.8 months, respectively. The GMRs and SRRs were evaluated 1 month after the booster vaccination using a validated assay.

The median age of the population was 43.0 years (83.1% of participants were 18 to 54 years of age). Overall, 45.1% of participants were male and 80.3% were white. Demographic characteristics were similar across the three groups.

The per‑protocol immunogenicity analysis set included 227, 236, and 231 participants in the NVX‑CoV2373, NVX‑CoV2540, and bivalent vaccine groups, respectively. The median time since the last COVID‑19 vaccination was 347.0 days. The median age of the population was 43.0 years (range: 18 to 75 years); 576 participants (83.0%) were 18 to 54 years of age, and 118 participants (17.0%) were 55 years of age or older. Overall, 45.1% of participants were male and 80.3% were white. Demographic characteristics were similar across the three groups. Following the booster dose and through the cut‑off date, the median follow‑up time was 48.0 days.

As an exploratory endpoint, neutralizing antibody responses induced by NVX‑CoV2540 were evaluated through Day 28 post‑dose. The NVX‑CoV2540 induced antibody titers for the Omicron BA.5 subvariant that would have been superior to those induced by NVX‑CoV2373 (the original Nuvaxovid vaccine) (GMT ratio of 2.5, with a lower bound of the 95% CI of 2.1) and to those induced by the bivalent vaccine (GMT ratio of 1.3 with a lower bound of the 95% CI of 1.06). Additionally, NVX‑CoV2540 would have met all three co‑primary endpoints relative to the Nuvaxovid vaccine, demonstrating a superior neutralizing antibody titer for the Omicron BA.5 variant, a non‑inferior SRR for the Omicron BA.5 variant, and a non‑inferior neutralizing antibody titer against the ancestral strain. Although these endpoints are exploratory, the response observed following booster vaccination with the NVX‑CoV2540 vaccine formulation are considered marginally supportive for the authorization of Nuvaxovid XBB.1.5.

Ongoing Clinical Studies with Nuvaxovid XBB.1.5

The immunogenicity of Nuvaxovid XBB.1.5 will be evaluated in the two ongoing studies 2019CoV‑313 and 2019CoV‑314. The outcomes of these studies have been requested as terms and conditions associated with the authorization.

Study 2019CoV-313

Study 2019CoV‑313 is designed to evaluate the safety and immunogenicity of a booster dose of Nuvaxovid XBB.1.5 in participants 18 years of age and older who:

• have previously been vaccinated with a messenger ribonucleic acid (mRNA) COVID‑19 vaccine, or

• who are vaccine‑naïve and SARS‑CoV‑2 seropositive at baseline.

In Part 1 of the study, approximately 330 participants previously vaccinated with an mRNA COVID‑19 vaccine received a booster dose of Nuvaxovid XBB.1.5 on Day 0.

In Part 2 of the study, approximately 330 unvaccinated participants with a clinical history of COVID‑19‑like disease during the previous year will receive a dose of Nuvaxovid XBB.1.5 on Day 0.

For both Part 1 and Part 2, immunogenicity data will form part of the basis of interim analyses and will be collected up to Day 180 post‑vaccination.

Study 2019CoV-314

Study 2019CoV‑314 is a Phase III randomized double‑blinded study designed to evaluate the immunogenicity of Omicron subvariant and bivalent SARS‑CoV‑2 vaccines in adolescents 12 to less than 18 years of age who have previously been vaccinated with mRNA COVID‑19 vaccines. Approximately 400 adolescent participants will receive a booster dose of either Nuvaxovid XBB.1.5 (NVX‑CoV2601) or a bivalent formulation targeting the ancestral and XBB.1.5 strains (NVX-CoV2373 + NVX-CoV2601). Immunogenicity data will form part of the basis of an interim analysis and will be collected up to Day 180 post‑vaccination.

In both studies 2019CoV‑313 and 2019CoV‑314, there was no group in which participants received 4 doses of the mRNA vaccines, which presents challenges in bridging (comparing) these data to any previous clinical study efficacy data. Although the magnitude of the immune response related to efficacy is unknown (in the absence of an immune‑correlate of protection threshold), observations from both studies indicate that the investigational Nuvaxovid platform vaccines induce targeted immune responses that will result in a heterologous boosting effect. This is expected to be of clinical benefit in light of the current circulating strains of SARS‑CoV‑2.

Summary of Immunogenicity

Nuvaxovid XBB.1.5 is anticipated to induce neutralizing antibodies against the currently circulating Omicron sublineages. This expectation is based on the immunogenicity data accrued with the original Nuvaxovid vaccine administered as a primary series and a booster (homologous or heterologous), along with preliminary data accrued with the investigational Nuvaxovid platform vaccines administered as heterologous booster doses. Furthermore, it is inferred that Nuvaxovid XBB.1.5 will induce superior antibody responses to the Omicron XBB.1.5 variant and non‑inferior responses to the ancestral strain when compared to the original Nuvaxovid vaccine. Nuvaxovid XBB.1.5 is expected to provide broader antibody responses against circulating and emerging variants compared to the original Nuvaxovid vaccine, while retaining cross‑reactive immunity and cross‑protection from severe illness caused by the ancestral strain and other variants.

Nuvaxovid XBB.1.5 has not been evaluated for use as a homologous or heterologous booster dose in any age bracket, which is recognized as a major gap in the data. However, considering the data collected from clinical studies using the original Nuvaxovid vaccine, NVX‑CoV2515, and NVX‑CoV2540 as booster doses, along with the data from published studies, the identified gap in the data does not preclude the approval of Nuvaxovid XBB.1.5 as a heterologous booster dose. Additionally, the risks associated with this gap in the data will be mitigated by issuance of the terms and conditions related to data from Studies 2019CoV‑313 Part 1 and 2019CoV‑314.

Estimates of current seroprevalence rates

A meta‑analysis of SARS‑CoV‑2 seroprevalence studies, standardized to those described in the WHO Unity protocol suggested that the prevalence of infection has been largely underestimated in most settings throughout the pandemic. Consistent with these observations, a second cycle of the Canadian COVID‑19 Antibody and Health Survey (CCAHS‑2) suggested that between April and August 2022, 98% of Canadians had antibodies against COVID‑19 and 54% had antibodies from a previous infection.

When evaluating seroprevalence due to infection in Canada by age group, the highest levels of seropositivity due to infection in 2022/2023 were observed in young adults. Estimates of infection-acquired seroprevalence decreased with increasing age. However, the difference between children and young adults is unclear since the data available for children is limited.

Cumulative data on the comparative protection provided by previous infection alone, vaccination alone, and hybrid immunity (immune protection from both vaccination and previous infection) indicate 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 re‑infection with Omicron sublineages. Furthermore, throughout the sponsor’s clinical studies with the original Nuvaxovid vaccine and the investigational Nuvaxovid platform vaccines, when participants are stratified by baseline status, those that are seropositive have been found to generate higher overall immune responses (as measured by GMTs) with lower GMFRs than their seronegative counterparts.

Indication

The New Drug Submission for Nuvaxovid XBB.1.5 was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Nuvaxovid (COVID‑19 Vaccine [recombinant protein, adjuvanted]) XBB.1.5 is indicated for active immunization to prevent coronavirus disease 2019 (COVID‑19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) in individuals 12 years of age and older.

For more information, refer to the Nuvaxovid XBB.1.5 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

The clinical safety of Nuvaxovid XBB.1.5 is inferred based on the following considerations, within the context of the current epidemiological landscape of SARS‑CoV‑2 variants of concern in Canada and globally:

• clinical safety of the original Nuvaxovid vaccine (administered as a primary series and booster doses) in individuals 12 years of age and older;

• clinical safety data from participants 18 to 64 years of age in Study 2019nCoV‑311 Part 1 following administration of an investigational Nuvaxovid platform vaccine targeting the Omicron BA.1 variant (NVX‑CoV2515) as a heterologous booster (third or fourth dose); and

• clinical safety data from participants 18 years of age and older in Study 2019nCoV‑311 Part 2 following administration of an investigational Nuvaxovid platform vaccine targeting the Omicron BA.5 variant (NVX‑CoV2540) as a heterologous booster (fourth dose or greater).

Additionally, the clinical safety of Nuvaxovid XBB.1.5 will be evaluated in Studies 2019nCoV‑313 and 2019nCoV‑314. The outcomes of these studies have been requested as terms and conditions associated with the authorization.

The Original Nuvaxovid Vaccine

Clinical safety of Nuvaxovid (administered as a primary series and booster doses) in individuals 12 years of age and older

The safety of the original Nuvaxovid vaccine has been previously characterized in several clinical studies conducted globally.

At the time of review of this New Drug Submission (NDS), Health Canada had not authorized an adolescent booster dose for the original Nuvaxovid vaccine. An ad hoc analysis was conducted as part of a pediatric expansion of Study 2019nCoV-301 in 1,499 adolescent participants. The pre‑specified safety analysis was conducted in a subset of 220 participants who were randomly selected for analysis of immunogenicity. Another safety analysis was conducted among a larger population of 1,499 participants, including the 220 participants in the pre‑specified safety analysis.

In the pre‑specified safety analysis (n = 220), participants were divided into two cohorts:

• Cohort 1, in which approximately 110 participants received two doses of the placebo in the initial vaccination period and two doses of the original Nuvaxovid vaccine in the blinded crossover vaccination period; and

• Cohort 2, in which approximately 110 participants received two doses of the original Nuvaxovid vaccine in the initial vaccination period and two doses of placebo in the blinded crossover vaccination period.

For the booster vaccination period, as of June 16, 2022, the median time to follow‑up after the third (booster) dose of NVX‑CoV2373 was 51 days in Cohort 1, 53 days in Cohort 2, and 52 days for Cohorts 1 and 2 combined. Approximately 19% of participants in Cohorts 1 and 2 combined were followed for at least 2 months after the booster vaccination.

For the 1,499 participants who received a third (booster) dose of NVX‑CoV2373 through the data extract date of September 7, 2022, the median time to follow‑up was 134 days (range: 33 to 156 days) for Cohort 1, 135 days (range: 30 to 157 days) for Cohort 2, and 135 days (range: 30 to 157 days) for Cohorts 1 and 2 combined. In Cohorts 1 and 2 combined, 98.9% of participants were followed for at least 2 months after the booster vaccination.

Solicited local and systemic treatment‑emergent adverse events (TEAEs) in the pre‑specified safety analysis set (n = 220) were reported in 80.5% and 85.8% of adolescent participants, respectively. The majority of participants (59.5%) reported events of Grade 1 or 2 severity. Each solicited local and systemic TEAE was reported in at least 10% of participants, with tenderness and pain (local) and headache, fatigue, muscle pain, malaise, and nausea/vomiting (systemic) being the most frequent (incidence of more than 25% of participants). Fatigue and malaise were the most frequent Grade 3 solicited TEAEs (incidence of more than 15% of participants). No Grade 4 solicited TEAEs were reported. No adolescent participant reported an adverse event consistent with a solicited local or systemic TEAE with an onset after 7 days from booster vaccination.

In the booster safety analysis set (n = 1,249), 87.6% of participants reported any solicited reaction. Grade 3 and 4 events were reported in 33.5% and 0.4% of participants, respectively. With respect to solicited local adverse events in this population, the incidence of pain/tenderness was the highest at 77.2%, with 11.6% of participants reporting it as a Grade 3 event and less than 0.1% of participants reporting it as a Grade 4 event. With respect to solicited systemic adverse events in this population, the incidences of fatigue/malaise, headache, and muscle pain were reported in 63.3%, 63.1%, and 60.4% of participants, respectively, with 21.2%, 12.3%, and 11.4% of participants reporting them as Grade 3 events, respectively. Less than 0.1% of participants reported each of these as a Grade 4 event.

In the booster safety analysis set, the median duration between the time of the second dose of NVX‑CoV2373 and the time of the third (booster) dose in Cohort 1 was 7.6 months (range: 6 to 8 months) and 10.6 months (range: 10 to 12 months) for Cohort 2.

In the pre‑specified safety analysis set (n = 220), unsolicited TEAEs through 28 days after the third (booster) dose of NVX‑CoV2373 were reported in 11 adolescent participants (5.0%), and a severe TEAE was reported in one participant (0.5%; cholelithiasis, determined to be unrelated to the study vaccine). No TEAEs were reported which resulted in study discontinuation or death, and no adverse events of special interest were reported (including potential immune‑mediated medical conditions [PIMMCs] and COVID‑19‑related TEAEs). Through 28 days after the third (booster) dose of NVX‑CoV2373, unsolicited TEAEs were reported in 77 of the 1,499 participants in the larger safety population (5.1%).

No cases of facial palsy (Bell’s palsy), anaphylactic shock/shock, myocarditis, pericarditis, or thrombosis with thrombocytopenia syndrome were reported.

Three serious adverse events were reported (cholelithiasis, type 2 diabetes mellitus, and suicide attempt), all were assessed by the investigator as not related to the study vaccine.

Unsolicited serious adverse events were reported in three adolescents of the 1,499 participants (0.2%) in the larger safety population through 28 days after the third (booster) dose of NVX‑CoV2373.

No TEAEs resulting in death occurred among the 1,499 participants through 28 days following the third (booster) dose of NVX‑CoV2373.

No adverse events of special interest were reported in any adolescent participant through 28 days following the third (booster) dose of NVX‑CoV2373, including PIMMCs reported by the site and based on protocol‑defined criteria and seven participants (0.5%) who reported COVID‑19‑related TEAEs.

No new safety signals were detected with the administration of a third (booster) dose of the original Nuvaxovid vaccine to adolescent patients. Although adolescents tend to have higher reactogenicity than adults and may be at higher risk for adverse events of special interest, such as myocarditis and pericarditis, the observed safety profile was similar to that observed for a homologous booster dose of the original Nuvaxovid vaccine in adults. These data were the basis for the extrapolation of safety data from adult participants to adolescent participants (12 to 17 years of age), including data supporting a strain change and heterologous boosting from investigational Nuvaxovid platform vaccines targeting the Omicron BA.1 and BA.5 variants in adults. The risks have been appropriately mitigated through labelling in the Nuvaxovid XBB.1.5 Product Monograph.

Investigational Nuvaxovid Platform Vaccine NVX-CoV2515

Clinical safety was assessed as part of Study 2019nCoV‑311, a multi‑part, Phase III, randomized, observer‑blinded study to evaluate investigational Nuvaxovid platform vaccines targeting the SARS-CoV-2 Omicron BA.1 strain in adults previously vaccinated with other COVID‑19 vaccines.

The main (secondary) safety endpoint was to assess the overall safety of one‑dose regimens of either NVX‑CoV2515, NVX‑CoV2373, or the bivalent NVX‑CoV2515 + NVX‑CoV2373 vaccines in participants previously vaccinated with two or three doses of the original Spikevax or Comirnaty vaccine.

Approximately 80% of participants experienced a solicited adverse event in each of the vaccine groups. More solicited local events were reported than systemic reactions. The median day of onset for solicited local adverse events was Day 1, with a median duration of two days. In Group C, two solicited local adverse events (listed as pain/tenderness) were reported which had an onset beyond seven days following vaccination. The median day of onset for solicited systemic adverse events was Day 1, with a median duration of two days. No systemic adverse events were reported which had an onset beyond seven days following vaccination. In Groups C, D, and E, the number of reported adverse events with a duration of more than seven days was 6, 2, and 2, respectively. The adverse events which had a duration of more than seven days were fatigue, malaise, muscle pain, and headache.

Overall, more female participants reported adverse events, including Grade 3 events, than male participants. Incidence rates by race and ethnicity are difficult to interpret due to the overwhelmingly high proportion of white participants. Adverse event rates appear to be similar with the limited data available.

There were 145, 137, and 123 unsolicited TEAEs in each of the vaccine groups (Groups C, D, and E), respectively. A small subset of these events were considered related to the study vaccine – 14 in Group C, 10 in Group D, and 12 in Group E. The most common TEAEs were infections and infestations, with only one event in this category considered to be related to study vaccination.

Four severe unsolicited TEAEs were reported, all of which occurred in Group D (in which participants received NVX‑CoV2373). These were upper respiratory tract infection, urinary tract infection, anaphylactic reaction (to nuts), and back pain. None of these events were considered related to the study vaccination. All events were considered to be resolved, with patients recovering.

Two serious TEAEs were reported in this study – one case of dysmenorrhea in Group C, and one anaphylactic reaction (to nuts) in Group D.

No new safety signals were identified with the administration of a heterologous booster dose of an investigational Nuvaxovid platform vaccine targeting the Omicron BA.1 variant (NVX‑CoV2515) in adults. The observed incidence of adverse events was similar to that observed for a booster dose of the original Nuvaxovid vaccine, and the known safety concerns (allergic reactions and myocarditis) are adequately addressed in the Product Monograph. The safety profile in adolescent patients is expected to be similar to the safety profile in adults, based on a comparison of the safety of a booster dose of the original Nuvaxovid vaccine in each of these age groups. A change in vaccine strain composition is similarly not expected to change the safety profile of the Nuvaxovid platform vaccines in an adolescent population.

Investigational Nuvaxovid Platform Vaccine NVX-CoV2540

In Part 2 of Study 2019nCoV‑311, participants were randomized to receive either NVX‑CoV2540 (targeting the Omicron BA.5 variant; Group F; n = 255), NVX‑CoV2373 (the original Nuvaxovid vaccine; Group G; n = 252), or the bivalent vaccine targeting the ancestral and Omicron BA.5 strains (NVX‑CoV2373 + NVX‑CoV2540; Group H; n = 259).

The main exploratory safety endpoint was to assess the overall safety after one and two doses of NVX‑CoV2540 in participants previously vaccinated with three or more doses of Spikevax and/or Comirnaty monovalent and/or bivalent vaccines. A secondary safety endpoint was to assess the overall safety after one and two doses of NVX‑CoV2373 + NVX‑CoV2540 and NVX‑CoV2373 in participants previously vaccinated with three or more doses of Spikevax and/or Comirnaty monovalent and/or bivalent vaccines.

Approximately 77% of participants experienced a solicited adverse event. More solicited local events were reported than systemic reactions. The median day of onset for solicited local adverse events was Day 1 (the day following vaccination), with a median duration of two days. No solicited local adverse events were reported which had an onset beyond seven days following vaccination. In each of Groups F and H, one adverse event was detected which had a duration of more than seven days (eight and nine days, respectively). The median day of onset for solicited systemic adverse events was Day 1, with a median duration of two days. There were no systemic adverse events with an onset beyond seven days following vaccination. In Groups F, G, and H, the number of reported adverse events with a duration of more than seven days was 5, 2, and 3, respectively. The adverse events which had a duration of more than seven days were fatigue/malaise and headache.

Overall, participants aged 55 and older had a similar incidence of adverse events to participants aged 18 to 54, and in some cases, a slightly lower incidence. More female participants reported adverse events, including Grade 3 events, than male participants. Incidence rates by race and ethnicity are difficult to interpret due to the overwhelmingly high proportion of white participants. Adverse event rates appear to be similar with the limited data available.

There were 82, 77, and 74 unsolicited TEAEs in each of the vaccine groups (Groups F, G, and H respectively). A small subset of these events were considered related to the study vaccine (3 in Group F, 6 in Group G, and 9 in Group H). The most common TEAEs were infections and infestations, with only one event in this category considered to be related to study vaccination. The most common events considered related to the study vaccination were nervous system disorders, namely, headache.

One case of psychiatric disorders (nightmare) was reported, which was considered related to the study vaccination.

One severe unsolicited TEAE was reported in Group F (NVX‑CoV2540), which was classified as an immunization reaction to the influenza vaccine. Three severe unsolicited TEAEs were reported in Group H (bivalent vaccine NVX‑CoV2373 + NVX‑CoV2540 formulation): diarrhea, limb injury, and pelvic pain. Only the event of diarrhea was considered related to the study vaccination. The participant recovered and the event resolved without medical treatment.

One new safety signal, nerve palsies, was identified in this study, with two events reported. However, the information currently available on cranial palsies is not sufficient to determine whether there is a causal relationship with the vaccine. These events have been included in the Product Monograph and the risk is considered appropriately mitigated.

The observed incidence of adverse events in this study was similar to the incidence observed for a booster dose of the original Nuvaxovid vaccine. The known safety concerns (allergic reactions and myocarditis) are adequately addressed by labelling in the Product Monograph. The safety profile of Nuvaxovid XBB.1.5 in the adolescent age group (12 to 17 years of age) is expected to be similar to the safety profile in adults, based on the data available for each age group from the booster dose of the original Nuvaxovid vaccine. A change in the vaccine strain composition is not expected to affect the safety profile of the product.

Risk Management Plan

A core (European Union [EU]) Risk Management Plan (RMP) and a Canadian RMP Addendum for Nuvaxovid XBB.1.5 were submitted by Novavax Inc. 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 Novavax Inc. as part of the NDS for Nuvaxovid XBB.1.5. 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 Post-Authorization Activity Table of Nuvaxovid XBB.1.5.

While clinical data for Nuvaxovid XBB.1.5 were not available at the time of authorization, the authorization was based on the extrapolation of clinical safety data for the original Nuvaxovid vaccine and the investigational Nuvaxovid platform vaccines NVX‑CoV2515 and NVX‑CoV2540, and post‑market safety data for the original Nuvaxovid vaccine to date. The RMP adequately captured the known and potential risks of this vaccine. This included two important identified risks: anaphylaxis, and myocarditis and pericarditis; and one important potential risk: vaccine‑associated enhanced disease, including vaccine‑associated enhanced respiratory disease. The RMP also listed eight areas of missing information (limited/no clinical data): “use in pregnancy and while breastfeeding”, “use in immunocompromised patients”, “use in frail patients with comorbidities”, “use in patients with autoimmune or inflammatory disorders”, “interaction with other vaccines”, “long‑term safety”, “use in pediatric subjects”, and “long‑term effectiveness.” An important limitation of the data for all approved age groups continues to be the long‑term safety and effectiveness of the vaccine. This limitation is managed through labelling and the RMP.

The proposed routine and additional pharmacovigilance activities for the above safety concerns are considered to be acceptable and are consistent with those for the currently authorized Nuvaxovid vaccine. Additional pharmacovigilance activities include continued safety surveillance of ongoing clinical and post-authorization studies undertaken for the original Nuvaxovid vaccine and Nuvaxovid XBB.1.5. Routine risk minimization measures (i.e., product monograph and labelling) are also considered to be appropriate.

Further safety data must be collected in the post-marketing setting, considering the limited clinical data available for Nuvaxovid XBB.1.5. 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.

Clinical Summary

The benefit of the availability of an updated vaccine (Nuvaxovid XBB.1.5) in the current epidemiological context was determined to outweigh the uncertainty resulting from less comprehensive data. Based on clinical trial data and post‑market safety for the original Nuvaxovid vaccine administered as a primary series and as a booster dose, it is anticipated that Nuvaxovid XBB.1.5 will have an acceptable safety profile. Considering the data provided, knowledge of other investigational monovalent and bivalent vaccines targeting the Omicron BA.1 and BA.5 variants, literature publications, market experiences with the original Nuvaxovid vaccine and non-clinical data, and the risks associated with COVID-19 as a respiratory virus of ongoing public health concern, the totality of available evidence reasons that Nuvaxovid XBB.1.5 is expected to elicit an immune response that will confer protection against COVID‑19. Further immunogenicity and safety data will be provided as part of the terms and conditions.

For more information, refer to the Nuvaxovid XBB.1.5 Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

The New Drug Submission for Nuvaxovid XBB.1.5 (severe acute respiratory syndrome coronavirus 2 [SARS‑CoV‑2] recombinant spike protein [Omicron XBB.1.5]) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance was issued in relation to Nuvaxovid XBB.1.5, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug (described in the What follow-up measures will the company take? section).

Nuvaxovid XBB.1.5 is a protein‑based vaccine used to prevent the coronavirus disease 2019 (COVID‑19) caused by SARS‑CoV‑2. It consists of a sterile, preservative‑free, aqueous buffered suspension of the SARS‑CoV‑2 recombinant spike protein from the Omicron XBB.1.5 strain that is co‑formulated with Matrix‑M adjuvant and a formulation buffer.

To support the authorization of Nuvaxovid XBB.1.5, new non‑clinical data were submitted. The data were accrued from the use of investigational Nuvaxovid platform monovalent and bivalent vaccines matched to subvariants of the Omicron variant, including the XBB.1.5 subvariant.

The non‑clinical data builds from and is directly linked to the non‑clinical pharmacodynamic, pharmacokinetic, and toxicology data from the original Nuvaxovid vaccine, which targets the original Wuhan strain of SARS‑CoV‑2. Nuvaxovid XBB.1.5 utilizes the same platform technology as that used for the original Nuvaxovid vaccine, therefore, no new safety concerns are expected.

The new non‑clinical data included three studies in non‑human primates and four studies in mice, all of which assessed the immunogenicity of the original Nuvaxovid vaccine as well as investigational Nuvaxovid platform vaccines matched to the Omicron variant (subvariants BA.1, BA.2, BA.5, BA.2.12.1, BQ.1.1, CH.1.1, XBB.1.5, and XBB.1.16). These vaccines were administered as a two‑dose primary series and/or a third‑dose booster, using monovalent and/or bivalent formulations. The protective efficacy of the original Nuvaxovid vaccine was evaluated as both a two‑dose primary series or as a single dose in naïve rhesus macaques.

Overall, when used as a two‑dose primary series in naïve animals, the Omicron variant‑specific vaccines induced a robust dose‑dependent immune response that was comparable to those induced by the original Nuvaxovid vaccine. Stronger responses were achieved when the variant‑specific vaccine matched the target antigen, and responses following immunization with Nuvaxovid XBB.1.5 were also broadly cross-reactive with other Omicron subvariants, including other XBB subvariants such as, EG.5.1 and FL.1.5.1. While a single dose also elicited these responses, the magnitude of response was substantially increased with a second dose. When used as a third‑dose booster in previously vaccinated animals, the Omicron variant‑specific vaccines induced an anamnestic antibody recall response that was strongest against the analogous variant but also broadly cross‑reactive. Both monovalent and bivalent formulations containing experimental XBB.1.5 recombinant spike vaccine were immunogenic as a third dose booster as a proof of concept, however the responses were higher with Nuvaxovid XBB.1.5.

In a SARS‑CoV‑2 challenge study in naïve rhesus macaques, two doses of the original Nuvaxovid vaccine administered 28 days apart induced mucosal immunity in both the lower and upper airway, and provided near total protection against viral replication in these areas. When assessed at the same time point following viral challenge, a single immunization at the same dose level was not as effective at reducing viral replication, particularly in the upper airway, and correspondingly lower neutralizing antibody titres were observed in this group.

The non‑clinical data submitted in support of Nuvaxovid XBB.1.5 is considered substantive evidence as proof‑of‑concept for the use of the vaccine in a clinical setting. Based on the new non‑clinical data provided, Nuvaxovid XBB.1.5, when administered as a two‑dose primary series in unvaccinated individuals or as a single dose in previously vaccinated individuals, is expected to elicit potent immune responses, that are anticipated to be cross‑reactive with the currently circulating Omicron subvariants. It is expected that this will likely translate to improved effectiveness with no new safety concerns.

For more information, refer to the Nuvaxovid XBB.1.5 Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

The New Drug Submission for Nuvaxovid XBB.1.5 (severe acute respiratory syndrome coronavirus 2 [SARS‑CoV‑2] recombinant spike protein [Omicron XBB.1.5]) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance was issued in relation to Nuvaxovid XBB.1.5.

Nuvaxovid XBB.1.5 is an adjuvanted, recombinant spike protein nanoparticle vaccine developed to prevent coronavirus disease 2019 (COVID‑19) caused by SARS‑CoV‑2. The vaccine is composed of a purified, full‑length SARS‑CoV‑2 recombinant spike protein derived from the Omicron variant lineage XBB.1.5. The SARS‑CoV‑2 recombinant spike protein (Omicron XBB.1.5) is co‑formulated with a saponin-based Matrix‑M adjuvant. The Matrix‑M adjuvant is added to enhance the magnitude of the spike protein-specific immune response. The two vaccine components, SARS‑CoV‑2 recombinant spike protein (Omicron XBB.1.5) and the Matrix‑M adjuvant, elicit B‑ and T‑cell immune responses to the spike protein, including neutralizing antibodies, which may contribute to protection against COVID‑19.

The submission for Nuvaxovid XBB.1.5 leverages information from the previous submission for the original Nuvaxovid vaccine which contains the recombinant spike protein derived from the ancestral Wuhan‑like strain. Both vaccines were developed using the same protein nanoparticle platform technology and similar manufacturing processes.

Characterization of the Drug Substance

The drug substance, SARS‑CoV‑2 (Omicron XBB.1.5), is a protein product of a recombinant SARS‑CoV‑2 spike gene encoding 1,256 amino acids of the spike protein (the full‑length 1,269 amino acid protein minus the signal peptide). The spike gene is optimized for expression in Spodoptera frugiperda (Sf9) insect cells from a full‑length, prefusion, stabilized SARS‑CoV‑2 (Omicron XBB.1.5) spike protein. A total of five amino acid changes, the same as the ancestral Wuhan‑like strain, are introduced in the spike gene, three in the S1/S2 furin cleavage site and two in the HR1 domain where two proline substitutions were inserted to stabilize the protein. Several detailed characterization studies are performed to ensure the drug substance consistently maintains the desired characteristic structures and biological activities.

The drug substance, SARS‑CoV‑2 recombinant spike protein (Omicron XBB.1.5), is co‑formulated with a saponin based adjuvant, Matrix‑M. The formulation of Matrix‑M consists of two individually formed nanoparticles (Matrix‑A and Matrix‑C), each with a different and well characterized saponin fraction (fraction A and fraction C) with complementary properties.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

The Nuvaxovid XBB.1.5 vaccine was developed using the same nanoparticle technology platform as that used to develop the original Nuvaxovid vaccine.

Drug Substance

The drug substance, SARS‑CoV‑2 recombinant spike protein (Omicron XBB.1.5), is a protein produced by recombinant deoxyribonucleic acid technology using a baculovirus expression system. The SARS‑CoV‑2 recombinant spike protein (Omicron XBB.1.5) is manufactured in an Sf9 insect cell line, which is infected with a baculovirus containing a modified SARS‑CoV‑2 spike gene derived from the Omicron variant lineage XBB.1.5. Following infection, spike proteins are expressed on the surface of the Sf9 cells. Once mature, the spike proteins are harvested, purified, and concentrated to produce the SARS‑CoV‑2 recombinant spike protein (Omicron XBB.1.5) drug substance.

The overall manufacturing process for the drug substance SARS‑CoV‑2 recombinant spike protein (Omicron XBB.1.5) is similar with the previously approved manufacturing process for the original Nuvaxovid vaccine. No modifications were made to the upstream process up to the harvest step. Only minor changes were made to the downstream process to address the isoelectric point difference between the XBB.1.5 and ancestral Wuhan‑like strains. Changes to the downstream process were validated through an abbreviated process performance qualification (PPQ). All results obtained for the PPQ lots met pre‑defined acceptance criteria and demonstrated that the SARS‑CoV‑2 recombinant spike protein (Omicron XBB.1.5) drug substance manufacturing process is consistent, controlled, and robust.

The manufacturing process used to produce the Matrix‑M adjuvant for the original Nuvaxovid vaccine remains the same as that for the Nuvaxovid XBB.1.5 Matrix‑M adjuvant. It is created by mixing two components, Matrix‑A and Matrix‑C, both of which are produced from purified saponin fractions (A and C) derived from saponin raw material that is extracted from the bark of Quillaja saponaria Molina trees. Cholesterol and phosphatidylcholine are present as excipients in the matrix solutions.

Drug Product

The manufacturing process for the Nuvaxovid XBB.1.5 drug product is similar to that of the manufacturing process for the original Nuvaxovid vaccine. The main change is the use of the SARS‑CoV‑2 recombinant spike protein (Omicron XBB.1.5) drug substance in place of the ancestral Wuhan‑like strain. The drug product manufacturing process consists of the preparation of the formulation buffer, processing of the drug substance (SARS‑CoV‑2 recombinant spike protein [Omicron XBB.1.5]) and adjuvant Matrix‑M components (Matrix‑A and Matrix‑C), combining the drug substance with the Matrix‑M adjuvant and adding the formulation buffer, blending, and final filling steps. For the XBB.1.5 drug product, variant‑specific testing methods have been developed and validated to replace the current method for measuring the protein concentration at release and on stability.

To further monitor the consistency of the XBB.1.5 drug product given the variant strain change, batches of XBB.1.5 drug product (five‑dose presentation) were manufactured. All results for the PPQ lots met pre‑defined acceptance criteria and demonstrated that the variant drug product manufacturing process is consistent, controlled, and robust.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of the SARS‑CoV‑2 recombinant spike protein (Omicron XBB.1.5) with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The process parameters and controls, analytical methods, and release specifications for Nuvaxovid XBB.1.5 are similar to those for the original Nuvaxovid vaccine. The drug substance and adjuvant are tested against suitable reference standards to verify that they meet approved specifications, and analytical procedures are validated and in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. A platform approach to validation was found to be sufficient based on the similarity to the original Nuvaxovid vaccine. Minor changes to the plasmid sequence do not affect process performance or drug substance quality based on physiochemical characterization and batch testing data.

Nuvaxovid XBB.1.5 is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

The proposed shelf lives are based on the extrapolation of aggregate stability data across the Nuvaxovid platform, which demonstrates that the stability profiles of the drug substance and drug product are highly similar regardless of changes made to the plasmid sequence for the production of the drug substance. Stability studies for Nuvaxovid XBB.1.5 are ongoing, and the sponsor shall provide stability updates as data are generated in ongoing studies.

A drug product shelf life of 12 months, when stored at 2 °C to 8 °C, is acceptable based on stability data generated from drug product lots of the original Nuvaxovid vaccine (ten‑dose and five‑dose presentations), and XBB.1.5 drug product lots.

In‑use storage conditions are outlined in the Nuvaxovid XBB.1.5 Product Monograph. After the first dose has been withdrawn, the vial/filled syringe may be held at 2 °C to 25 °C for up to 12 hours. After this time, the vial/filled syringe must be discarded.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The Nuvaxovid XBB.1.5 drug substance and drug product are manufactured at the same manufacturing site using the same facilities and equipment used to manufacture the original Nuvaxovid vaccine. The facility for the manufacturing and control of Nuvaxovid XBB.1.5 has been issued an Establishment License issued by Health Canada. Other than minor changes to the plasmid sequence and testing of the drug substance and drug product, the manufacturing and controls remain the same. Therefore, an on-site evaluation was not required.

Adventitious Agents Safety Evaluation

The manufacturing process of Nuvaxovid XBB.1.5 incorporates adequate control measures to prevent contamination and maintain microbial control. Controlled selection and appropriate specifications for raw materials and excipients, specifications, in‑process controls and release testing for starting materials, and the drug substance and drug product, are in place to assure that adventitious agents are controlled for Nuvaxovid XBB.1.5. Therefore, the overall control strategy for adventitious agents is considered acceptable.