Summary Basis of Decision for Nuvaxovid

The New Drug Submission for Nuvaxovid (severe acute respiratory syndrome coronavirus 2 [SARS‑CoV‑2] recombinant spike protein) 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, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug.

As described above, the clinical review of the New Drug Submission for Nuvaxovid was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The clinical efficacy, immunogenicity, and safety of Nuvaxovid were primarily evaluated using the available data from two ongoing pivotal, placebo-controlled, Phase III studies: Study 2019nCoV-301 conducted in the United States and Mexico, and Study 2019nCoV-302 conducted in the United Kingdom. In addition, supportive data were also evaluated from four ongoing clinical studies: Study 2019nCoV-101 (Part 1), Study 2019nCoV-101 (Part 2), Study 2019nCoV-501, and Study ICMR/SII-COVOVAX. These studies were conducted in Australia, South Africa, the United States, and India. The Nuvaxovid vaccine used in clinical studies contained the recombinant SARS-CoV-2 spike protein derived from the original (Wuhan) strain of SARS-CoV-2.

Clinical Pharmacology

Nuvaxovid is a sterile, preservative-free, aqueous buffered suspension of the SARS-CoV-2 recombinant spike (rS) protein. It is co-formulated with Matrix-M adjuvant and a formulation buffer. The SARS-CoV-2 rS protein in Nuvaxovid 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 original (Wuhan) strain. The Matrix-M adjuvant contains Quillaja saponaria saponins fraction A and fraction 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 coronavirus disease 2019 (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.

For further details, please refer to the Nuvaxovid 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 efficacy of Nuvaxovid was evaluated in three clinical studies. The Phase IIa/b Study 2019nCoV-501 served as a proof of concept study for efficacy. Vaccine efficacy was subsequently evaluated in the two pivotal, placebo-controlled, Phase III studies: Study 2019nCoV-301 and Study 2019nCoV-302. All three studies were ongoing at the time of Nuvaxovid authorization.

The primary efficacy endpoint for all studies was the vaccine efficacy of Nuvaxovid against the first episode of laboratory‑confirmed (polymerase‑chain reaction [PCR]-positive) symptomatic mild, moderate, or severe COVID-19 (with minor differences in the definitions across studies) with an onset at least 7 days following the administration of Dose 2 in participants seronegative for SARS-CoV-2 infection at baseline. For the pivotal studies, the vaccine efficacy success criteria for the primary endpoint as predefined by the sponsor, was a vaccine efficacy rate with a lower bound of the 95% confidence interval (LBCI) greater than 30%. Health Canada's vaccine efficacy success criteria as defined in the Guidance for Market Authorization Requirements for COVID-19 Vaccines is a target threshold of at least 50% vaccine efficacy, with an LBCI above 30%. Although there were some differences in study design, the efficacy analysis population (referred to as the Per-Protocol Efficacy [PP-EFF] analysis set) for all studies included baseline seronegative participants who received both doses of either Nuvaxovid or placebo (Dose 1 on Day 0 and Dose 2 between Days 21 and 28) who did not experience an exclusionary protocol deviation, and did not have evidence of SARS-CoV-2 infection through 6 days after Dose 2.

Both pivotal studies excluded participants who were significantly immunocompromised, pregnant, or who had a history of laboratory-confirmed COVID-19. Participants with clinically stable underlying comorbidity were included in both studies, as were participants with well-controlled human immunodeficiency virus (HIV) infection. It is noteworthy that the data provided from both of the pivotal studies were collected prior to the emergence of the Delta and Omicron variants.

Pivotal Efficacy Studies

Study 2019nCoV-301

Study 2019nCoV-301 was a Phase III, multicentre, randomized, observer-blinded, placebo-controlled study conducted in participants 18 years of age and older in the United States and Mexico. Upon enrolment, participants were stratified by age (18 to 64 years or 65 years and older) and were randomized in a 2:1 ratio to receive two intramuscular injections of Nuvaxovid or placebo, 21 days apart.

The enrolment of adult participants for Study 2019nCoV-301 was completed on February 18, 2021. Following the collection of sufficient efficacy and safety data to support the application, participants were permitted to be re-vaccinated with two injections of the alternative study product to what they initially received (i.e. those who received Nuvaxovid could receive placebo and those who received placebo could receive Nuvaxovid) 21 days apart. This period, which commenced on April 20, 2021, was referred to as the blinded crossover period. Safety and efficacy events were evaluated until each participant’s first blinded crossover vaccination or as of the data cut-off date of May 31, 2021. Participants are to be followed for assessments of safety and efficacy against COVID-19 for up to 24 months after the second dose.

The demographic and baseline characteristics were balanced amongst participants who received Nuvaxovid or placebo. Of the 29,949 participants randomized, 15.1% of participants in the Nuvaxovid group and 23.3% of participants in the placebo group requested unblinding to receive an authorized COVID-19 vaccine. In the PP-EFF analysis set, Nuvaxovid recipients (total number [n] = 17,312) had a median age of 47 years (range: 18 to 95 years), 88% were 18 to 64 years of age, 12% were aged 65 and older, and 48% were female. In the Nuvaxovid group, 94% of recipients were from the United States and 6% were from Mexico. Most of the Nuvaxovid recipients (76%) were White, 11% were Black or African American, 6% were American Indian (including Native Americans) or Alaskan Native, and 4% were Asian. Of all Nuvaxovid recipients, 22% were Hispanic or Latino. In 16,493 (95%) of the Nuvaxovid recipients, at least one pre-existing comorbidity or lifestyle characteristic associated with an increased risk of severe COVID-19 was present. Comorbidities included: obesity (body mass index [BMI] ≥30 kg/m²); chronic lung disease; diabetes mellitus type II, cardiovascular disease; chronic kidney disease; or HIV. Other high-risk characteristics included an age of 65 years or older (with or without comorbidities) or an age of less than 65 years with comorbidities and/or living or working conditions involving known frequent exposure to SARS-CoV-2 or to densely populated circumstances.

As of the data cut-off date of May 31, 2021, the primary efficacy analysis population (referred to as the PP-EFF analysis set) included 25,452 participants who received two doses of either Nuvaxovid (n = 17,312) or placebo (n = 8,140) as two doses, 21 to 28 days apart. Participants in this analysis set did not experience an exclusionary protocol deviation, and did not have evidence of SARS‑CoV‑2 infection through 6 days after the second dose. Cases of COVID-19 were confirmed by PCR through a central laboratory.

As of the data cut-off point, 14 cases of COVID-19 were reported in Nuvaxovid recipients and 63 cases were reported in the placebo recipients from 7 days onward following the administration of Dose 2. The vaccine efficacy of Nuvaxovid to prevent the onset of COVID-19 from 7 days following Dose 2 was estimated to be 90.4% (95% Confidence Interval [CI]: 82.9, 94.6). Based on this outcome, Nuvaxovid met the study's primary efficacy endpoint criterion for success with an LBCI greater than 30%. In addition, Nuvaxovid met Health Canada's required threshold of at least 50% vaccine efficacy, with an LBCI greater than 30%.

In the PP-EFF analysis set, there were no cases of moderate or severe COVID-19 reported in the 17,312 Nuvaxovid participants compared with 10 cases of moderate COVID-19 and 4 cases of severe COVID-19 reported in the 8,140 placebo recipients.

The efficacy results for Study 2019nCoV-301 reflect enrolment that occurred during a time period when strains classified as variants of concern or variants of interest were circulating in the Unites States and Mexico. Based on exploratory sequencing conducted in the study, the Alpha variant made up the majority of the cases (31 of the 61 cases for which these data were available).

Study 2019nCoV-302

Study 2019nCoV-302 was a Phase III, multicentre, randomized, observer-blinded, placebo-controlled study conducted in participants 18 to 84 years of age in the United Kingdom. Upon enrolment, participants were stratified by age (18 to 64 years or 65 to 84 years) and were randomized in a 1:1 ratio to receive two intramuscular injections of Nuvaxovid or placebo, 21 days apart.

Enrolment for Study 2019nCoV-302 was completed on November 28, 2020. The data cut-off dates for efficacy and safety were January 29, 2021 and February 23, 2021, respectively. Participants are to be followed for assessments of safety and efficacy against COVID-19 for up to 12 months after the last vaccination.

The demographic and baseline characteristics were balanced amongst participants who received Nuvaxovid or placebo. Of the 15,187 participants randomized, 33.8% of participants in the Nuvaxovid group and 35.4% of participants in the placebo group requested to receive an authorized COVID-19 vaccine. In the PP-EFF analysis set, Nuvaxovid recipients had a median age of 56 years (range: 18 to 84 years), 72% were 18 to 64 years old, 28% were aged 65 to 84, and 49% were female. The majority (95%) of Nuvaxovid recipients were White, 3% were Asian, 1.0% were multiple races, and 0.4% were Black or African American. Of all Nuvaxovid recipients, 0.9% were Hispanic or Latino. Forty-five percent (45%) of Nuvaxovid recipients had at least one comorbid condition.

As of the data cut-off date of January 29, 2021, the PP-EFF analysis set included 14,039 participants who received two doses of either Nuvaxovid (n = 7,020) or placebo (n = 7,019), 21 to 28 days apart. None of the participants experienced an exclusionary protocol deviation and none had evidence of SARS‑CoV‑2 infection through 6 days after the second dose. Cases of COVID-19 were confirmed by PCR through a central laboratory.

As of the data cut-off point, 10 cases of COVID-19 were reported in Nuvaxovid recipients and 96 cases in placebo recipients from 7 days onward following the administration of Dose 2. The vaccine efficacy of Nuvaxovid was estimated to be 89.7% (95% CI: 80.2, 94.6) for prevention of the onset of COVID-19 from 7 days following Dose 2. Based on this outcome, Nuvaxovid met the study's primary efficacy endpoint criterion for success with an LBCI greater than 30%. In addition, Nuvaxovid met Health Canada's required threshold of at least 50% vaccine efficacy, with an LBCI greater than 30%.

Nine cases of moderate COVID‑19 and no cases of severe COVID-19 were reported in the 7,020 Nuvaxovid recipients compared with 63 cases of moderate COVID‑19 and 5 cases of severe COVID-19 reported in the 7,019 placebo recipients in the PP-EFF analysis set. These efficacy results reflect enrolment that occurred during a time period when strains classified as variants of concern or variants of interest were circulating in the United Kingdom. Based on exploratory sequencing conducted in the study, the Alpha variant made up the majority of the cases (66 out of the 95 cases for which these data were available).

Supportive Efficacy

Study 2019nCoV‑501

Study 2019nCoV-501 was a Phase IIa/b, multicentre, randomized, observer-blinded, placebo-controlled study conducted in South Africa. The study enrolled HIV-negative participants who were 18 to 84 years of age as well as medically stable HIV-positive participants 18 to 64 years of age. As of the data cut-off date of February 23, 2021, the PP-EFF analysis set included 2,770 participants who had received two doses of either Nuvaxovid (n = 1,408) or placebo (n = 1,362), 21 days apart.

Demographic and baseline characteristics were balanced amongst participants who received Nuvaxovid or placebo. In the PP-EFF analysis set, for participants who received Nuvaxovid, the median age was 28 years (range: 18 to 84 years); 40% were female; 91% were Black or African American, 2% were White, 3% were multiple races, and 1% were Asian; 2% were Hispanic or Latino; and 5.5% were HIV-positive.

As of the data cut-off point, there were 51 cases of COVID-19 reported in Nuvaxovid recipients and 96 cases in placebo recipients from 7 days onward following the administration of Dose 2. The vaccine efficacy of Nuvaxovid was 48.6% (95% CI: 28.4, 63.1) for prevention of the onset of COVID-19 from 7 days after Dose 2. Nuvaxovid met the study's primary efficacy endpoint criterion for success with an LBCI >0%, thereby demonstrating proof of concept of efficacy.

These efficacy results reflect enrolment that occurred during a time period when strains classified as variants of concern or variants of interest were circulating in South Africa. Based on exploratory DNA sequence analysis conducted in the study, the Beta variant made up the majority of the cases (38 out of the 41 cases for which these data were available).

Immunogenicity

The immunogenicity of Nuvaxovid was primarily evaluated in the pivotal studies 2019nCoV-301 and Study 2019nCoV-302, along with Study 2019nCoV-501, and Study ICMR/SII-COVOVAX. In all four studies, blood samples for serologic assessments were collected from all enrolled participants before vaccination, during the immediate period following the first set of vaccinations (Day 0, 21 and 35), and as planned long-term follow-up (Months 12, 18 and 24). Based on the specifics of each study, amounts of anti-spike protein immunoglobulin G (IgG) were measured and compared to amounts on Day 0 using geometric mean titers (GMTs) reported as geometric mean enzyme‑linked immunosorbent assay (ELISA) units (GMEUs), geometric mean fold rises (GMFRs), and seroconversion rates (SCRs), or the percentage of subjects with a postvaccination titer ≥4-fold over baseline and ≥2-fold over a pre-existing titer. Similarly, neutralization antibody levels were measured from baseline at Day 0 comparing the GMFRs of active vaccine to placebo, as well as corresponding SCRs.

Study 2019nCoV-301

In the pivotal Study 2019nCoV-301, the immunogenicity analysis was conducted in a subset of 1,200 randomly selected participants following the initial set of vaccinations. This subset was intentionally over-selected for seniors by selecting near equally from the two main age categories (49.4% being 18 to <65 years of age, and 50.6% being ≥65 years of age). Therefore, this subset was not representative of the study population analyzed for efficacy in the PP-EFF analysis, but was useful for exploring the effect of age on the immune response of Nuvaxovid.

In participants who were SARS-CoV-2 seronegative at baseline, serum IgG antibody GMEUs in the Nuvaxovid group were approximately 1.7-fold higher in the younger cohort than in the older cohort at Day 35 (14 days after Dose 2). However, SCRs in the Nuvaxovid groups were markedly increased relative to placebo across all age groups (97.3% vs. 4.5% for participants ≥18 years of age; 98.0% vs 3.7% for 18 to <65 years of age; and 96.6% vs 5.3% for ≥65 years of age). Similar results were also seen for human angiotensin-converting enzyme 2 (hACE2) receptor binding inhibition antibodies and neutralizing antibodies.

Study 2019nCoV-302

In the pivotal Study 2019nCoV-302, the per-protocol immunogenicity (PP-IMM) anti-spike protein serology subset included 831 participants (5.5%), with 414 in the Nuvaxovid group and 417 in the placebo group. The PP-IMM neutralization assay subset included 761 (5.0%) participants, with 381 in the Nuvaxovid group and 380 in the placebo group.

Two weeks following Dose 2 (Day 35), serum GMTs of the anti-spike protein IgG in the Nuvaxovid group were increased approximately 300- to 400-fold relative to the placebo group across all age groups (46,679.3 endotoxin units [EU]/mL vs. 129.5 EU/mL for participants 18 to 84 years of age). Serum GMTs of the anti-spike protein IgG in the Nuvaxovid group were approximately 1.4-fold higher in the younger cohort (18 to 64 years) than in the older cohort (65 to 84 years). At Day 35, neutralizing antibody levels were also increased in Nuvaxovid recipients relative to placebo recipients, regardless of baseline serostatus, across all age groups: 18 to 84 years, 18 to 64 years, and 65 to 84 years. In most participants, neutralizing antibody GMTs in the Nuvaxovid group were markedly increased approximately 80- to 120-fold relative to the placebo group across all age groups (1214.6 vs 11.3 for participants 18 to 84 years of age) at 2 weeks following Dose 2 (Day 35). Neutralizing antibody GMTs in the Nuvaxovid group were approximately 1.4-fold higher in the younger cohort (18 to 64 years) than in the older cohort (65 to 84 years). This finding is consistent with findings from Study 2019nCoV-301.

Study 2019nCoV-501

In the supportive Study 2019nCoV-501, immune responses following Dose 2 of Nuvaxovid were markedly higher compared with those following Dose 1, regardless of HIV status or SARS-CoV-2 serostatus at baseline. In HIV-negative and HIV-positive serologically naïve participants, GMFRs for anti-spike protein IgG antibodies following Dose 2 were 283.7 at Day 35 relative to 123.0 at Day 0. Following Dose 1, these values were 10.7 at Day 21 relative to 4.4 at Day 0. Among participants who were SARS-CoV-2 seronegative at baseline, anti-spike protein IgG antibody responses at Day 35 were approximately 2-fold higher for HIV-negative participants than those for HIV-positive participants. However, for participants who were seropositive at baseline, anti-spike protein IgG antibody responses at Day 35 were comparable between HIV-negative and HIV-positive participants. Regardless of HIV status, anti-spike protein IgG antibody responses at Day 35 were markedly higher in SARS-CoV-2 seropositive participants compared with seronegative participants, which is indicative of cell-mediated immune memory.

Neutralizing antibody responses against wild-type virus showed a similarly robust pattern of induction at Day 35 (14 days after second vaccination) to those seen for anti-spike protein IgG antibodies. At Day 35, the GMFR in neutralizing antibodies were measured for all participants (stratified by serostatus: SARS‑CoV‑2 seronegative or seropositive at baseline). In HIV‑negative participants, 53.4‑ to 70.4‑fold increases in the GMFR were measured in those who received Nuvaxovid, and 1.1‑ to 1.2‑fold increases were measured in those who received the placebo. In HIV‑positive participants, 30.6‑ to 36.9‑fold increases in the GMFR were measured in those who received Nuvaxovid, and 0.9‑ to 1.2‑fold increases were measured in those who received the placebo.

In HIV-negative participants, seroconversion rates were 97.1% and 97.4% for baseline SARS-CoV-2 seronegative and seropositive individuals, respectively. In stable HIV-positive participants, seroconversion rates were 98.4% and 92.3% for baseline SARS-CoV-2 seronegative and seropositive individuals, respectively. Among baseline SARS-CoV-2 seronegative participants, neutralizing antibody responses were two-fold higher in HIV-negative participants compared with stable HIV-positive participants. However, responses were comparable among baseline SARS-CoV-2 seropositive participants, regardless of HIV status. Neutralizing antibody responses at Day 35 were markedly higher in SARS-CoV-2 seropositive compared to seronegative participants, regardless of HIV status. Taken together, prior exposure to COVID-19 infection or another COVID-19 vaccine may improve immune response to this vaccine regardless of HIV status.

ICMR/SII-COVOVAX Study

The ICMR/SII-COVOVAX study was primarily conducted as an immunobridging Phase II/III noninferiority study comparing the Novavax vaccine produced in the United States with a future commercialized vaccine to be mass produced in India under the domestic brand of Covovax (a hybrid United States drug substance/India drug product).

The Phase III portion of the study randomized 1,400 participants. A total of 1,396 (99.7%) participants received Dose 1 of a study vaccine (Covovax or Novavax vaccine), and 1,375 (98.2%) received Dose 2 with 1,361 (97.2%) completing Day 36 follow-up. Of these participants, 458 (32.7%) were enrolled in the Immunogenicity and Reactogenicity Cohort and were randomized 3:1 to receive Dose 1 of Covovax or Novavax vaccine. A total of 452 of 458 (98.7%) participants received Dose 2 with 449 of 458 (98%) participants providing blood samples for immunogenicity assessments on Day 36 (Visit 3). Although the median age was 33 to 34 years of age within the immunogenicity cohort, demographics and baseline characteristics were well-balanced relative to the general population in India with baseline SARS-CoV-2 seropositivity being about 34% in both groups.

Baseline GMEUs of anti-spike protein IgG antibodies were comparable between the groups. For both groups, the rise in GMEUs (GMFR) of anti-spike protein IgG antibodies was higher than 17-fold (17.7 for Covovax and 20.3 for Novovax) at Day 22 after Dose 1, and higher than 65-fold (65.6 for Covovax, 88.6 for Novovax) at Day 36 (14 days after Dose 2). The immunogenicity of Covovax was assessed based on the primary endpoint of the ratio of GMEUs of anti‑spike protein IgG antibodies, with a prespecified requirement of a noninferiority margin of 0.67 for the lower bound of the 95% CI for Day 36. The primary immunogenicity endpoint was met as the GMEU ratio between the Covovax and Novavax vaccine products at Day 36 was 0.92 (95% CI [0.79, 1.06]) with the lower bound of the 95% CI (0.79) exceeding the noninferiority margin of 0.67. Similar GMFR and GMEU ratio findings were noted for neutralizing antibodies measured by a microneutralization assay using wild type SARS CoV-2.

Taken together, Nuvaxovid (and the Covovax version) appear to provide a robust humoral immune response (both binding and neutralizing antibodies against SARS-CoV-2 spike protein) following Dose 2. These immune responses were observed regardless of SARS-CoV-2 serostatus, age, or HIV status, though the response may be mildly attenuated in older age groups or in stable-HIV-positive patients. However, this may not be a clinically meaningful difference. Duration of immunity in the post-marketing period will require additional larger scale immunogenicity studies to determine the need for, and spacing of, future booster doses of Nuvaxovid.

Indication

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

• Nuvaxovid (COVID-19 Vaccine [recombinant protein, adjuvanted]) 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 18 years of age and older.

For more information, refer to the Nuvaxovid 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 evidence of safety for Nuvaxovid was primarily based on pooled data from the two pivotal Studies 2019nCoV-301 and 2019nCoV-302, and the supportive Study 2019nCoV-501, described in the Clinical Efficacy section above.

At the time of the analysis, a total of 48,698 participants 18 years of age and older received at least one dose of Nuvaxovid (n = 29,297) or placebo (n = 19,401). The median duration of follow-up was 70 days after Dose 2, with 32,993 (66%) participants completing more than 2 months of follow-up. At the time of vaccination, the median age of participants who received Nuvaxovid was 48 years (range 18 to 95 years): 84.1% of participants were between 18 and 64 years of age and 15.9% of participants were 65 years of age or older.

Reactogenicity

Solicited adverse events (AEs) were consistently collected and pooled across the three studies but excluded data from the 2019nCoV-302 substudy. Adverse events that occurred at the injection site were recorded as local reactogenicity. These AEs included pain, tenderness, erythema/redness, and swelling/induration. Adverse events that were more generalized and occurred at other sites throughout the body were recorded as systemic reactogenicity. These AEs included fever, nausea/vomiting, headache, fatigue/malaise, myalgia/muscle pain, and arthralgia/joint pain. Any reactions that persisted for more than 7 days after vaccination were also recorded as a treatment‑emergent adverse event (TEAE) starting on the same day as the reactogenicity event. There was a general trend of increased local and general reactogenicity within the Nuvaxovid versus (vs.) placebo groups, especially after Dose 2. However, these differences were attenuated in the stable HIV-positive subset for tenderness, erythema, and for swelling in the HIV-positive subset in Study 2019nCoV-501.

The pooled reactogenicity data included participants 18 years of age and older who received at least one dose of Nuvaxovid (n = 21,395) or placebo (n = 12,197). Overall, 21,395 pooled participants were assessed for local reactogenicity after Dose 1 of Nuvaxovid and 20,259 after Dose 2. From the placebo group, there were 12,197 pooled participants studied after Dose 1 and 11,434 after Dose 2. The rates for any local AE of any grade temporally associated with Nuvaxovid administration were 57.4% after Dose 1 and 75.4% after Dose 2 in participants 18 to 64 years of age (younger cohort). Corresponding rates for placebo recipients in the younger cohort were 20.3% after Dose 1 and 19.8% after Dose 2. The rates for any local AE of any grade temporally associated with Nuvaxovid administration were 37.3% after Dose 1 and 60.0% after Dose 2 in participants 65 years of age and older (older cohort). Corresponding rates for placebo recipients in the older cohort were 14.4% after Dose 1 and 14.4% after Dose 2. Following Dose 2, the most frequently reported solicited local AEs (in Nuvaxovid and placebo recipients, respectively) were: tenderness at the injection site (69.3% vs. 14.4% in the younger cohort and 54.9% vs. 9.6% in the older cohort), followed by pain (57.7.0% vs. 12.7% in the younger cohort and 40.5% vs. 9.5% in the older cohort), erythema (6.3% vs. 0.3% in the younger cohort and 5.3% vs. 0.3% in the older cohort) and swelling (5.8% vs. 0.3% in the younger cohort and 5.7% vs. 0.6% in the older cohort).

Overall, reports of solicited systemic adverse reactions increased with successive doses of Nuvaxovid, but not with placebo. Similar to local reactogenicity, there was an increase of Grade 3 or higher AEs in the Nuvaxovid group but not the placebo group. In the younger cohort, the rate for any systemic AE of any grade temporally associated with Nuvaxovid administration was 47.5% after Dose 1 and 66.5% after Dose 2. Corresponding rates for placebo recipients for the younger cohort were 37.9% and 32.7%, respectively. In the older cohort, the rates for any systemic AE of any grade temporally associated with Nuvaxovid administration were 31.7% after Dose 1 and 47.0% after Dose 2. Corresponding rates for placebo recipients in the older cohort were 29.4% and 25.4%, respectively. The most frequently reported solicited systemic AEs after Dose 2 of Nuvaxovid (vs. placebo) were: fatigue (46.8% [vs. 19.0%] in the younger cohort and 28.6% [vs 13.9%] in the older cohort), muscle pain/myalgia (46.0% [vs. 10.7%] in the younger cohort and 26.4% [vs. 9.4%] in the older cohort), headache (43.3% [vs. 18.5%] in the younger cohort and 23.6% [vs. 12.8%] in the older cohort), malaise (36.9% [vs. 10.7%] in the younger cohort and 21.0% [vs. 8.3%] in the older cohort), joint pain/arthralgia (21.5% [vs. 6.5%] in the younger cohort and 12.5% [vs. 5.6%] in the older cohort), followed by nausea/vomiting (11.3% [vs. 5.2%] in the younger cohort and 5.1% [vs. 3.3%] in the older cohort) and fever (5.7% [vs. 0.5%] in the younger cohort and 1.9% [vs. 0.9%] in the older cohort). Similar to local reactogenicity, the younger cohort had higher relative rates of systemic AEs compared with the older cohort.

Unsolicited Adverse Events

Data regarding unsolicited AEs were collected from Day 0 to 49 (28 days following Dose 2 of the vaccine) across the three studies and were presented as incidence rates (IR) of events per 100 person-years (e/100 PY). The data strongly reflected the above solicited reactogenicity but extended beyond the first 7 days. This was illustrated in the System Organ Class (SOC) of General Disorders and Administrative Site Conditions, where higher incidence rates were observed for Nuvaxovid recipients in subcategories such as injection site pain followed by fatigue, pyrexia, and chills. Similarly, higher incident rates were observed in Nuvaxovid recipients in the SOCs of Musculoskeletal and Connective Tissue Disorders (e.g., myalgia and pain in an extremity), and Nervous System Disorder (e.g., headaches). Unsolicited AEs occurring in other SOCs and their corresponding subcategories were substantially less common, and interpretation was indeterminate.

The same pattern was seen for unsolicited severe AEs (Grade 3 or higher) unsolicited AEs during the period from Day 0 to 28 days following Dose 2 of Nuvaxovid, controlling for background placebo events. The reported unsolicited severe AEs include: fatigue (8% and 8% in the older and younger group, respectively); injection site pain (3% and 4%); malaise (4% and 2%); pyrexia (2% and 4%); headaches (4% and 3%); myalgia (4% and 4%); and hypertension (2% and 9%).

Unsolicited serious adverse events (SAEs) were reported from Day 0 to the end of follow-up for all events. These included events clearly unrelated to vaccination. In the pooled analysis, the SOC of Infections and Infestations had the highest event counts and incident rates in participants receiving Nuvaxovid and placebo (46 events and an incident rate of 0.63 e/100 PY for Nuvaxovid; 55 events and an incident rate of 1.16 e/100 PY for placebo). The majority of the events in both groups were associated with COVID-19, COVID-19 pneumonia, pneumonia, and appendicitis, with all incidence rates higher in the placebo group.

In the younger cohort, there were no SAEs with an incidence rate greater than 0.10 e/100 PY in the Nuvaxovid group while three events had incidence rates greater than 0.10 e/100 PY in the placebo group: COVID-19 pneumonia (0.25 e/100 PY), COVID-19 (0.23 e/100 PY), and appendicitis (0.15 e/100 PY). In the older cohort, SAEs that occurred at an incidence rate greater than 0.20 e/100 PY were COVID-19 (0.37 e/100 PY) and prostate cancer (0.28 e/100 PY) in participants who received Nuvaxovid, and pneumonia (0.51 e/100 PY), COVID-19 (0.26 e/100 PY), COVID 19 pneumonia (0.26 e/100 PY), and atrial fibrillation (0.26 e/100 PY) in participants who received the placebo.

Overall, there were more potential immune-mediated medical conditions in the Nuvaxovid group (27 events with an incident rate of 0.37 e/100 PY) than placebo (8 events with an incident rate of 0.04 e/100 PY), as well as across the two age groups. The main SOCs of concern where the incident rates for the Nuvaxovid group were higher than placebo included Musculoskeletal and Connective Tissue Disorders (0.08 vs 0.04 e/100 PY) including the cluster of arthritis and polymyalgia rheumatica, Nervous System Disorders (0.08 vs. 0.04 e/100 PY) but with no clear clustering of conditions, Endocrine Disorders (0.06 vs. 0.00 e/100 PY) including a clustering around autoimmune thyroiditis (Grave’s disease), and Eye Disorders (0.06 vs. 0.00 e/100 PY) clustering around uveitis and iridocyclitis. Health Canada recommended these disease groupings be monitored in the post-marketing period.

Based on compelling case reports, autoimmune conditions that may warrant further review in the post-marketing period include: immune thrombocytopenic purpura (ITP), Bell’s palsy, Grave’s disease, uveitis, iridocyclitis, rheumatoid arthritis, psoriasis and psoriatic arthritis, polymyalgia rheumatica, and chilblains. Within this group, seven cases of myocarditis and/or pericarditis were also identified and carefully reviewed. Of these, two cases among male teenagers (19 and 16 years of age) were pathognomonic for vaccine-associated myocarditis already described with approved messenger ribonucleic acid (mRNA) vaccines. A statement is included within the Product Monograph for Nuvaxovid to better inform providers and patients of the potential risk of myocarditis pending additional post-marketing data.

Special Populations

Clinical studies of Nuvaxovid include participants 65 years of age and older and their data contribute to the overall assessment of safety and efficacy. The safety and efficacy of Nuvaxovid in individuals under 18 years of age have not yet been established. Use in pediatric subjects is included in the Risk Management Plan (RMP) as missing information.

The safety and efficacy of Nuvaxovid in pregnant women have not yet been established. Women who were pregnant or breastfeeding were excluded from the clinical studies. As of October 26, 2021, a total of 137 pregnancies were reported in the two pivotal studies (2019nCoV-301 and 2019nCoV-302): 95 in the vaccine group and 42 in the placebo group. Of the pregnancies in Nuvaxovid recipients, 8 resulted in live births, 11 were voluntarily terminated, 16 resulted in spontaneous abortion (miscarriage) and 60 were ongoing at the time of authorization. Due to the limited duration of follow-up, the outcome of the remaining pregnancies is pending.

It is unknown if Nuvaxovid is excreted in human milk. Data are not available to assess the effects of the vaccine on the breastfed infant or on milk production/excretion. Use in pregnancy and while breastfeeding is included in the RMP as missing information.

No data are currently available on significantly immunocompromised persons, including individuals taking immunosuppressant therapy. Immunocompromised persons may have a diminished immune response to the vaccine and use in immunocompromised patients is included in the RMP as missing (limited/ no clinical data) information.

Risk Management Plan

A Core (European Union) Risk Management Plan (RMP) and a Canadian RMP Addendum for Nuvaxovid 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 plan, and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The following information relates to the RMP submitted by Novavax Inc., as part of the New Drug Submission for Nuvaxovid. 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 for Nuvaxovid.

Based on results from non-clinical and clinical studies, the RMP included no important identified risks and three important potential risks: vaccine‑associated enhanced disease, including vaccine‑associated enhanced respiratory disease; anaphylaxis; and myocarditis and pericarditis. There were eight areas of missing (limited/no clinical data) information identified: "use during 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". The proposed routine and additional pharmacovigilance activities for the above risks are considered to be acceptable and the sponsor confirmed that they would be applied in the Canadian context. Additional pharmacovigilance activities include continued safety surveillance of ongoing clinical studies as well as five planned post-authorization studies: two non-interventional safety studies, two non-interventional effectiveness studies, and one pregnancy exposure registry. 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 (European Union) RMP and Canadian Addendum in a timely manner if a signal of safety issue is identified in ongoing post-authorization surveillance.

In addition, in the post-market period the sponsor will provide information with respect to the following:

• Older adults: Older adults were included in the clinical development program. The sponsor will submit monthly safety reports to Health Canada, which will include analyses of subpopulations by age and gender.
• Children: Children were not included in the clinical development program. This subpopulation was identified as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada. Studies of Nuvaxovid in children are planned.
• Pregnant women: More information is needed about the use of the vaccine for pregnant women. This subpopulation was identified as missing information in the RMP. The sponsor will monitor and submit monthly safety reports to Health Canada. The sponsor will assess outcomes in 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 submit monthly safety reports to Health Canada. The sponsor will assess outcomes in 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. The sponsor will submit monthly safety reports to Health Canada.
• Anaphylaxis: The risk of anaphylaxis was identified as an important potential risk in the RMP. This risk will be assessed via routine pharmacovigilance activities, and reported in monthly safety reports.
• Myocarditis and Pericarditis: The risk of myocarditis and pericarditis was identified as an important potential risk in the RMP. This risk will be assessed via routine pharmacovigilance activities, and reported in monthly safety reports.
• Indigenous populations in Canada: Adverse drug reactions (ADRs) from all subpopulations, including Indigenous, will be reported as expeditiously as applicable, and will be assessed in the monthly safety reports.

The sponsor is required to promptly report adverse reactions and provide Monthly Safety Summary Reports. These reports will be reflected in the Post-Authorization Activity Table for Nuvaxovid.

Results related to safety and effectiveness from ongoing and planned studies will be submitted for review as they become available. Together, the results from these studies and the monthly safety summary reports are expected to address data gaps related to the long-term safety and effectiveness of the vaccine, interactions with other vaccines, and specific subpopulations (e.g., pregnant and breastfeeding women, pediatric populations younger than 18 years of age, patients with autoimmune or inflammatory disorders, immunocompromised patients and frail patients with comorbidities).

Collectively, the results of the clinical safety evaluation demonstrated that Nuvaxovid met the vaccine safety requirements as specified in Health Canada’s Guidance for Market Authorization Requirements for COVID-19 Vaccines. Overall, Nuvaxovid is a safe vaccine with some local and systemic reactogenicity associated with the immune response after the second dose. The authorization is accompanied by terms and conditions to manage uncertainties and mitigate risks related to the drug. Appropriate warnings and precautions are in place in the approved Nuvaxovid Product Monograph to address the identified risks.

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