Regulatory Decision Summary for Nuvaxovid

COVID-19 is a serious and potentially fatal or life-threatening human infection. Vaccination is an important way to protect against the disease and help stop the pandemic; the availability of safe and effective vaccines will reduce the spread and severity of COVID-19 and reduce its social and economic consequences.

To support authorization of Nuvaxovid, efficacy, immunogenicity, and safety data from six ongoing clinical trials (i.e. 2019nCoV-101 [Part 1 and 2], -501, -301, -302 and ICMR/SII-COVOVAX) conducted in Australia, South Africa, the United Kingdom, the United States, Mexico, and India were provided.

Of the six ongoing trials, 2019nCoV-301 and -302 were considered the pivotal trials and established the efficacy of Nuvaxovid. Both trials are Phase 3, multi-centre, randomized, observer-blinded, and placebo-controlled. 2019nCoV-301 randomized a total of 29,949 participants 18 years of age and older in the United States and Mexico in a 2:1 ratio to receive 2 intramuscular (IM) injections of Nuvaxovid or placebo, 21 days apart; 2019nCoV-302 randomized 15,187 participants 18 to 84 years of age in the United Kingdom in a 1:1 ratio to receive 2 IM injections of Nuvaxovid or placebo, 21 days apart. Participants with clinically stable underlying co-morbidity were included in both studies as were participants with well-controlled HIV infection. Both studies excluded participants who were significantly immunocompromised, were pregnant or had a history of laboratory-confirmed diagnosed COVID-19.

The primary efficacy endpoint for both studies was the vaccine efficacy (VE) against the first episode of PCR-positive symptomatic (i.e. mild, moderate, or severe) COVID-19 with onset at least 7 days after second dose in participants seronegative for SARS-CoV-2 infection at baseline.

The primary efficacy analysis set for 2019nCoV-301 included 25,452 participants who received either Nuvaxovid (n=17,312) or placebo (n=8,140). Demographic and baseline characteristics were balanced in groups. In participants who received Nuvaxovid, the median age was 47 years (range: 18 to 95 years); 88% (n=15,264) were 18 to 64 years old and 12% (n=2,048) were aged 65 and older; and 48% were female. VE 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. No cases of moderate or severe COVID-19 were reported in the vaccine group compared with 10 cases of moderate and 4 cases of severe COVID-19 in the placebo group.

The primary efficacy analysis set for 2019nCoV-302 included 14,039 participants who received either Nuvaxovid (n = 7,020) or placebo (n = 7,019). Demographic and baseline characteristics were balanced between groups. In participants who received Nuvaxovid, the median age was 56 years (range: 18 to 84 years); 72% (n = 5,067) were 18 to 64 years old and 28% (n = 1,953) were aged 65 to 84; and 49% were female. VE 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. Nine cases of moderate and no cases of severe COVID-19 were reported in the 7,020 Nuvaxovid participants compared with 63 cases of moderate and 5 cases of severe COVID-19 reported in the 7,019 placebo participants.

Notably, the efficacy data provided from both pivotal trials were collected when the Alpha variant was the primary strain of the virus circulating and prior to the emergence of Delta and Omicron variants. Novavax is required to provide data regarding protection against current and emerging variants of concern, when available.

The pooled safety data analysis included 2019nCoV-301,-302, and -501. The median duration of follow-up was 70 days after the second dose, with 32,993 (66%) participants completing more than 2 months 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.

The frequency and severity of solicited local and systemic reactions were collected within 7 days following each dose of NUVAXOVID or placebo in participants who recorded reactogenicity events in a diary in the pooled safety population. Of the pooled reactogenicity data, which includes participants > 18 years of age who received at least one dose of Nuvaxovid (n=21,395) or placebo (n=12,197), the most frequent adverse reactions were injection site tenderness (68%), injection site pain (56%), fatigue (45%), myalgia (44%), headache (41%), malaise (35%), arthralgia (20%), and nausea or vomiting (11%). Adverse reactions were usually mild to moderate in severity with a median duration of ≤ 2 days for local events and ≤ 1 day for systemic events following vaccination. When compared to the fist dose, local and systemic adverse reactions were more frequently reported after the second dose.

Across the pooled studies, participants were monitored for unsolicited adverse events after receipt of Dose 1 through 28 days after Dose 2 (49 days). Serious adverse events (SAEs) across both treatment groups were uncommon and incidence rates for SAEs were similar between Nuvaxovid and placebo recipients. A slightly higher incidence rate for SAEs occurred among participants ≥ 65 years of age. There were no other notable patterns of imbalance between treatment groups for specific categories of serious adverse events or adverse events of interest. No deaths related to the vaccine were reported in the main and supportive clinical studies.

Myocarditis was identified in two teenage men shortly after receiving a second dose of vaccine resulting in a mild clinical course with complete resolution and no sequelae. Currently available information is insufficient to determine a causal relationship with the vaccine.

The overall frequency of non-serious unsolicited adverse events was higher in the Nuvaxovid group than in placebo with events of fatigue, injection site pain, pyrexia, and myalgia occurring beyond the 7-day post-injection period largely accounting for the differences between the treatment groups. In addition, an imbalance of chills and pain in the extremity were reported. Chills occurred in 0.55% (n=166) of participants who received Nuvaxovid and 0.11% (n=21) of participants who received placebo. Pain in the extremity occurred in 1.36% (n=410) of participants who received Nuvaxovid and 0.36% (n=72) of participants who received placebo. There were no other notable imbalances between treatment groups for unsolicited non-serious adverse events that would suggest a causal relationship to Nuvaxovid.

Overall, Nuvaxovid is a safe vaccine with expected local and systemic reactogenicity associated with the vaccine immune response.

The Risk Management Plan (RMP) is designed to describe known and potential safety issues, to present the monitoring plan, and, when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review by MHPD, the RMP was considered acceptable and identified appropriate monitoring (pharmacovigilance) activities and risk minimization measures based on the safety profile of the product. This included providing information in the product monograph and identifying populations where more data are needed. The RMP will be updated to reflect additional safety information as this is collected. In addition to regulatory requirements for post-market monitoring and prioritized reporting of adverse events following immunization, monthly safety summary reports on the vaccine will be provided to Health Canada. Results related to safety and effectiveness from ongoing and planned studies will be submitted as they become available.

Important limitations of the data at this time include the lack of information on the long-term safety and efficacy of the vaccine, the duration of protection and protection against current and emerging variants are unknown, and the lack of or limited data on special populations (e.g. individuals who are significantly immunocompromised, pregnant, had a history of COVID-19, or with severe comorbidities). These limitations are considered adequately managed through labelling, terms and conditions associated with authorization, and the RMP. It is noteworthy that participants of pivotal studies are being followed for up to 12 or 24 months for safety and efficacy.

Manufacture of the Novavax COVID-19 vaccine (NUVAXOVID) consists of production of the recombinant SARS-CoV-2 spike (rS) protein from the original strain, followed by formulation with the Matrix-M adjuvant. Evidence was provided to demonstrate that the vaccine is manufactured under Good Manufacturing Practices (GMP) at all manufacturing sites providing supply to Canada, and that in-process controls, process parameters, and quality control release tests have been established to monitor product quality throughout the process. The specifications used to evaluate key quality attributes and consistency of production were found acceptable. This information, together with the terms and conditions imposed on the authorization, support authorization.

Based on the totality of the information, the benefit-risk profile for Nuvaxovid for the active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 18 years of age and older is considered favourable. The efficacy of the vaccine was established and the vaccine was well tolerated by participants. Nuvaxovid is therefore recommended for authorization under Division 8 of the Food and Drug Regulations.