NUVAXOVID Dispersion for injection Ref.[28183] Active ingredients: SARS-CoV-2 protein subunit vaccine (NVX-CoV2373)

Pharmacotherapeutic group: Vaccine, other viral vaccines
ATC code: J07BX03

Mechanism of action

Nuvaxovid is composed of purified full-length SARS-CoV-2 recombinant spike (S) protein that is stabilised in its prefusion conformation. 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 S protein-specific immune response. The two vaccine components elicit B- and T-cell immune responses to the S protein, including neutralising antibodies, which may contribute to protection against COVID-19.

Clinical efficacy

The clinical efficacy, safety, and immunogenicity of Nuvaxovid is being evaluated in two pivotal, placebo-controlled, Phase 3 studies, Study 1 (2019nCoV-301) conducted in North America and Study 2 (2019nCoV-302) conducted in the United Kingdom, and a Phase 2a/b study, Study 3, conducted in South Africa.

Study 1 (2019nCoV-301)

Study 1 is an ongoing Phase 3, multicentre, randomised, observer-blinded, placebo-controlled study in participants 18 years of age and older in United States and Mexico. Upon enrolment, participants were stratified by age (18 to 64 years and ≥65 years) and assigned in a 2:1 ratio to receive Nuvaxovid or placebo. The study excluded participants who were significantly immunocompromised due to immunodeficiency disease; active cancer on chemotherapy; received chronic immunosuppressive therapy or received immunoglobulin or blood-derived products within 90 days; were pregnant or breastfeeding; or had a history of laboratory-confirmed diagnosed COVID-19. Participants with clinically stable underlying comorbidity were included as were participants with well-controlled HIV infection.

Enrolment of adults completed in February 2021. Participants will be followed for up to 24 months after the second dose for assessments of safety, and efficacy against COVID-19. Following collection of sufficient safety data to support application for emergency use authorisation, initial recipients of placebo were invited to receive two injections of Nuvaxovid 21 days apart and initial recipients of Nuvaxovid to receive two injections of placebo 21 days apart (“blinded crossover”). All participants were offered the opportunity to continue to be followed in the study.

The primary efficacy analysis population (referred to as the Per-Protocol Efficacy [PP-EFF] analysis set) included 25,452 participants who received either Nuvaxovid (n=17,312) or placebo (n=8,140), received two doses (Dose 1 on day 0; Dose 2 at day 21, median 21 days [IQR 21-23], range 14-60), did not experience an exclusionary protocol deviation, and did not have evidence of SARS-CoV-2 infection through 7 days after the second dose.

Demographic and baseline characteristics were balanced amongst participants who received Nuvaxovid and those who received placebo. In the PP-EFF analysis set for 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; 48% were female; 94% were from the United States and 6% were from Mexico; 76% were White, 11% were Black or African American, 6% were American Indian (including Native Americans) or Alaskan Native, and 4% were Asian; 22% were Hispanic or Latino. At least one pre-existing comorbidity or lifestyle characteristic associated with an increased risk of severe COVID-19 was present in 16,493 (95%) participants. Comorbidities included: obesity (body mass index (BMI) ≥30 kg/m²); chronic lung disease; diabetes mellitus type 2, cardiovascular disease; chronic kidney disease; or human immunodeficiency virus (HIV). Other high-risk characteristics included age ≥65 years (with or without comorbidities) or age <65 years with comorbidities and/or living or working conditions involving known frequent exposure to SARS-CoV2 or to densely populated circumstances.

COVID-19 cases were confirmed by polymerase chain reaction (PCR) through a central laboratory. Vaccine efficacy is presented in Table 2.

Table 2. Vaccine efficacy against PCR-confirmed COVID-19 with onset from 7 days after second vaccination 1 – PP-EFF analysis set; Study 2019nCoV-301:

¹ VE evaluated in participants without major protocol deviations, who are seronegative (for SARS-CoV-2) at baseline and do not have a laboratory confirmed current SARS-CoV-2 infection with symptom onset up to 6 days after the second dose, and who have received the full prescribed regimen of trial vaccine.
² Mean disease incidence rate per year in 1,000 people.
³ Based on log-linear model of PCR-confirmed COVID-19 infection incidence rate using Poisson regression with treatment group and age strata as fixed effects and robust error variance, where VE = 100 × (1 – relative risk) (Zou 2004).
⁴ Met primary efficacy endpoint criterion for success with a lower bound confidence interval (LBCI) >30%. at the planned primary confirmatory analysis

Vaccine efficacy of Nuvaxovid to prevent the onset of COVID-19 from seven days after Dose 2 was 90.4% (95% CI 82.9 – 94.6). No cases of severe COVID-19 were reported in the 17,312 Nuvaxovid participants compared with 4 cases of severe COVID-19 reported in the 8,140 placebo recipients in the PP-EFF analysis set.

Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates for male and female participants and racial groups, and across participants with medical comorbidities associated with high risk of severe COVID-19. There were no meaningful differences in overall vaccine efficacy in participants who were at increased risk of severe COVID-19 including those with 1 or more comorbidities that increase the risk of severe COVID-19 (e.g. BMI ≥30 kg/m², chronic lung disease, diabetes mellitus type 2, cardiovascular disease, and chronic kidney disease).

Efficacy results reflect enrolment that occurred during the time period when strains classified as Variants of Concern or Variants of Interest were predominantly circulating in the two countries (US and Mexico) where the study was conducted. Sequencing data were available for 61 of the 77 endpoint cases (79%). Of these, 48 out of 61 (79%) were identified as Variants of Concern or Variants of Interest. The most common Variants of Concern identified were: Alpha with 31/61 cases (51%), Beta (2/61, 4%) and Gamma (2/61, 4%), while the most common Variants of Interest were Iota with 8/61 cases (13%), and Epsilon (3/61, 5%).

Study 2 (2019nCoV-302)

Study 2 is an ongoing Phase 3, multicentre, randomised, observer-blinded, placebo-controlled study in participants 18 to 84 years of age in the United Kingdom. Upon enrolment, participants were stratified by age (18 to 64 years; 65 to 84 years) to receive Nuvaxovid or placebo. The study excluded participants who were significantly immunocompromised due to immunodeficiency disease; current diagnosis or treatment for cancer; autoimmune disease/condition; received chronic immunosuppressive therapy or received immunoglobulin or blood-derived products within 90 days; bleeding disorder or continuous use of anticoagulants; history of allergic reactions and/or anaphylaxis; were pregnant; or had a history of laboratory-confirmed diagnosed COVID-19. Participants with clinically stable disease, defined as disease not requiring significant change in therapy or hospitalisation for worsening disease during the 4 weeks before enrolment were included. Participants with known stable infection with HIV, hepatitis C virus (HCV), or hepatitis B virus (HBV) were not excluded from enrolment.

Enrolment was completed in November 2020. Participants are being followed for up to 12 months after the primary vaccination series for assessments of safety and efficacy against COVID-19.

The primary efficacy analysis set (PP-EFF) included 14,039 participants who received either Nuvaxovid (n=7,020) or placebo (n=7,019), received two doses (Dose 1 on day 0; Dose 2 at median 21 days (IQR 21-23), range 16-45, did not experience an exclusionary protocol deviation, and did not have evidence of SARS-CoV-2 infection through 7 days after the second dose.

Demographic and baseline characteristics were balanced amongst participants who received Nuvaxovid and participants who received placebo. In the PP-EFF analysis set for participants who received Nuvaxovid, median age was 56.0 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; 49% were female; 94% were White; 3% were Asian; 1% were multiple races, <1% were Black or African American; and <1% were Hispanic or Latino; and 45% had at least one comorbid condition.

Table 3. Vaccine efficacy analysis of PCR-confirmed COVID-19 with onset at least 7 days after the second vaccination - (PP-EFF population): Study 2 (2019nCoV-302):

¹ Mean disease incidence rate per year in 1000 people.
² Based on Log-linear model of occurrence using modified Poisson regression with logarithmic link function, treatment group and strata (age-group and pooled region) as fixed effects and robust error variance [Zou 2004].
³ Met primary efficacy endpoint criterion for success with a lower bound confidence interval (LBCI) >30%, efficacy has been confirmed at the interim analysis.
⁴ Based on the Clopper-Pearson model (due to few events), 95% CIs calculated using the Clopper-Pearson exact binomial method adjusted for the total surveillance time.

These results reflect enrolment that occurred during the time period when the B.1.17 (Alpha) variant was circulating in the UK. Identification of the Alpha variant was based on S gene target failure by PCR. Data were available for 95 of the 106 endpoint cases (90%). Of these, 66 out of 95 (69%) were identified as the Alpha variant with the other cases classified as non-Alpha.

No cases of severe COVID-19 were reported in the 7,020 Nuvaxovid participants compared with 4 cases of severe COVID-19 reported in the 7,019 placebo recipients in the PP-EFF analysis set.

Licensed seasonal influenza vaccine co-administration sub-study

Overall, 431 participants were co-vaccinated with inactivated seasonal influenza vaccines; 217 substudy participants received Nuvaxovid and 214 received placebo. Demographic and baseline characteristics were balanced amongst participants who received Nuvaxovid and participants who received placebo. In the per-protocol immunogenicity (PP-IMM) analysis set for participants who received Nuvaxovid (n=191), median age was 40 years (range: 22 to 70 years); 93% (n=178) were 18 to 64 years old and 7% (n=13) were aged 65 to 84; 43% were female; 75% were White; 23% were multiracial or from ethnic minorities; and 27% had at least one comorbid condition. Co-administration resulted in no change to influenza vaccine immune responses as measured by hemagglutination inhibition (HAI) assay. A 30% reduction in antibody responses to Nuvaxovid was noted as assessed by an anti-spike IgG assay with seroconversion rates similar to participants who did not receive concomitant influenza vaccine (see section 4.5 and section 4.8).

Study 3 (2019nCoV-501)

Study 3 is an ongoing Phase 2a/b, multicentre, randomised, observer-blinded, placebo-controlled study in HIV-negative participants 18 to 84 years of age and people living with HIV (PLWH) 18 to 64 years of age in South Africa. PLWH were medically stable (free of opportunistic infections), receiving highly active and stable antiretroviral therapy, and having an HIV-1 viral load of <1000 copies/mL.

Enrolment was completed in November 2020.

The primary efficacy analysis set (PP-EFF) included 2,770 participants who received either Nuvaxovid (n=1,408) or placebo (n=1,362), received two doses (Dose 1 on day 0; Dose 2 on day 21), did not experience an exclusionary protocol deviation, and did not have evidence of SARS-CoV-2 infection through 7 days after the second dose.

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

A total of 147 symptomatic mild, moderate, or severe COVID-19 cases among all adult participants, seronegative (to SARS-CoV-2) at baseline, were accrued for the complete analysis (PP-EFF Analysis Set) of the primary efficacy endpoint, with 51 (3.62%) cases for Nuvaxovid versus 96 (7.05%) cases for placebo. The resultant vaccine efficacy of Nuvaxovid was 48.6% (95% CI: 28.4, 63.1).

These results reflect enrolment that occurred during the time period when the B.1.351 (Beta) variant was circulating in South Africa.

Elderly population

Nuvaxovid was assessed in individuals 18 years of age and older. The efficacy of Nuvaxovid was consistent between elderly (≥65 years) and younger individuals (18 to 64 years).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Nuvaxovid in one or more subsets of the paediatric population in prevention of COVID-19, see section 4.2 for information on paediatric use.

Conditional approval

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.