Nuvaxovid JN.1 dispersion for injection, COVID-19 Vaccine (recombinant, adjuvanted) - Summary of Product Characteristics (SmPC) (2024)

Pharmacotherapeutic group: Vaccine, protein subunit, ATC code: J07BN04

Mechanism of action

Nuvaxovid JN.1 is composed of purified full-length SARS-CoV-2 Omicron JN.1 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.

Nuvaxovid JN.1 (Omicron-adapted Nuvaxovid)

The efficacy of Nuvaxovid JN.1 is inferred from the efficacy data of the Nuvaxovid (Original, Wuhan strain) vaccine and immunogenicity data from the adapted vaccine of the Omicron BA.5 strain.

In study 2019nCoV-311 Part 2, a total of 694 participants 18 years of age and older, who were evaluated for immunogenicity and previously received 3 or more doses of the Pfizer-BioNTech COVID-19 vaccine or the Moderna COVID-19 vaccine received 1 of the following as a booster dose: Nuvaxovid (Original, Wuhan strain), Nuvaxovid monovalent Omicron BA.5 vaccine or Nuvaxovid bivalent Original/Omicron BA.5 vaccine. The booster doses were administered a median of 11 - 13 months after the last vaccination, respectively. GMRs and seroresponse rates were evaluated at 1 month after vaccination.

The primary objective of the study was to demonstrate superiority with respect to level of pseudovirus neutralizing antibody titer (ID₅₀) and non-inferiority with respect to seroresponse rate of the anti-Omicron BA.5 immune response induced by a dose of the Nuvaxovid bivalent Original/Omicron BA.5 vaccine relative to the response elicited by a dose of Nuvaxovid (Original, Wuhan strain), and to assess non-inferiority with respect to level of ID₅₀ for the original SAR-CoV-2 strain for the Nuvaxovid bivalent Original/Omicron BA.5 vaccine compared to Nuvaxovid (Original, Wuhan strain).

Superiority of the anti-Omicron BA.5 ID₅₀ for the Nuvaxovid bivalent Original/Omicron BA.5 vaccine relative to Nuvaxovid (Original, Wuhan strain) was demonstrated, as the lower bound of the two-sided 95% confidence interval (CI) for GMR was >1. Non-inferiority of the anti-Original ID₅₀ for the Nuvaxovid bivalent Original/Omicron BA.5 vaccine relative to Nuvaxovid (Original, Wuhan strain) was met, as the lower bound of the two-sided 95% CI for GMR was >0.67.

Non-inferiority of the seroresponse rate to the Omicron BA.5 variant for the Nuvaxovid bivalent Original/Omicron BA.5 vaccine relative to Nuvaxovid (Original, Wuhan strain) was met, as the lower limit of the two-sided 95% CI for the difference in percentages of participants with seroresponse was >-5%. For more details see Table 2.

Exploratory immunogenicity analyses included an assessment of the ID₅₀ GMT ratio and difference in seroresponse rates for the Nuvaxovid monovalent Omicron BA.5 vaccine compared to Nuvaxovid (Original, Wuhan strain). The GMT ratio following the booster dose with Nuvaxovid monovalent Omicron BA.5 vaccine compared with the booster dose of Nuvaxovid (Original, Wuhan strain) was 2.5 (two-sided 95% CIs: 2.10, 2.94). The difference in seroresponse rates between the booster dose with Nuvaxovid monovalent Omicron BA.5 vaccine and the booster dose with Nuvaxovid (Original, Wuhan strain) was 33.2% (two-sided 95% CIs: 25.4%, 40.7%). While not formally assessed, these responses would have met the three success criteria for the study.

Table 2: Omicron BA.5 and Wuhan pseudovirus neutralising antibody titres (ID₅₀) and seroresponse rates following booster vaccination with Nuvaxovid monovalent BA.5 vaccine, Nuvaxovid (Original, Wuhan strain), and Nuvaxovid bivalent Original/Omicron BA.5 Vaccine – PP pseudovirus neutralization assay subset; Study 2019nCoV-311 Part 2

Abbreviations: CI = confidence interval; GMFR = geometric mean fold rise; GMT = geometric mean titre; GMTR = geometric mean titre ratio; ID₅₀ = 50% inhibitory dilution; LB = lower bound; LLOQ = lower limit of quantitation; n1 = number of participants in the assay-specific PP-IMM analysis set within each visit with non-missing data; n2 = number of participants in the assay-specific PP-IMM analysis set with non-missing data at both day 0 and day 28; n3 = number of participants who reported ≥ 4 fold increase with percentages calculated based on n2 as the denominator; NT = not tested; PP-IMM = per-protocol immunogenicity; SRR = seroresponse rate.

¹ Baseline was defined as the last non-missing assessment prior to booster vaccination.

² The 95% CI for GMT and GMFR were calculated based on the t-distribution of the log-transformed values then back transformed to the original scale for presentation.

³ An ANCOVA with vaccine group and age group (18-54, ≥ 55 years) as fixed effects and baseline value (Day 0) as covariate was performed that included all vaccine groups to estimate the adjusted GMT for all vaccine groups. Each pairwise comparison included the data from two groups only to estimate the adjusted GMTR between the two vaccine groups. The mean difference between vaccine groups and the corresponding CI limits was then exponentiated to obtain the ratio of ID₅₀ GMTs and the corresponding 95% CIs.

⁴ The SRR was defined as percentage of participants at each post vaccination visit with a titer ≥ 4-fold rise in ID₅₀ level from baseline if the baseline value is equal or above LLOQ or ≥ 4-fold times the LLOQ if the baseline value is below the LLOQ and calculated based on n2 as the denominator.

⁵ The 95% CI for SRR was calculated using the Clopper-Pearson method.

⁶ 95% CI for the difference in SRR was calculated based on the method of Miettinen and Nurminen.

Nuvaxovid (Original, Wuhan strain)

Clinical efficacy

Primary series

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 with an adult main study conducted in participants 18 years of age and older in the United States and Mexico, and a paediatric expansion occurring in participants 12 through 17 years of age in the United States.

Participants 18 years of age and older

Upon enrolment in the adult main study, 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; had 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-CoV-2 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 3.

Table 3: 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%).

Efficacy in adolescents 12 through 17 years of age

The assessment of efficacy and immunogenicity of Nuvaxovid in adolescent participants 12 through 17 years of age occurred in the United States in the ongoing paediatric expansion portion of the Phase 3 multicentre, randomised, observer-blinded, placebo-controlled 2019nCoV-301 study. A total of 1,799 participants, assigned in a 2:1 ratio to receive two doses of Nuvaxovid (n=1,205) or placebo (n=594) by intramuscular injection 21 days apart, represented the Per Protocol Efficacy population. Participants with confirmed infection or prior infection due to SARS-CoV-2 at the time of randomisation were not included in the primary efficacy analysis.

Enrolment of adolescents completed in June 2021. Participants were followed for up to 24 months after the second dose for assessments of safety, efficacy, and immunogenicity against COVID-19. Following a 60-day safety follow-up period, initial adolescent 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.

COVID-19 was defined as first episode of PCR-confirmed mild, moderate, or severe COVID-19 with at least one or more of the predefined symptoms within each severity category. Mild COVID-19 was defined as fever, new onset cough or at least 2 or more additional COVID-19 symptoms.

There were 20 cases of PCR-confirmed symptomatic mild COVID-19 (Nuvaxovid, n=6 [0.5%]; placebo, n=14 [2.4%]) resulting in a point estimate of efficacy of 79.5% (95% CI: 46.8%, 92.1%).

At the time of this analysis, the Delta (B.1.617.2 and AY lineages) variant of concern (VOC) was the predominant variant circulating in the US and accounted for all cases from which sequence data are available (11/20, 55%).

Immunogenicity in adolescents 12 through 17 years of age

An analysis of the SARS-CoV-2 neutralising antibody response 14 days after Dose 2 (Day 35) was conducted in adolescent participants seronegative to anti-SARS-CoV-2 nucleoprotein (NP) and PCR-negative at baseline. Neutralising antibody responses were compared with those observed in seronegative/PCR-negative adult participants aged 18 through 25 years from the adult main study (Per Protocol Immunogenicity (PP-IMM) Analysis Set) as shown in Table 4. Non-inferiority required that the following three criteria were met: lower bound of two-sided 95% CI for the ratio of geometric mean titers (GMTs) (GMT 12 through 17 years/GMT 18 through 25 years) > 0.67; point estimate of the ratio of GMTs ≥ 0.82; and the lower bound of the two-sided 95% CI for difference of seroconversion rates (SCRs) (SCR 12 through 17 years minus SCR 18 through 25 years) > -10%. These non-inferiority criteria were met.

Table 4 : Adjusted Ratio of Geometric Mean of Microneutralisation Assay Neutralising Antibody Titers for SARS-CoV-2 S Wild-Type Virus at Day 35 Overall and Presented by Age Group (PP-IMM Analysis Set)¹

Abbreviations: ANCOVA = analysis of covariance; CI = confidence interval; GMR = ratio of GMT, which is defined as the ratio of 2 GMTs for comparison of 2 age cohorts; GMT = geometric mean titer; LLOQ = lower limit of quantitation; MN = microneutralisation; N = number of participants in assay-specific PP-IMM Analysis Set in each part of study with non-missing response at each visit; PP-IMM = Per-Protocol Immunogenicity; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

¹ Table includes participants in the active vaccine group only.

² An ANCOVA with age cohort as main effect and baseline MN Assay neutralising antibodies as covariate was performed to estimate the GMR. Individual response values recorded as below the LLOQ were set to half LLOQ.

³ Represents (n1, n2) populations defined as:

Study 2 (2019nCoV-302)

Study 2 was a 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 were 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 (Table 5).

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 5: 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.1.1.7 (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 sub-study 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 was a 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.

Booster dose

Immunogenicity in participants 18 years of age and older

Study 2019nCoV-101, Part 2

The safety and immunogenicity of a booster dose of Nuvaxovid was evaluated in an ongoing Phase 2 randomised, observer-blinded, placebo-controlled clinical study administered as a single booster dose (Study 2019nCoV-101, Part 2) in healthy adult participants aged 18 to 84 years of age who were seronegative to SARS-CoV-2 at baseline. A total of 254 participants (Full Analysis Set) received two doses of Nuvaxovid (0.5 mL, 5 micrograms 3 weeks apart) as the primary vaccination series. A subset of 104 participants received a booster dose of Nuvaxovid approximately 6 months after receiving Dose 2 of the primary series. A single booster dose of Nuvaxovid induced an. approximate 96-fold increase in neutralising antibodies from a GMT of 63 pre-booster (Day 189) to a GMT of 6,023 post-booster (Day 217) and an approximate 4.1-fold increase from a peak GMT (14 days post-Dose 2) of 1,470.

Study 2019nCoV-501

In Study 3, a Phase 2a/b randomised, observer-blinded, placebo-controlled study, the safety and immunogenicity of booster dose was evaluated in healthy HIV-negative adult participants 18 to 84 years of age and medically stable PLWH 18 to 64 years of age who were seronegative to SARS-CoV-2 at baseline. A total of 1,173 participants (PP-IMM Analysis Set) received a booster dose of Nuvaxovid approximately 6 months after completion of the primary series of Nuvaxovid (Day 201). An approximate 52-fold increase in neutralising antibodies was shown from a GMT of 69 pre-booster (Day 201) to a GMT of 3,600 post-booster (Day 236) and an approximate 5.2-fold increase from a peak GMT (14 days post-Dose 2) of 694.

Safety and immunogenicity of COVID-19 vaccines given as booster doses following completion of a primary vaccination series with another authorised COVID-19 vaccine was evaluated in an independent study in the UK.

The independent, multicentre, randomised, controlled, Phase 2 investigator-initiated trial (CoV-BOOST, EudraCT 2021-002175-19) investigated the immunogenicity of a booster in adults aged 30 years and older with no history of laboratory-confirmed SARS-CoV-2 infection. Nuvaxovid was administered at least 70 days after completion of a ChAdOx1 nCov-19 (Oxford– AstraZeneca) primary vaccination series or at least 84 days after completion of a BNT162b2 (Pfizer– BioNTech) primary vaccination series. Neutralising antibody titers measured by a wild-type assay were assessed 28 days post-booster dose. Within the group assigned to receive Nuvaxovid, 115 participants received a two-dose primary series of ChAdOx1 nCov-19 and 114 participants received a two-dose primary series of BNT162b2, prior to receiving a single booster dose (0.5 mL) of Nuvaxovid. Nuvaxovid (Original, Wuhan strain) demonstrated a booster response regardless of the vaccine used for primary vaccination.

Booster dose in adolescents 12 through 17 years of age

The effectiveness of booster doses of Nuvaxovid in adolescents 12 through 17 years of age is inferred from data gathered for booster doses of the vaccine in adults in studies 2019nCoV-101 and 2019nCoV-501, as Nuvaxovid has been shown to induce a comparable immune response and effectiveness after the primary series in adolescents as in adults, and the ability to boost the vaccine-induced immune response was shown in adults.

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) for the primary series.

Paediatric population

The licensing authority 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).