NUVAXOVID injection dispersion medication leaflet

Nuvaxovid dispersion for injection

COVID-19 Vaccine (recombinant, adjuvanted)

These are multidose vials which contain 5 doses or 10 doses of 0.5 mL per vial (see section 6.5).

One dose (0.5 mL) contains 5 micrograms of the SARS-CoV-2 spike protein* and is adjuvanted with

Matrix-M.

Adjuvant Matrix-M containing per 0.5 mL dose: Fraction-A (42.5 micrograms) and Fraction-C(7.5 micrograms) of Quillaja saponaria Molina extract.

*produced by recombinant DNA technology using a baculovirus expression system in an insect cellline that is derived from Sf9 cells of the Spodoptera frugiperda species.

For the full list of excipients, see section 6.1.

Dispersion for injection (injection).

The dispersion is colourless to slightly yellow, clear to mildly opalescent (pH 7.2)

Nuvaxovid is indicated for active immunisation to prevent COVID-19 caused by SARS-CoV-2 inindividuals 12 years of age and older.

The use of this vaccine should be in accordance with official recommendations.

Primary vaccination series

Nuvaxovid is administered intramuscularly as a course of 2 doses of 0.5 mL each. It is recommendedto administer the second dose 3 weeks after the first dose (see section 5.1).

There are no data available on the interchangeability of Nuvaxovid with other COVID-19 vaccines tocomplete the primary vaccination course. Individuals who have received a first dose of Nuvaxovidshould receive the second dose of Nuvaxovid to complete the vaccination course.

Booster dose in individuals 12 years of age and older

A booster dose of Nuvaxovid (0.5 mL) may be administered intramuscularly approximately 3 monthsafter the primary series of Nuvaxovid in individuals 12 years of age and older (homologous boosterdose).

Nuvaxovid may also be given as a booster dose in individuals 18 years of age and older following aprimary series comprised of an mRNA vaccine or adenoviral vector vaccine (heterologous boosterdose). The dosing interval for the heterologous booster dose is the same as that authorised for abooster dose of the vaccine used for primary vaccination (see section 5.1).

The safety and efficacy of Nuvaxovid in children aged less than 12 years have not yet beenestablished. No data are available.

No dose adjustment is required in elderly individuals ≥ 65 years of age.

Nuvaxovid is for intramuscular injection only, preferably into the deltoid muscle of the upper arm.

Do not inject the vaccine intravascularly, subcutaneously, or intradermally.

The vaccine should not be mixed in the same syringe with any other vaccines or medicinal products.

For precautions to be taken before administering the vaccine, see section 4.4.

For instructions on handling and disposal of the vaccine, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Events of anaphylaxis have been reported with Nuvaxovid. Appropriate medical treatment andsupervision should always be readily available in case of an anaphylactic reaction following theadministration of the vaccine.

Close observation for at least 15 minutes is recommended following vaccination. An additional doseof the vaccine should not be given to those who have experienced anaphylaxis to a prior dose of

Nuvaxovid.

There is an increased risk of myocarditis and pericarditis following vaccination with Nuvaxovid.

These conditions can develop within just a few days after vaccination and have primarily occurredwithin 14 days. (see section 4.8).

Available data suggest that the course of myocarditis and pericarditis following vaccination is notdifferent from myocarditis or pericarditis in general.

Healthcare professionals should be alert to the signs and symptoms of myocarditis and pericarditis.

Vaccinees (including parents or caregivers) should be instructed to seek immediate medical attentionif they develop symptoms indicative of myocarditis or pericarditis such as (acute and persisting) chestpain, shortness of breath, or palpitations following vaccination.

Healthcare professionals should consult guidance and/or specialists to diagnose and treat thiscondition.

Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation, or stress‐relatedreactions may occur in association with vaccination as a psychogenic response to the needle injection.

It is important that precautions are in place to avoid injury from fainting.

Vaccination should be postponed in individuals suffering from an acute severe febrile illness or acuteinfection. The presence of a minor infection and/or low-grade fever should not delay vaccination.

As with other intramuscular injections, the vaccine should be given with caution in individualsreceiving anticoagulant therapy or those with thrombocytopenia or any coagulation disorder (such ashaemophilia) because bleeding or bruising may occur following an intramuscular administration inthese individuals.

The efficacy, safety, and immunogenicity of the vaccine has been assessed in a limited number ofimmunocompromised individuals. The efficacy of Nuvaxovid may be lower in immunosuppressedindividuals.

The duration of protection afforded by the vaccine is unknown as it is still being determined byongoing clinical trials.

Individuals may not be fully protected until 7 days after their second dose. As with all vaccines,vaccination with Nuvaxovid may not protect all vaccine recipients.

This vaccine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

This vaccine contains potassium, less than 1 mmol (39 mg) per dose, that is to say, essentially‘potassium-free’.

Co-administration of Nuvaxovid with inactivated influenza vaccines has been evaluated in a limitednumber of participants in an exploratory clinical trial sub-study, see section 4.8 and section 5.1.

The binding antibody response to SARS-CoV-2 was lower when Nuvaxovid was given concomitantlywith inactivated influenza vaccine. The clinical significance of this is unknown.

Concomitant administration of Nuvaxovid with other vaccines has not been studied.

There is limited experience with use of Nuvaxovid in pregnant women. Animal studies do not indicatedirect or indirect harmful effects with respect to pregnancy, embryo/foetal development, parturition, orpost-natal development, see section 5.3.

Administration of Nuvaxovid in pregnancy should only be considered when the potential benefitsoutweigh any potential risks for the mother and foetus.

It is unknown whether Nuvaxovid is excreted in human milk.

No effects on the breast-fed newborn/infant are anticipated since the systemic exposure of the breast-feeding woman to Nuvaxovid is negligible.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity,see section 5.3.

Nuvaxovid has no or negligible influence on the ability to drive and use machines. However, some ofthe effects mentioned under section 4.8 may temporarily affect the ability to drive or use machines.

Summary of the safety profile after primary series

The safety of Nuvaxovid was evaluated from an interim analysis of pooled data from 5 ongoingclinical trials conducted in Australia, South Africa, the United Kingdom, the United States and

Mexico. At the time of the analysis, a total of 49,950 participants aged 18 years and older received atleast one dose of the two-dose primary series of Nuvaxovid (n=30,058) or placebo (n=19,892). At thetime of vaccination, the median age was 48 years (range 18 to 95 years). The median duration offollow-up was 70 days post-Dose 2, with 32,993 (66%) participants completing more than 2 monthsfollow-up post-Dose 2.

Of the pooled reactogenicity data, which includes participants aged 18 years and older enrolled in thetwo phase 3 studies who received any dose of Nuvaxovid (n=20,055) or placebo (n=10,561), the mostfrequent adverse reactions were injection site tenderness (75%), injection site pain (62%), fatigue(53%), myalgia (51%), headache (50%), malaise (41%), arthralgia (24%), and nausea or vomiting(15%). Adverse reactions were usually mild to moderate in severity with a median duration of lessthan or equal to 2 days for local events and less than or equal to 1 day for systemic events followingvaccination.

Overall, there was a higher incidence of adverse reactions in younger age groups: the incidence ofinjection site tenderness, injection site pain, fatigue, myalgia, headache, malaise, arthralgia, andnausea or vomiting was higher in adults aged 18 to less than 65 years than in those aged 65 years andabove.

Local and systemic adverse reactions were more frequently reported after Dose 2 than after Dose 1.

Licensed inactivated seasonal influenza vaccines were co-administered to participants on the same dayas Dose 1 of Nuvaxovid (n=217) or placebo (n=214) in the opposite deltoid muscle of the arm in 431participants enrolled in an exploratory Phase 3 (2019nCoV-302) sub-study. The frequency of local andsystemic adverse reactions in the influenza sub-study population was higher than in the main studypopulation following Dose 1 in both Nuvaxovid and placebo recipients.

The safety of Nuvaxovid in adolescents was evaluated in an interim analysis of the paediatricexpansion portion of an ongoing Phase 3 multicentre, randomised, observer-blinded, placebo-controlled study (Study 2019nCoV-301). Safety data were collected in 2,232 participants 12 through17 years of age, with and without evidence of prior SARS CoV-2 infection, in United States whoreceived at least one dose of Nuvaxovid (n=1,487) or placebo (n=745). Demographic characteristicswere similar among participants who received Nuvaxovid and those who received placebo.

The most frequent adverse reactions were injection site tenderness (71%), injection site pain (67%),headache (63%), myalgia (57%), fatigue (54%), malaise (43%), nausea or vomiting (23%), arthralgia(19%) and pyrexia (17%). Fever was observed more frequently in adolescents aged 12 through to 17years compared to adults, with the frequency being very common after the second dose in adolescents.

Adverse reactions were usually mild to moderate in severity with a median duration of less than orequal to 2 days for local events and less than or equal to 1 day for systemic events followingvaccination.

Summary of the safety profile after booster dose

In an independent study (CoV-BOOST study, EudraCT 2021-002175-19) evaluating the use of a

Nuvaxovid booster dose in individuals who had completed primary vaccination with an authorisedmRNA COVID-19 vaccine or adenoviral vector COVID-19 vaccine, no new safety concerns wereidentified.

The safety and immunogenicity of a booster dose of Nuvaxovid was evaluated in an ongoing Phase 3,multicenter, randomized, observer-blinded, placebo-controlled study (Study 2019nCoV-301). Overall,12,777 participants received a booster dose of the vaccine at least 6 months after the two-dose primaryseries (median of 11 months between completion of primary series and booster dose). Of the 12,777participants who received a booster dose, 39 participants did not receive Nuvaxovid for all three doses.

The safety analyses included evaluation of solicited local and systemic adverse reactions within 7 daysafter a booster dose for participants who completed the electronic diary (n=10,137).

The most frequent solicited adverse reactions were injection site tenderness (73%), injection site pain(61%), fatigue (52%), muscle pain (51.%), headache (45.%), malaise (40%), and joint pain (26.%).

The safety of a booster dose of Nuvaxovid was evaluated in an interim analysis of an ongoing Phase3 study (Study 2019nCoV-301). A total of 1,499 participants received a booster dose approximately9 months after receiving Dose 2 of the primary series. A subset of 220 participants who received thebooster dose were evaluated for solicited adverse reactions within 7 days after the booster dose (Ad

Hoc Booster Safety Analysis Set), of whom 190 completed the electronic diary.

Solicited adverse reactions occurred at higher frequencies and with higher grade in adolescentscompared to adults. The most frequent solicited adverse reactions were injection site tenderness(72%), headache (68%), fatigue (66%), injection site pain (64%), muscle pain (62%), malaise (47%),and nausea/vomiting (26%) with a median duration of 1 to 2 days following vaccination. No newsafety concerns from the time of the booster dose administration through 28 days after administrationwere noted among participants.

Adverse reactions observed during clinical studies are listed below according to the followingfrequency categories:

Very common (≥ 1/10),

Common (≥ 1/100 to < 1/10),

Uncommon (≥ 1/1,000 to < 1/100),

Rare (≥ 1/10,000 to < 1/1,000),

Very rare (< 1/10,000),

Not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions from Nuvaxovid clinical trials and post- authorisation experience inindividuals 12 years of age and older

MedDRA System Very Common Uncommon Rare Not known

Organ Class common (≥ 1/100 to (≥ 1/1,000 to (≥ 1/10,000 to (cannot be(≥ 1/10) < 1/10) < 1/100) < 1/1,000) estimated fromthe availabledata)

Blood and Lymphadenopathylymphatic systemdisorders

Immune system Anaphylaxisdisorders

Nervous system Headache Paraesthesiadisorders Hypoaesthesia

Cardiac Myocarditisdisorders Pericarditis

Vascular Hypertensionddisorders

Gastrointestinal Nausea ordisorders vomitinga

Skin and Rashsubcutaneous Erythematissue disorders Pruritus

Urticaria

Musculoskeletal Myalgiaaand connective Arthralgiaatissue disorders

General disorders Injection site Injection site Injection site Injection siteand tendernessa rednessa,c pruritus warmthadministration site Injection site Injection site Chillsconditions paina swellinga

Fatiguea Pyrexiae

Malaisea,b Pain inextremitya Higher frequencies of these events were observed after the second dose.b This term also included events reported as influenza-like illness.c This term includes both injection site redness and injection site erythema (common).d Hypertension was not reported in adolescents aged 12 through 17 years in the clinical study.

e Pyrexia was observed more frequently in adolescents aged 12 through 17 years compared to adults, with the frequencybeing very common after the second dose in adolescents.

Throughout the clinical trials, an increased incidence of hypertension following vaccination with

Nuvaxovid (n=46, 1.0%) as compared to placebo (n=22, 0.6%) was observed in older adults duringthe 3 days following vaccination.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V and include batch/Lot number if available.

No case of overdose has been reported. In the event of an overdose, monitoring of vital functions andpossible symptomatic treatment is recommended.

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

Nuvaxovid is composed of purified full-length SARS-CoV-2 recombinant spike (S) protein that isstabilised in its prefusion conformation. The addition of the saponin-based Matrix-M adjuvantfacilitates activation of the cells of the innate immune system, which enhances the magnitude of the Sprotein-specific immune response. The two vaccine components elicit B- and T-cell immuneresponses to the S protein, including neutralising antibodies, which may contribute to protectionagainst COVID-19.

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 studywith 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.

Upon enrolment in the adult main study, participants were stratified by age (18 to 64 years and ≥ 65years) and assigned in a 2:1 ratio to receive Nuvaxovid or placebo. The study excluded participantswho were significantly immunocompromised due to immunodeficiency disease; had active cancer onchemotherapy; 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 wereincluded as were participants with well-controlled HIV infection.

Enrolment of adults completed in February 2021. Participants will be followed for up to 24 monthsafter the second dose for assessments of safety, and efficacy against COVID-19. Following collectionof sufficient safety data to support application for emergency use authorisation, initial recipients ofplacebo 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 participantswere 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] analysisset) 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-2infection 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 to64 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 associatedwith an increased risk of severe COVID-19 was present in 16,493 (95%) participants. Comorbiditiesincluded: 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 withcomorbidities 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 2.

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

Nuvaxovid Placebo

Incidence Incidence

Partici- COVID- Rate Per Partici- COVID- Rate Per % Vaccinepants 19 cases Year Per pants 19 cases Year Per Efficacy

Subgroup N n (%)2 1,000 N n (%)3 1,000 (95% CI)

People2 People2

Primary efficacy endpoint

All 17,312 14 (0.1) 3.26 8,140 63 (0.8) 34.01 90.4%participants (82.9, 94.6)3,41 VE evaluated in participants without major protocol deviations, who are seronegative (for SARS-CoV-2) at baseline anddo 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 treatmentgroup 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 plannedprimary confirmatory analysis

Vaccine efficacy of Nuvaxovid to prevent the onset of COVID-19 from seven days after Dose 2 was90.4% (95% CI 82.9,94.6). No cases of severe COVID-19 were reported in the 17,312 Nuvaxovidparticipants 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 maleand female participants and racial groups, and across participants with medical comorbiditiesassociated with high risk of severe COVID-19. There were no meaningful differences in overallvaccine efficacy in participants who were at increased risk of severe COVID-19 including those with 1or more comorbidities that increase the risk of severe COVID-19 (e.g., BMI ≥ 30 kg/m2, chronic lungdisease, 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 (USand Mexico) where the study was conducted. Sequencing data were available for 61 of the 77 endpointcases (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 8/61cases (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 through17 years of age occurred in the United States in the ongoing paediatric expansion portion of the Phase3 multicentre, randomised, observer-blinded, placebo-controlled 2019nCoV-301 study. A total of1,799 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 SARSCoV-2 at the time ofrandomisation were not included in the primary efficacy analysis.

Enrolment of adolescents completed in June 2021. Participants were followed for up to 24 monthsafter 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 toreceive two injections of Nuvaxovid 21 days apart and initial recipients of Nuvaxovid to receive twoinjections of placebo 21 days apart (“blinded crossover”). All participants were offered the opportunityto continue to be followed in the study.

COVID-19 was defined as first episode of PCR-confirmed mild, moderate, or severe COVID-19 withat least one or more of the predefined symptoms within each severity category. Mild COVID-19 wasdefined 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 thepredominant variant circulating in the US and accounted for all cases from which sequence data areavailable (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) wasconducted in adolescent participants seronegative to anti-SARS-CoV-2 nucleoprotein (NP) and PCR-negative at baseline. Neutralising antibody responses were compared with those observed inseronegative/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 3. Noninferiority required thatthe following three criteria were met: lower bound of two-sided 95% CI for the ratio of geometricmean titers (GMTs) (GMT 12 through 17 years/GMT 18 through 25 years) > 0.67; point estimate ofthe ratio of GMTs ≥ 0.82; and the lower bound of the two-sided 95% CI for difference ofseroconversion rates (SCRs) (SCR 12 through 17 years minus SCR 18 through 25 years) > -10%.

These noninferiority criteria were met.

Table 3 : 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

Paediatric Expansion Adult Main Study 12 through 17(12 through 17 Years) (18 through 25 Years) Years

Assay Timepoint N=390 N=416 versus18 through 25

Years

GMT GMT GMR95% CI2 95% CI2 95% CI2

Microneutralisation Day 35 (14 3859.6 2633.6 1.46(1/dilution) days after (3422.8, 4352.1) (2388.6, 2903.6) (1.25, 1.71)3

Dose 2)

Abbreviations: ANCOVA = analysis of covariance; CI = confidence interval; GMR = ratio of GMT, which is defined as theratio 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 syndromecoronavirus 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 performedto estimate the GMR. Individual response values recorded as below the LLOQ were set to half LLOQ.3 Represents (n1, n2) populations defined as:

n1 = number of participants in adult main study (18 through 25 years) with non-missing neutralising antibodies resultn2 = number of participants in paediatric expansion (12 through 17 years) with non-missing neutralising antibodies result

Study 2 (2019nCoV-302)

Study 2 was a Phase 3, multicentre, randomised, observer-blinded, placebo-controlled study inparticipants 18 to 84 years of age in the United Kingdom. Upon enrolment, participants were stratifiedby age (18 to 64 years; 65 to 84 years) to receive Nuvaxovid or placebo. The study excludedparticipants who were significantly immunocompromised due to immunodeficiency disease; currentdiagnosis or treatment for cancer; autoimmune disease/condition; received chronicimmunosuppressive 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 withclinically stable disease, defined as disease not requiring significant change in therapy orhospitalisation for worsening disease during the 4 weeks before enrolment were included. Participantswith known stable infection with HIV, hepatitis C virus (HCV), or hepatitis B virus (HBV) were notexcluded from enrolment.

Enrolment was completed in November 2020. Participants were followed for up to 12 months after theprimary 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 median21 days (IQR 21-23), range 16-45, did not experience an exclusionary protocol deviation, and did nothave 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 whoreceived Nuvaxovid, median age was 56.0 years (range: 18 to 84 years); 72% (n=5,067) were 18 to64 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 4: Vaccine efficacy analysis of PCR-confirmed COVID-19 with onset at least 7 days afterthe second vaccination - (PP-EFF population): Study 2 (2019nCoV-302)

Nuvaxovid Placebo

Incidence Incidence

Partici- COVID- Rate Per Partici- COVID- Rate Per % Vaccinepants 19 cases Year Per pants 19 cases Year Per Efficacy

Subgroup N n (%) 1,000 N n (%) 1,000 (95% CI)

People1 People1

Primary efficacy endpoint

All 89.7%participants 7,020 10 (0.1) 6.53 7,019 96 (1.4) 63.43 (80.2, 94.6)2, 3

Subgroup analyses of the primary efficacy endpoint18 to 64years of 5,067 9 (0.2) 12.30 5,062 87 (1.7) 120.22 89.8%age (79.7, 94.9)265 to 84years of 1,953 1 (0.10)2 --- 1,957 9 (0.9)2 --- 88.9%age (20.2, 99.7)41 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, treatmentgroup 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 hasbeen confirmed at the interim analysis.4 Based on the Clopper-Pearson model (due to few events), 95% CIs calculated using the Clopper-Pearson exact binomialmethod adjusted for the total surveillance time.

These results reflect enrolment that occurred during the time period when the B.1.1.7 (Alpha) variantwas 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%) wereidentified 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 4cases 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 baselinecharacteristics were balanced amongst participants who received Nuvaxovid and participants whoreceived placebo. In the per-protocol immunogenicity (PP-IMM) analysis set for participants whoreceived Nuvaxovid (n=191), median age was 40 years (range: 22 to 70 years); 93% (n=178) were 18to 64 years old and 7% (n=13) were aged 65 to 84; 43% were female; 75% were White; 23% weremultiracial or from ethnic minorities; and 27% had at least one comorbid condition. Co-administrationresulted in no change to influenza vaccine immune responses as measured by hemagglutinationinhibition (HAI) assay. A 30% reduction in antibody responses to Nuvaxovid was noted as assessed byan anti-spike IgG assay with seroconversion rates similar to participants who did not receiveconcomitant 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 ofage in South Africa. PLWH were medically stable (free of opportunistic infections), receiving highlyactive 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-2infection 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 whoreceived 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%) casesfor 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) variantwas circulating in South Africa.

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 2randomised, 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 wereseronegative to SARS-CoV-2 at baseline. A total of 254 participants (Full Analysis Set) received twodoses of Nuvaxovid (0.5 mL, 5 micrograms 3 weeks apart) as the primary vaccination series. A subsetof 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-foldincrease 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) of1,470.

Study 2019nCoV-501

In Study 3, a Phase 2a/b randomised, observer-blinded, placebo-controlled study, the safety andimmunogenicity of booster dose was evaluated in healthy HIV-negative adult participants 18 to84 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 apeak GMT (14 days post-Dose 2) of 694.

Safety and immunogenicity of COVID-19 vaccines given as booster doses following completion of aprimary vaccination series with another authorised COVID-19 vaccine was evaluated in anindependent 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 30years and older with no history of laboratory-confirmed SARS-CoV-2 infection. Nuvaxovid wasadministered at least 70 days after completion of a ChAdOx1 nCov-19 (Oxford-AstraZeneca) primaryvaccination series or at least 84 days after completion of a BNT162b2 (Pfizer-BioNTech) primaryvaccination series. Neutralising antibody titers measured by a wild-type assay were assessed 28 dayspost-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 demonstrateda 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 inferredfrom 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 afterthe primary series in adolescents as in adults, and the ability to boost the vaccine-induced immuneresponse was shown in adults.

Nuvaxovid was assessed in individuals 18 years of age and older. The efficacy of Nuvaxovid wasconsistent between elderly (≥ 65 years) and younger individuals (18 to 64 years) for the primary series.

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 section4.2 for information on paediatric use.

Not applicable.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeat-dosetoxicity, local tolerance and reproductive and developmental toxicity.

In vitro genotoxicity studies were conducted with the Matrix-M adjuvant. The adjuvant was shown tobe non-genotoxic. Carcinogenicity studies were not performed. Carcinogenicity is not expected.

A developmental and reproductive toxicity study was performed in female rats administered fourintramuscular doses (two prior to mating; two during gestation) of 5 micrograms SARS-CoV-2 rSprotein (approximately 200-fold excess relative to the human dose of 5 micrograms on a weight-adjusted basis) with 10 micrograms Matrix-M adjuvant (approximately 40-fold excess relative to thehuman dose of 50 micrograms on a weight-adjusted basis). No vaccine-related adverse effects onfertility, pregnancy/lactation, or development of the embryo/foetus and offspring through post-natal

Day 21 were observed.

Disodium hydrogen phosphate heptahydrate

Sodium dihydrogen phosphate monohydrate

Sodium chloride

Polysorbate 80

Sodium hydroxide (for adjustment of pH)

Hydrochloric acid (for adjustment of pH)

Water for injections

Adjuvant (Matrix-M)

Cholesterol

Phosphatidylcholine (including all-rac-α-Tocopherol)

Potassium dihydrogen phosphate

Potassium chloride

Disodium hydrogen phosphate dihydrate

Sodium chloride

Water for injections

For adjuvant: see also section 2.

This medicinal product must not be mixed with other medicinal products or diluted.

Unopened vial12 months at 2°C to 8°C, protected from light.

Unopened Nuvaxovid vaccine has been shown to be stable up to 12 hours at 25°C. Storage at 25°C isnot the recommended storage or shipping condition but may guide decisions for use in case oftemporary temperature excursions during the 12-month storage at 2°C to 8°C.

Chemical and physical in-use stability has been demonstrated for 12 hours at 2°C to 8°C or 6 hours atroom temperature (maximum 25°C) from the time of first needle puncture to administration.

From a microbiological point of view, after first opening (first needle puncture), the vaccine should beused immediately. If not used immediately, in-use storage times and conditions are the responsibilityof the user and should not exceed 12 hours at 2°C to 8°C or 6 hours at room temperature (maximum25°C).

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the vials in the outer carton in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

Multidose vial5-dose vial2.5 mL of dispersion in a vial (type I glass) with a stopper (bromobutyl rubber) and an aluminiumoverseal with blue plastic flip-off cap.

Each vial contains 5 doses of 0.5 mL.

Pack size: 2 multidose vials or 10 multidose vials10-dose vial5 mL of dispersion in a vial (type I glass) with a stopper (bromobutyl rubber) and an aluminiumoverseal with blue plastic flip-off cap.

Each vial contains 10 doses of 0.5 mL.

Pack size: 2 multidose vials or 10 multidose vials

Not all pack sizes may be marketed.

This vaccine should be handled by a healthcare professional using aseptic techniques to ensure thesterility of each dose.

Preparation for use

* The vaccine comes ready to use.

* Unopened vaccine should be stored at 2°C to 8°C and kept within the outer carton to protectfrom light.

* Immediately prior to use, remove the vaccine vial from the carton in the refrigerator.

* Record the date and time of discard on the vial label. Use within 12 hours after first puncture.

Inspect the vial

* Gently swirl the multidose vial before and in between each dose withdrawal. Do not shake.

* Each multidose vial contains a colourless to slightly yellow, clear to mildly opalescentdispersion free from visible particles.

* Visually inspect the contents of the vial for visible particulate matter and/or discolourationprior to administration. Do not administer the vaccine if either are present.

Administer the vaccine

* An overfill is included per vial to ensure that a maximum of 5 doses (vial of 2.5 mL) or10 doses (vial of 5 mL) of 0.5 mL each can be extracted.

* Each 0.5 mL dose is withdrawn into a sterile needle and sterile syringe to be administered byintramuscular injection, preferably in the deltoid muscle of the upper arm.

* Do not mix the vaccine in the same syringe with any other vaccines or medicinalproducts.

* Do not pool excess vaccine from multiple vials.

Storage after first needle puncture

* Store the opened vial between 2°C to 8°C for up to 12 hours or at room temperature(maximum 25°C) for up to 6 hours after first puncture, see section 6.3.

Discard

* Discard this vaccine if not used within 12 hours when stored between 2°C to 8°C or 6 hourswhen stored at room temperature after first puncture of the vial, see section 6.3.

* Any unused medicinal product or waste material should be disposed of in accordance withlocal requirements.

Novavax CZ a.s.

Líbalova 2348/1, Chodov149 00 Praha 4

Czechia

EU/1/21/1618/001 10 multidose vials (10 doses per vial)

EU/1/21/1618/002 10 multidose vials (5 doses per vial)

EU/1/21/1618/003 2 multidose vials (10 doses per vial)

EU/1/21/1618/004 2 multidose vials (5 doses per vial)

Date of first authorisation: 20 December 2021

Date of latest renewal: 03 October 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.