Nuvaxovid (Novavax) Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ............................................................................................... 2

TABLE OF CONTENTS ................................................................................................................. 3

PART I: HEALTH PROFESSIONAL INFORMATION .......................................................................... 5

1 INDICATIONS .................................................................................................................. 5

1.1 Pediatrics ...................................................................................................................... 5

1.2 Geriatrics ...................................................................................................................... 5

2 CONTRAINDICATIONS ..................................................................................................... 5

3 SERIOUS WARNINGS AND PRECAUTIONS ........................................................................ 5

4 DOSAGE AND ADMINISTRATION ..................................................................................... 5

4.1 Dosing Considerations .................................................................................................. 5

4.2 Recommended Dose and Dosage Adjustment ............................................................. 5

4.3 Reconstitution .............................................................................................................. 6

4.4 Administration .............................................................................................................. 6

5 OVERDOSAGE ................................................................................................................. 6

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ...................................... 6

7 WARNINGS AND PRECAUTIONS ...................................................................................... 8

7.1 Special Populations ...................................................................................................... 9

7.1.1 Pregnant Women ......................................................................................................... 9

7.1.2 Breast-feeding .............................................................................................................. 9

7.1.3 Pediatrics ...................................................................................................................... 9

7.1.4 Geriatrics .................................................................................................................... 10

8 ADVERSE REACTIONS ..................................................................................................... 10

8.1 Adverse Reaction Overview ....................................................................................... 10

8.2 Clinical Trial Adverse Reactions .................................................................................. 10

8.5 Post-Market Adverse Reactions ................................................................................. 20

9 DRUG INTERACTIONS .................................................................................................... 20

10 CLINICAL PHARMACOLOGY ............................................................................................ 20

10.1 Mechanism of Action ................................................................................................. 20

11 STORAGE, STABILITY AND DISPOSAL .............................................................................. 21

12 SPECIAL HANDLING INSTRUCTIONS ................................................................................ 21

PART II: SCIENTIFIC INFORMATION ........................................................................................... 22

13 PHARMACEUTICAL INFORMATION ................................................................................. 22

14 CLINICAL TRIALS ............................................................................................................ 22

14.1 Trial Design and Study Demographics ........................................................................ 22

14.2 Study Results .............................................................................................................. 26

15 MICROBIOLOGY ............................................................................................................ 30

16 NON-CLINICAL TOXICOLOGY .......................................................................................... 30

PATIENT MEDICATION INFORMATION ...................................................................................... 32

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

NUVAXOVID ™ (COVID-19 Vaccine (Recombinant protein, Adjuvanted)) is indicated for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 12 years of age and older.

1.1 Pediatrics

The safety and efficacy of NUVAXOVID in individuals under 12 years of age have not yet been established.

1.2 Geriatrics

Clinical studies of NUVAXOVID include participants 65 years of age and older and their data contribute to the overall assessment of safety and efficacy (See 8 ADVERSE REACTIONS and 14 CLINICAL TRIALS).

2 CONTRAINDICATIONS

NUVAXOVID is contraindicated in individuals who are hypersensitive to the active ingredient or to any ingredients in the formulation, including any non-medicinal ingredient, or component of the container. (For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).

3 SERIOUS WARNINGS AND PRECAUTIONS

At the time of approval, there are no known serious warnings or precautions associated with this product.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

NUVAXOVID is a suspension for intramuscular injection that should be administered by a trained healthcare worker.

4.2 Recommended Dose and Dosage Adjustment

The vaccination course for NUVAXOVID is a primary series of two doses of 0.5 mL each. The second dose is to be administered 3 weeks after the first dose.

There are no data available on the interchangeability of NUVAXOVID with other COVID-19 vaccines to complete the primary vaccination series.

Booster dose

Individuals 18 years of age and older: A booster dose of NUVAXOVID (0.5 mL) may be administered intramuscularly approximately 6 months after completion of the second dose of the primary series.

4.3 Reconstitution

NUVAXOVID must not be reconstituted, mixed with other medicinal products, or diluted.

4.4 Administration

Use aseptic techniques for preparation and administration to ensure the sterility of each dose.

NUVAXOVID is colourless to slightly yellow, clear to mildly opalescent suspension, free of particles.

• Gently swirl the multidose vial before and in between each dose withdrawal. Do not shake.
• Prior to administration, visually inspect the contents of the vial for visible particulate matter and/or discolouration prior to administration. Also, visually inspect the vial for cracks or any abnormalities, such as evidence of tampering. If any of these conditions exists, the vaccine should not be administered.

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

• Do not inject the vaccine intravascularly, subcutaneously, or intradermally.
• Do not mix the vaccine in the same syringe with any other vaccines or medicinal products.
• Do not pool excess vaccine from multiple vials.

NUVAXOVID does not contain a preservative. Store the opened vial between 2°C to 25°C for up to 6 hours of first needle puncture.

• Record the date and time of discard on the vial label.
• Discard this vaccine if not used within 6 hours after first puncture of the vial.

5 OVERDOSAGE

In the case of a suspected vaccine overdose, monitoring of vital functions and symptomatic treatment are recommended.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

To help ensure the traceability of vaccines for patient immunization record-keeping as well as safety monitoring, health professionals should record the time and date of administration, quantity of administered dose (if applicable), anatomical site and route of administration, brand name and generic name of the vaccine, the product lot number and expiry date.

Table 1: Dosage Forms, Strengths, Composition and Packaging

Composition

SARS-CoV-2 recombinant spike protein (original [Wuhan] strain) 5 mcg

Matrix-M adjuvant (Quillaja saponaria saponins fraction-A and fraction-C) 50 mcg

NUVAXOVID does not contain any preservatives or human-derived materials.

NUVAXOVID is supplied as:

• A 2.5 mL suspension in a clear glass vial (type I glass) with a stopper (bromobutyl rubber) and an aluminium overseal with blue plastic flip-off cap.

  • Each vial contains 5 doses of 0.5 mL.
  • The vials are packaged in a secondary carton containing two (2) or ten (10) multidose vials per carton.

• A 5 mL suspension in a clear glass vial (type I glass) with a stopper (bromobutyl rubber) and an aluminium overseal with blue plastic flip-off cap.

  • Each vial contains 10 doses of 0.5 mL.
  • The vials are packaged in a secondary carton containing ten (10) multidose vials per carton.

Not all presentations may be marketed.

7 WARNINGS AND PRECAUTIONS

General

Vaccination should be postponed in individuals suffering from an acute severe febrile illness or acute infection.

As with any vaccine, vaccination with NUVAXOVID may not protect all recipients.

Individuals may not be optimally protected until 7 days after their second dose. (See 14 CLINICAL TRIALS).

Acute Allergic Reactions

Events of anaphylaxis have been reported. Appropriate medical treatment and supervision should always be readily available in case of an anaphylactic reaction following the administration of the vaccine.

Close observation for at least 15 minutes is recommended following vaccination; 30 minutes is a preferred interval when there is a specific concern about a possible vaccine reaction. A second dose of the vaccine should not be given to those who have experienced anaphylaxis to the first dose of NUVAXOVID.

Cardiovascular

Myocarditis and Pericarditis

Myocarditis and pericarditis have been reported following NUVAXOVID administration.

Available data suggest that the course of myocarditis and pericarditis following vaccination is not different from myocarditis and pericarditis in general.

Available data cannot determine a causal association with NUVAXOVID.

Vaccinated individuals (including parents or caregivers) should be instructed to seek immediate medical attention if they develop symptoms indicative of myocarditis or pericarditis such as (acute and persisting) chest pain, shortness of breath, or palpitations following vaccination.

Hematologic

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

Driving and Operating Machinery

NUVAXOVID has no known influence on the ability to drive and use machines. However, some of the adverse reactions mentioned under 8 ADVERSE REACTIONS may temporarily affect the ability to drive or use machines.

Fertility

It is unknown whether NUVAXOVID has an impact on fertility. Animal studies do not indicate direct or indirect harmful effects with respect to female fertility or reproductive toxicity (see 16 NON-CLINICAL TOXICOLOGY).

Immune

Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished immune response to the vaccine.

Syncope

Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response to the needle injection. Procedures should be in place to prevent injury from fainting and manage syncopal reactions.

7.1 Special Populations

7.1.1 Pregnant Women

The safety and efficacy of NUVAXOVID in pregnant women have not yet been established.

Administration of NUVAXOVID in pregnancy should only be considered when the potential benefits outweigh any potential risks for the mother and fetus.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NUVAXOVID during pregnancy. Women who are vaccinated with NUVAXOVID during pregnancy are encouraged to enroll in the registry by visiting https://c-viper.pregistry.com/.

7.1.2 Breast-feeding

It is unknown if NUVAXOVID is excreted in human milk. A risk to the newborns/infants cannot be excluded. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for immunization against COVID-19.

7.1.3 Pediatrics

The safety and efficacy of NUVAXOVID in children and adolescents less than 12 years of age have not yet been established.

7.1.4 Geriatrics

Clinical studies of NUVAXOVID include participants 65 years of age and older and their data contribute to the overall assessment of safety and efficacy (See 8 ADVERSE REACTIONS and 14 CLINICAL TRIALS sections).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The safety profile of NUVAXOVID presented below for participants 18 years of age and older is based on data generated from an interim analysis of pooled data from 3 ongoing clinical trials conducted in the United Kingdom (Study 1), the United States and Mexico (Study 2) and South Africa (Study 3). At the time of the analysis, a total of 48,698 participants ≥ 18 years of age received at least one dose of NUVAXOVID (n=29,297) or placebo (n=19,401). 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.

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.

Of the pooled data following the booster vaccination in adults, frequencies and severity (all grades) of solicited adverse events generally increased, with most events being mild to moderate in severity.

In addition, the safety of NUVAXOVID was evaluated in adolescents in an interim analysis of the pediatric expansion portion of an ongoing Phase 3 placebo-controlled clinical trial conducted in the United States (Study 2019nCoV-301). Safety data was collected in 2,232 participants aged 12 through 17 years, with and without evidence of prior SARS-CoV-2 infection, who received at least one dose of NUVAXOVID (n=1,487) or placebo (n=745). Demographic characteristics were similar among adolescent participants who received NUVAXOVID and those who received placebo, and were generally similar to the adult portion of this study with regard to gender, race and ethnicity among adolescents who received NUVAXOVID. At the time of vaccination, the median age was 14 years (67.1% aged 12 to < 15 years; 32.9% aged 15 to < 18 years).

The most frequent adverse reactions in participants 12 years through 17 years of age 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%).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another vaccine. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse vaccine reactions in real-world use.

Primary Series

Adults 18 years of age and older

The safety analysis of the pooled data was performed once the median follow-up duration of at least 2 months after vaccination was completed. The median duration of follow-up was 70 days post-Dose 2, with 32,993 (66%) participants completing more than 2 months follow-up. Participants are being monitored for adverse reactions through approximately 12 to 24 months after Dose 2.

When compared with Dose 1, local and systemic adverse reactions were more frequently reported after Dose 2.

Solicited Local and Systemic Adverse Reactions

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.

The reported frequency and severity of solicited local reactions are presented by age group in Table 2 (18 to 64 years of age) and Table 3 (≥ 65 years of age).

Table 2: Frequency and Percentages of Participants with Solicited Local Adverse Reactions, by Maximum Severity, Within 7 Days of Each Dose – (Participants 18 to 64 Years of Age)

Source: pooled safety data from studies 2019nCoV-501, -301, -302 (excluding data from influenza vaccine substudy)

^a Grade 3 pain: Defined as any use of narcotic pain reliever or prevents daily activity.

^b Grade 4 pain, tenderness: Defined as Emergency Room (ER) visit or hospitalization.

^c Grade 3 tenderness: Defined as significant discomfort at rest.

^d Grade 3 erythema/redness: Defined as >10 cm.

^e Grade 3 induration/swelling: Defined as >10 cm or prevents daily activity.

Table 3: Frequency and Percentages of Participants with Solicited Local Adverse Reactions, by Maximum Severity, Within 7 Days of Each Dose – (Participants ≥65 Years of Age)

Source: pooled safety data from studies 2019nCoV-501, -301, -302 (excluding data from influenza vaccine substudy)

^a Grade 3 pain: Defined as any use of narcotic pain reliever or prevents daily activity.

^b Grade 3 tenderness: Defined as significant discomfort at rest.

^c Grade 3 erythema/redness: Defined as >10 cm.

^d Grade 3 induration/swelling: Defined as >10 cm or prevents daily activity.

The reported frequency and severity of solicited systemic reactions are presented in Table 4 (18 to 64 years of age) and Table 5 (≥65 years of age).

Table 4: Frequency and Percentages of Participants with Solicited Systemic Adverse Reactions, by Maximum Severity, Within 7 Days of Each Dose – (Participants 18 to 64 Years of Age)

Source: pooled safety data from studies 2019nCoV-501, -301, -302 (excluding data from influenza vaccine substudy)

^a Grade 3 nausea/vomiting: Defined as prevents daily activity or requires outpatient intravenous hydration.

^b Grade 4 nausea/vomiting: Defined as ER visit or hospitalization for hypotensive shock.

^c Grade 3 headache: Defined as significant; any use of narcotic pain reliever or prevents daily activity.

^d Grade 4 headache, fatigue/malaise, myalgia, arthralgia: Defined as ER visit or hospitalization.

^e Grade 3 fatigue/malaise, myalgia, arthralgia: Defined as significant; prevents daily activity.

^f Grade 3 fever: Defined as 39.0 to 40°C (102.1 to 104°F).

^g Grade 4 fever: Defined as >40°C (>104°F).

Table 5: Frequency and Percentages of Participants with Solicited Systemic Adverse Reactions, by Maximum Severity, Within 7 Days of Each Dose – (Participants ≥65 Years of Age)

Source: pooled safety data from studies 2019nCoV-501, -301, -302 (excluding data from influenza vaccine substudy)

^a Grade 3 nausea/vomiting: Defined as prevents daily activity or requires outpatient intravenous hydration.

^b Grade 3 headache: Defined as significant; any use of narcotic pain reliever or prevents daily activity.

^c Grade 4 headache, malaise, arthralgia: Defined as ER visit or hospitalization.

^d Grade 3 fatigue/malaise, myalgia, arthralgia: Defined as significant; prevents daily activity.

^e Grade 3 fever: Defined as 39.0 to 40°C (102.1 to 104°F).

^f Grade 4 fever: Defined as >40°C (>104°F).

Unsolicited Adverse Events

Across the pooled studies, participants were monitored for unsolicited adverse events after receipt of Dose 1 through 28 days after Dose 2 (49 days). The overall frequency of unsolicited adverse events for participants who received at least one dose of NUVAXOVID (n=29,297) or placebo (n=19,401) was 157 events per 100 person-years (e/100 PY) (18 to 64 years of age) and 153 e/100 PY (≥ 65 years of age) for those who received the vaccine and 133 e/100 PY (18 to 64 years of age) and 124 e/100 PY (≥ 65 years of age) for participants who received placebo.

Overall, the 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 was reported. Chills occurred in 0.56% (n=165) of participants (N=29,297) who received NUVAXOVID and 0.10% (n=20) of participants (N=19,401) who received placebo. Pain in the extremity occurred in 1.46% (n=428) of participants who received NUVAXOVID and 0.37% (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.

Serious Adverse Events and Other Adverse Events of Interest

Participants were monitored for unsolicited serious adverse events and adverse events of interest, including but not limited to neurologic, inflammatory, vascular, and autoimmune disorders, from receipt of first vaccination through the respective data cut-off dates for each individual study within the pooled data analysis set. Serious adverse events and adverse events of special interest will continue to be recorded until the end of the studies, approximately 12 to 24 months after Dose 2 across the pooled clinical trials.

Serious adverse events (SAEs) across both treatment groups were uncommon (defined as ≥1/1,000 to <1/100), with a higher incidence rate in participants who receive placebo (4.09 events per 100 person-years) than in participants who received NUVAXOVID (3.82 events per 100 person-years). A slightly higher incidence rate occurred among participants ≥ 65 years of age. Incidence rates for SAEs in the younger age cohort (18 to 64 years) were 3.31 events per 100 person-years in NUVAXOVID participants and 3.59 events per 100 person-years in placebo participants. Incidence rates for SAEs in the older age cohort (≥ 65 years) was 6.69 events per 100 person-years in NUVAXOVID recipients and 6.65 events per 100 person-years in placebo recipients.

In the younger age cohort (18 to 64 years), there were no SAEs with an incidence rate greater than 0.10 events per 100 person-years in the NUVAXOVID group while 3 events, COVID-19 pneumonia (0.25), COVID-19 (0.23), and appendicitis (0.15) had incidence rates greater than 0.10 events per 100 person-years in the placebo group. In the older age cohort, SAEs that occurred at an incidence rate greater than 0.20 events per 100 person years in participants who received NUVAXOVID were COVID-19 (0.37) and prostate cancer (0.28) compared with pneumonia (0.51), COVID-19 (0.26), COVID 19 pneumonia (0.26), and atrial fibrillation (0.26) in the placebo group.

SAEs of cholecystitis, including acute cholecystitis, occurred with a higher incidence rate per 100 person-years in NUVAXOVID (0.11) than in placebo recipients (0.00), although the percentage of participants experiencing the event was infrequent (0.03%). All participants had a history of or a concurrent finding of cholelithiasis (gallstones) and most participants had additional risk factors including obesity and ≥ 40 years of age. Time to onset ranged from 6 to 64 days from the last dose of vaccine, with more than half of the events occurring more than 1 month following the last dose. All events resolved following cholecystectomy.

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.

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.

Adolescents 12 through 17 years of age

The safety analysis of NUVAXOVID in adolescents was performed once the median follow-up duration of at least 2 months after vaccination was completed. The median duration of follow-up was 71 days post Dose 2. Of the 1,468 participants who received both NUVAXOVID doses, 1,277 (87.0%) had at least 60 days of follow-up after their second vaccination.

Solicited Adverse Reactions

The reported number and percentage of the solicited local and systemic adverse reactions in participants 12 through 17 years of age are presented in Table 6 and Table 7 respectively.

Table 6: Frequency and Percentages of Adolescent Participants with Solicited Local Adverse Reactions, by Maximum Severity, Within 7 Days of Each Dose – (Participants 12 through 17 Years of Age)

^a Grade 3 tenderness: Defined as significant discomfort at rest.

^b Grade 3 pain: Defined as any use of narcotic pain reliever or prevents daily activity.

^c Grade 3 erythema/redness: Defined as >10 cm.

^d Grade 3 induration/swelling: Defined as >10 cm or prevents daily activity.

Table 7: Frequency and Percentages of Adolescent Participants with Solicited Systemic Adverse Reactions, by Maximum Severity, Within 7 Days of Each Dose – (Participants 12 through 17 Years of Age)

^a Grade 3 fatigue/malaise, myalgia, arthralgia: Defined as significant; prevents daily activity.

^b Grade 3 headache: Defined as significant; any use of narcotic pain reliever or prevents daily activity.

^c Grade 4 headache: Defined as ER visit or hospitalization.

^d Grade 3 fever: Defined as 39.0 to 40°C (102.1 to 104°F).

^e Grade 4 fever: Defined as >40°C (>104°F).

^f Grade 3 nausea/vomiting: Defined as prevents daily activity or requires outpatient intravenous hydration.

^g Grade 4 nausea/vomiting: Defined as ER visit or hospitalization for hypotensive shock.

Unsolicited Adverse Reactions

For the safety analyses performed for the pediatric expansion portion of the main Phase 3 study, 2,232 adolescents aged 12 through 17 years of age (NUVAXOVID, n=1,487; placebo, n=745) are being monitored for unsolicited adverse reactions through approximately 12 to 24 months after Dose 2.

The overall frequency of unsolicited adverse events was similar between the NUVAXOVID (16.3%) and placebo (15.8%) groups. Lymphadenopathy occurred in 0.7% (n=10) of adolescents who received NUVAXOVID and in

0% of adolescents who received placebo. There were no other notable patterns or numerical imbalances between treatment groups.

Serious Adverse Events

As of 06 October 2021, serious adverse events were reported in 0.5% (n=7) of adolescents who received NUVAXOVID and 0.3% (n=2) who received placebo. There were no notable patterns or imbalances between treatment groups for specific categories of serious adverse events that would suggest a causal relationship to NUVAXOVID.

Booster Dose

Adults 18 Years of Age and Older

A booster dose of NUVAXOVID was evaluated in an ongoing Phase 2a/b randomized, placebo-controlled, observer-blinded clinical study conducted in South Africa (Study 2019nCoV-501), and an ongoing Phase 3, multi-centre, randomised, observer-blinded, placebo-controlled study in participants 18 years of age and older in the United States and Mexico (Study 2019nCoV-301). Solicited adverse reactions were reported within 7 days after the booster dose only in Study 2019nCoV-301 (Table 8 and Table 9), and unsolicited adverse reactions were reported in both Studies 2019nCoV-301 and Study 2019nCoV-501 through approximately 1 month after the booster dose. In Study 2019nCoV-301, safety was presented for two cohorts of participants; Cohort 1 participants received a booster dose of NUVAXOVID approximately 8 months after the second dose of the crossover primary series and Cohort 2 participants received a booster dose of NUVAXOVID approximately 11 months after the second dose of the initial primary series.

Table 8: Frequency and Percentages of Participants with Solicited Local Adverse Reactions, by Maximum Severity, Within 7 Days After a Booster Dose of NUVAXOVID – (Participants 19 to 79 Years of Age)

Source: safety data from studies study 2019nCoV-301

^a Grade 3 pain: Defined as any use of narcotic pain reliever or prevents daily activity.

^b Grade 4 pain, tenderness: Defined as Emergency Room (ER) visit or hospitalization.

^c Grade 3 tenderness: Defined as significant discomfort at rest.

^d Grade 3 erythema/redness: Defined as >10 cm.

^e Grade 3 induration/swelling: Defined as >10 cm or prevents daily activity.

Table 9: Frequency and Percentages of Participants with Solicited Systemic Adverse Reactions, by Maximum Severity, Within 7 Days of a Booster Dose – (Participants 19 to 79 Years of Age)

Source: safety data from studies study 2019nCoV-301

^a Grade 3 nausea/vomiting: Defined as prevents daily activity or requires outpatient intravenous hydration.

^b Grade 3 headache: Defined as significant; any use of narcotic pain reliever or prevents daily activity.

^c Grade 4 headache, malaise, arthralgia: Defined as ER visit or hospitalization.

^d Grade 3 fatigue/malaise, myalgia, arthralgia: Defined as significant; prevents daily activity.

^e Grade 3 fever: Defined as 39.0 to 40°C (102.1 to 104°F).

^f Grade 4 fever: Defined as >40°C (>104°F).

Unsolicited Adverse Reactions

Across the pooled studies of 2019nCoV-301 and 2019nCoV-501, participants were monitored for unsolicited adverse events after receipt of booster through 28 days. Events considered treatment related included injection site pain (0.18%), injection site swelling (0.14%), injection site erythema (0.05%), injection site induration (0.05%), lymphadenopathy (0.05%), neuralgia (0.05%) vaccination site lymphadenopathy (0.05%), and vaccination site nodule (0.05%).

Serious Adverse Reactions

In study 2019nCoV-301, through at least 28 days post-booster dose, serious adverse events were reported in no participants in Cohort 1 and in 2 (1.3%) participants in Cohort 2. None of the serious adverse events were considered causally related to the use of NUVAXOVID.

In study 2019nCoV-501, through at least 35 days post-booster dose, one serious adverse event was reported in 1 (<0.1%) participant. None of the serious adverse events were considered causally related to the use of NUVAXOVID.

8.5 Post-Market Adverse Reactions

The following adverse reactions have been identified during post-authorization use of NUVAXOVID.

Immune System Disorders: Anaphylaxis

Cardiac Disorders: Myocarditis and/or pericarditis (see 7 WARNINGS AND PRECAUTIONS)

Nervous System Disorders: Hypoaesthesia/paraesthesia

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure.

9 DRUG INTERACTIONS

No interaction studies have been performed. Co-administration of NUVAXOVID with inactivated influenza vaccines has been evaluated in a limited number of adults (217 that received NUVAXOVID and 214 that received placebo) in an exploratory sub-study of 2019nCoV-302 (See 14 CLINICAL TRIALS sections). The binding antibody response to SARS-CoV-2 was 30% lower when NUVAXOVID was given concomitantly with inactivated influenza vaccine. The clinical significance of this is unknown.

Concomitant administration of NUVAXOVID with non-influenza vaccines has not been studied.

Do not mix NUVAXOVID with other vaccines/products in the same syringe.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

NUVAXOVID is composed of purified full-length SARS-CoV-2 recombinant spike (S) protein nanoparticle that is stabilized 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 neutralizing antibodies, which may contribute to protection against COVID-19.

11 STORAGE, STABILITY AND DISPOSAL

Storage Prior to Use

The unopened NUVAXOVID multidose vials are stored refrigerated between 2° to 8°C (36° to 46°F) for a maximum of 9 months. Store in the original carton to protect from light.

Storage of Punctured vials

Chemical and physical in-use stability has been demonstrated from the time of first needle puncture to administration for 6 hours at 2°C to 25°C.

NUVAXOVID does not contain a preservative. Store the opened vial between 2°C to 25°C for up to 6 hours after first puncture. (See 4.4 Administration for further discard details and instructions).

12 SPECIAL HANDLING INSTRUCTIONS

Store in a refrigerator (2°C to 8°C).

Do not freeze.

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

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Proper name: SARS-CoV-2 recombinant spike (rS) protein with Matrix-M adjuvant

Product Characteristics:

SARS-CoV-2 recombinant spike protein is produced in the Spodoptera frugiperda insect cell line infected with a baculovirus that encodes full-length, SARS-CoV-2 spike gene-producing trimeric spike proteins from the original (Wuhan) strain. Matrix-M adjuvant contains Quillaja saponaria saponin fraction-A and Quillaja saponaria saponin fraction-C.

NUVAXOVID (COVID-19 Vaccine [Recombinant protein, Adjuvanted]) is a sterile, preservative-free, aqueous buffered suspension of the SARS-CoV-2 recombinant spike (rS) protein from the original (Wuhan) strain that is co-formulated with Matrix-M adjuvant and a formulation buffer. (See Table 1 for the full list of non-medicinal ingredients).

NUVAXOVID is a colourless to slightly yellow, clear to mildly opalescent suspension for intramuscular injection (pH 7.2). The vaccine is provided in a multidose vial containing 5 or 10 doses per vial. Each dose contains 5 mcg of SARS-CoV-2 recombinant spike protein with 50 mcg of Matrix-M adjuvant.

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

NUVAXOVID used in clinical trials contains the recombinant SARS-CoV-2 spike (S)-protein, derived from the original (Wuhan) strain of SARS-CoV-2.

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. An additional Phase 2a/b study, Study 3 (2019nCoV-501), evaluated the safety and immunogenicity of NUVAXOVID in participants in South Africa. Study 1 also had a pediatric expansion involving adolescent participants, who were 12 to 17 years of age living in the United States.

Adults 18 Years of Age and Older

Study 1 (2019nCoV-301)

Study 1 is an ongoing Phase 3, multi-centre, randomised, observer-blinded, placebo-controlled adult main study conducted in participants 18 years of age and older in the United States and Mexico and a pediatric 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; active cancer on chemotherapy; received chronic immunosuppressive therapy or received immunoglobulin or blood-derived products within 90 days; were pregnant; or had a history of laboratory-confirmed diagnosed COVID-19. Participants with clinically stable underlying co-morbidity were included as were participants with well-controlled human immunodeficiency virus (HIV) infection. Enrolment of adults completed in February 2021; safety and efficacy events were evaluated until each participant’s first blinded crossover vaccination or as of the data cut-off date of 31 May 2021. Participants will be followed for up to 24 months after the second dose for assessments of safety, and efficacy against COVID-19.

No less than 6 months after completion of the second dose of the primary vaccination series (initial or crossover) with NUVAXOVID, participants who remained in the study (United States only) received a booster dose of NUVAXOVID in an open-label manner. Approximately half of the participants received a booster dose of NUVAXOVID approximately 8 months after the second dose of the crossover primary series (Cohort 1) and approximately half of the participants received a booster dose approximately 11 months after the second dose of the initial primary series (Cohort 2). Booster dosing was initiated on 13 December 2021, with enrolment completed on 12 May 2022. Immunogenicity and safety data were collected from 298 participants immediately prior to booster vaccination through 28 days after booster vaccination based on data cut-off date of 15 March 2022.

Demographic and baseline characteristics were balanced amongst participants who received NUVAXOVID and those who received placebo. Of the 29,949 participants randomized, 15.1% of participants in the vaccine group and 23.3% of participants in the placebo group requested unblinding to receive an authorized COVID-19 vaccine. In the Per-Protocol Efficacy (PP-EFF) analysis set for participants who received NUVAXOVID (n=17,312), which included all participants who received the full prescribed regimen of trial vaccine, had no exclusionary protocol deviations, and did not have evidence of SARS-CoV-2 infection through 6 days after the second dose, 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 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.

Study 2 (2019nCoV-302)

Study 2 is an ongoing Phase 3, multi-centre, 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) and assigned in a 1:1 ratio 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 hospitalization for worsening disease during the 4 weeks before enrolment were included, as were participants with known stable infection with HIV, hepatitis C virus (HCV), or hepatitis B virus (HBV).

Enrolment was completed in November 2020; data cut-off dates for efficacy and safety were 29 January 2021 and 23 February 2021, respectively. Participants are being followed for up to 12 months after the last vaccination for assessments of safety and efficacy against COVID-19.

Demographic and baseline characteristics were balanced amongst participants who received NUVAXOVID and participants who received placebo. Of the 15,187 participants randomized, 33.8% of participants in the vaccine group and 35.4% of participants in the placebo group requested to receive an authorized COVID-19 vaccine. In the Per-Protocol Efficacy (PP-EFF) analysis set for participants who received NUVAXOVID (n=7,020), which included all participants who received the full prescribed regimen of trial vaccine, had no exclusionary protocol deviations, and did not have evidence of SARS-CoV-2 infection through 6 days after the second dose, the median age (range) 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; 49% were female; 95% were White; 3% were Asian; 1.0% were multiple races, 0.4% were Black or African American; 1% were Hispanic or Latino; and 45% had at least one comorbid condition.

Study 3 (2019nCoV-501)

Study 3 is an ongoing Phase 2a/b randomised, observer-blinded, placebo-controlled study in healthy HIV-negative participants 18 to 84 years of age and medically stable people living with HIV (PLWH) 18 to 64 years of age in South Africa. Upon enrolment, participants were assigned in a 1:1 ratio to receive NUVAXOVID or placebo. The study excluded participants who were significantly immunocompromised due to immunodeficiency disease; active cancer (malignancy) within 3 years; autoimmune disease/condition; received chronic immunosuppressive therapy or received immunoglobulin or blood-derived products within 90 days (excluding HAART in PLWH); 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 hospitalization for worsening disease during the 2 months before enrolment were included. Enrolment was completed in November 2020; data cut-off dates for efficacy and safety were 18 January 2021 and 23 February 2021, respectively. Participants are being followed for up to 12 months after the last vaccination for assessments of safety and efficacy against COVID-19.

Approximately 6 months after completion of the second dose of the primary series vaccination with NUVAXOVID, participants who remained in the study received a booster dose of NUVAXOVID in a blinded manner. Booster dosing was initiated on 26 March 2021, with enrolment completed on 04 May 2021. Immunogenicity and safety data were collected from 1,898 participants immediately prior to booster vaccination through 35 days after booster vaccination based on a data cut-off date of 15 September 2021.

Demographic and baseline characteristics were balanced amongst participants who received NUVAXOVID and participants who received placebo. Of the 4,408 participants who received at least one dose of NUVAXOVID or placebo, the median age (range) was 28 years (range: 18 to 84 years); 94% (n=4,164) were HIV-negative and 6% (n=244) were PLWH; 96% (n=4,224) were 18 to 64 years old and 4% (n=184) were aged 65 to 84; 43% were female; 95% were Black or African American; 3% were White; 1% were Asian; 2% were multiple races, 2% were Hispanic or Latino; and 23% had at least one comorbid condition.

Adolescents 12 through 17 Years of Age

Study 1 (2019nCoV-301)

Study 1 is an ongoing Phase 3, multi-centre, randomised, observer-blinded, placebo-controlled study initially in adults (see above) with a subsequent pediatric expansion occurring in participants 12 through 17 years of age in the United States.

Upon enrolment in the pediatric expansion phase of Study 1, participants were randomised in a 2:1 ratio to receive NUVAXOVID or placebo without any stratification factors including age. The study excluded participants using the same criteria used in the adult phase of the same study. Enrolment of adolescents was completed in June 2021; safety, immunogenicity and efficacy events were evaluated until each participant’s first blinded crossover vaccination (described below) or as of 06 October 2021 (data extraction date). Participants will be followed for up to 24 months after the second dose for assessments of safety, immunogenicity and efficacy against COVID-19. Following collection of sufficient safety data to support an interim order application , initial adolescent recipients of placebo were invited to receive two injections of NUVAXOVID given 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.

Demographic and baseline characteristics were balanced amongst participants who received NUVAXOVID and those who received placebo. Of the 2,247 participants randomized, 4.0% of participants in the vaccine group and 5.3% of participants in the placebo group requested unblinding to receive an authorized COVID-19 vaccine. In the Safety Analysis Set (SAS) for participants who received at least one dose of NUVAXOVID (n=1,487) or placebo (n=745), the median age was 14.0 years with an age distribution skewed to younger ages due to availability of an authorized COVID-19 vaccine for participants 16 years and older during the implementation of this study. The age distribution of participants was balanced between NUVAXOVID and placebo recipients with 67.1% in the total group (12 to 14 years of age) and 32.9% in the total group (15 to 17 years of age). Of all participants, 47.5% were female; 74.4% were White, 13.9% were Black or African American, 2.1% were American Indian or Alaska Native, 3.4% were Asian with the remainder of Mixed Origin or other categories; 18.5% were of Hispanic or Latino ethnicity. The majority of all subjects (53.2%) in the SAS had a normal BMI (18.0-24.9 kg/m²) but 16.9% were overweight (BMI of 25.0-29.9 kg/m²) and 26.8% obese (BMI of ≥ 30.0 kg/m²). No other clinically relevant comorbidities were described in the adolescent phase of this study.

14.2 Study Results

Primary Series

Efficacy in Adults 18 Years of Age and Older After Two Doses

Study 1 (2019nCoV-301)

As of the cut-off date of 31 May 2021, 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 between days 21 to 28), did not experience an exclusionary protocol deviation, and did not have evidence of SARS-CoV-2 infection through 6 days after the second dose.

COVID-19 cases were confirmed by polymerase chain reaction (PCR) through a central laboratory. Vaccine efficacy overall and a subgroup analysis by age and by mild, moderate, or severe COVID-19 are presented in Table 10.

Table 10: Vaccine efficacy analyses of PCR-confirmed COVID-19 with onset from 7 days after second vaccination^a - PP-EFF analysis set; Study 1 (2019nCoV-301)

^aVaccine efficacy evaluated in participants without major protocol deviations who were seronegative and PCR-negative to SARS-CoV-2 at baseline and do not have a laboratory confirmed current SARS-CoV-2 infection with symptom onset through 6 days after the second dose, and who have received the full prescribed regimen of trial vaccine.

^bMean disease incidence rate per year in 1,000 people.

^cBased 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 vaccine efficacy = 100 × (1 – relative risk).

^dMet primary efficacy endpoint criterion for success with a lower bound confidence interval (LBCI) > 30%.

^eFor participants ≥65 years of age, the event rates were too low (two or fewer events) to allow meaningful interpretation.

Vaccine efficacy of NUVAXOVID to prevent the onset of COVID-19 from 7 days after Dose 2 was 90.40% (PP-EFF analysis set).

Study 2 (2019nCoV-302)

As of the cut-off date of 29 January 2021, the primary efficacy PP-EFF analysis set 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 between 21 and 28 days), did not experience an exclusionary protocol deviation, and did not have evidence of SARS-CoV-2 infection through 6 days after the second dose.

Vaccine efficacy overall and a subgroup analysis by age and by severity of COVID-19 are presented in Table 11.

Table 11: Vaccine efficacy analysis of PCR-confirmed COVID-19 with onset at least 7 days after the second vaccination^a - PP-EFF analysis set: Study 2 (2019nCoV-302)

^aVaccine efficacy evaluated in participants without major protocol deviations who were seronegative and PCR-negative to SARS-CoV-2 at baseline and do not have a laboratory confirmed current SARS-CoV-2 infection with symptom onset through 6 days after the second dose, and who have received the full prescribed regimen of trial vaccine.

^bMean disease incidence rate per year in 1000 people.

^cBased 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.

^dMet primary efficacy endpoint criterion for success with a lower bound confidence interval (LBCI) > 30%.

^eBased 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.

Vaccine efficacy of NUVAXOVID to prevent the onset of COVID-19 from 7 days after Dose 2 was 89.7% (PP-EFF analysis set).

Immunogenicity and Efficacy in Adolescents 12 through 17 years of age

Study 1 (2019nCoV-301)

An analysis of the SARS-CoV-2 neutralizing antibody response 35 days after Dose 2 was conducted in a subset of adolescent participants 12 through 17 years of age and a subset of participants 18 through 25 years of age from the adult main study. Non-inferior immune responses as assessed by geometric mean titers and seroconversion rates were demonstrated in a comparison of adolescents 12 through 17 years of age to participants 18 through 25 years of age (Table 12).

Table 12: SARS-CoV-2 Neutralizing Antibody Geometric Mean Titer Ratio and Seroconversion Rate – Comparison of Adolescents 12 Years Through 17 Years of Age to Participants 18 Years Through 25 Years of Age – Per-Protocol Immunogenicity Analysis Set^a

CI = Confidence interval; GMR = Geometric mean ratio; GMT = Geometric mean titer; SCR = Seroconversion rate ^a PP-IMM Analysis Set included participants who received two doses (0.5 mL 3 weeks apart) of NUVAXOVID in the initial vaccination period, had immunogenicity blood samples collected at Days 0 and 35, did not have serologic or virologic evidence of SARS-CoV-2 infection up to the Day 35 blood draw and without major protocol deviations through the Day 35 blood draw.

^b The 95% CI for GMT is calculated based on the t-distribution of the log-transformed values, then back transformed to the original scale for presentation.

^c GMR is defined as the ratio of two geometric mean titers for comparison of two age cohorts. An analysis of covariance (ANCOVA) with age cohort as main effect and baseline microneutralization assay neutralizing antibodies as covariate was performed to estimate the GMR.

^d Noninferiority was achieved if the following 3 pre-specified criteria were met simultaneously: 1) Lower bound of two-sided 95% CI for the ratio of GMTs (GMT_12-17yo/GMT_18-25yo) > 0.67; 2) Point estimate of the ratio of GMTs ≥ 0.82; and 3) Lower bound of the two-sided 95% CI for difference of SCRs (SCR_12-17yo - SCR_18-25yo) was > -10%.

^e Validated virus neutralizing assay (VNA) with wild-type virus (SARS-CoV-2 hCoV-19/Australia/VIC01/2020 [GenBank MT007544.1]; 360biolabs, Melbourne, Australia). The lower limit for quantification for this assay was a titer of 20, with titers below this level documented as 10.

^f SCR is defined as percentage of participants with a ≥ 4-fold difference in titers between Day 35 and Day 0. The 95% CI for SCR was calculated using the Clopper-Pearson exact method.

^g Difference in SCR in the adolescent primary series expansion (Study 1) for 12 years through 17 years of Study 1 minus SCR in Adult Main Study (Study 1) for 18 years through 25 years. The 95% CI for the difference of SCR between groups was calculated with the method of Miettinen and Nurminen.

A descriptive efficacy analysis evaluating PCR-confirmed COVID-19 cases was performed in 1,799 participants who were included in the per-protocol efficacy (PP-EFF) Analysis Set, which required receipt of two doses (Dose 1 on day 0; Dose 2 on day 21), no exclusionary protocol deviation(s), and no evidence of SARS-CoV-2 infection through 6 days after the second dose. 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. In the PP-EFF Analysis Set, 47.2% were female; 76.1% were White, 12.9% were Black or African American, 1.1% were American Indian or Alaska Native, 3.6% were Asian with the remainder of Mixed Origin or other categories; 15.8% were Hispanic or Latino ethnicity; median age of 14.0 years (range 12-17 years) and 25.3% were classified as obese as per BMI. The median interval between doses of study vaccine was 22 days (range 14-43 days).

As of 06 October 2021 (data extraction date), 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%) (Table 13). 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%). As of the data extraction date, the PP-EFF Analysis Set had a median follow-up of 64 days following 7 days post-Dose 2 during the pre-crossover period.

Table 13: Vaccine Efficacy Against PCR-confirmed COVID-19 with Onset from 7 Days After Second Vaccination^a (PP-EFF Analysis Set)

^a Vaccine efficacy (VE) evaluated in participants without major protocol deviations who were seronegative (for SARS-CoV-2) at baseline and did not have a laboratory confirmed current SARS-CoV-2 infection with symptom onset through 6 days after the second dose, and who had received two doses of vaccine or placebo as randomized.

^b Based on Modified Poisson regression with logarithmic link function and treatment group as fixed effect and robust error variance (Zou 2004).

^c All cases for which sequence data are available (vaccine n=2; placebo n=7) were due to the Delta variant.

Booster Dose

Immunogenicity in Adults 18 Years of Age and Older

Study 1 (2019nCoV-301)

As of the cut-off date of 15 March 2022, the immunogenicity analysis population (referred to as the Per-Protocol Immunogenicity [PP-IMM] analysis set) included 243 participants who completed both doses of their primary series vaccination with NUVAXOVID, received a single booster dose of NUVAXOVID, completed Day 35 blood samples, did not have a positive nasal swab PCR or positive serum anti-nucleoprotein (NP) antibodies on or before the booster dose (if available), had not received an EUA vaccine and remained blinded during the primary series of vaccination. Of these participants, 117 received a single booster dose of NUVAXOVID approximately 8 months after the second dose of the crossover primary series vaccination (Cohort 1) and 126 received a single booster dose of NUVAXOVID approximately 11 months after the second dose of the initial primary series vaccination (Cohort 2). Immune responses were measured by a microneutralization assay against SARS-CoV-2 wild-type virus (ancestral Wuhan strain) that defined the titer as the concentration that yielded >50% viral inhibition [MN50]. In both cohorts, a single booster dose of NUVAXOVID elicited robust MN50 responses at 28 days after booster administration with neutralizing antibody GMTs of 4,235.8 and 5,972.6 in Cohort 1 and Cohort 2, respectively, that were higher than those reported at 14 days after primary series vaccination with NUVAXOVID (1,162.3 and 1,914.3, respectively). The ratios of MN50 titers at 28 days post-booster dose versus at 14 days post-primary series vaccination were 3.7 (95% CI: 2.9 – 4.7) and 3.1 (95% CI: 2.5 – 4.0) for Cohort 1 and Cohort 2, respectively.

Study 3 (2019nCoV-501)

At the cut-off date of 15 September 2021, the PP-IMM analysis set included 623 HIV-negative participants who completed both doses of their primary series vaccination with NUVAXOVID, received a single booster dose of NUVAXOVID, had at least 1 baseline and 1 serum sample result available after booster vaccination, were negative for hepatitis B virus and hepatitis C virus at baseline, and did not have a positive nasal swab PCR or anti-NP antibodies on or before the booster dose. A single booster dose of NUVAXOVID administered 6 months after the second dose of the primary series vaccination elicited robust neutralizing antibody (MN50) responses against the SARS-CoV-2 wild-type virus (ancestral Wuhan strain) at 35 days after booster administration with a neutralizing antibody GMT of 3,812.6 that was higher than that reported at 14 days after completion of primary series vaccination with NUVAXOVID (1,402.3). The ratio of neutralizing antibody titers (MN50) against SARS-CoV-2 wild-type virus (ancestral Wuhan strain) at 35 days post-booster dose versus at 14 days post-primary series vaccination was 2.7 (95% CI: 2.4 – 3.0).

15 MICROBIOLOGY

No microbiological information is required for this vaccine product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology: In a repeat-dose toxicity study conducted in New Zealand White rabbits, 50 mcg SARS-CoV-2 rS with or without 50 mcg Matrix-M adjuvant was administered intramuscularly up to 4 times (days 1, 8,

15 and 36) and demonstrated SARS-CoV-2 rS with Matrix-M adjuvant was well-tolerated with no adverse findings. Effects on clinical pathology parameters (fibrinogen, CRP, and/or globulin), which resolved during the recovery interval, and histopathology (subacute inflammation at injection sites and adjacent tissue), which were decreased at the recovery interval, were consistent with immune stimulation following administration of a vaccine.

Carcinogenicity: NUVAXOVID has not been evaluated for carcinogenicity in animals, as carcinogenicity studies were not considered relevant to this vaccine.

Genotoxicity: In vitro genotoxicity studies were conducted with the Matrix-M adjuvant. The adjuvant was shown to be non-mutagenic in both the bacterial reverse mutation assay and mammalian cell micronucleus assay.

Reproductive and Developmental Toxicology: A developmental and reproductive toxicity study was performed in female rats administered four intramuscular doses (two prior to mating; two during gestation) of 5 micrograms SARS-CoV-2 rS protein (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 the human dose of 50 micrograms on a weight-adjusted basis). No vaccine-related adverse effects on fertility, pregnancy/lactation, or development of the embryo/foetus and offspring through post-natal Day 21 were observed.