Comirnaty Omicron Xbb.1.5 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 ............................................................................................................ 2

PART I: HEALTH PROFESSIONAL INFORMATION .................................................................... 6

1 INDICATIONS ........................................................................................................... 6

1.1 Pediatrics ..................................................................................................................... 6

1.2 Geriatrics ..................................................................................................................... 6

2 CONTRAINDICATIONS .............................................................................................. 6

3 SERIOUS WARNINGS AND PRECAUTIONS ................................................................. 6

4 DOSAGE AND ADMINISTRATION.............................................................................. 6

4.1 Dosing Considerations ................................................................................................ 6

4.2 Recommended Dose and Dosage Adjustment ........................................................... 8

4.2.1 Vaccination Schedule for Individuals 12 Years of Age and Older .......................... 8

4.2.2 Vaccination Schedule for Individuals Aged 5 Years to <12 Years .......................... 8

4.2.3 Vaccination Schedule for Individuals Aged 6 Months to <5 Years ......................... 8

4.3 Reconstitution ............................................................................................................. 9

4.3.1 For 12 Years of Age and Older: DO NOT DILUTE (Single Dose or Multiple Dose Vials with Gray Cap and Gray Label Border) .................................................................... 9

4.3.2 For Age 5 Years to <12 Years: DILUTE PRIOR TO USE (Multiple Dose Vials with Orange Cap and Orange Label Border) .......................................................................... 13

4.3.3 For Age 5 Years to <12 Years: DO NOT DILUTE (Single Dose or Multiple Dose Vials with Blue Cap and Blue Label Border)................................................................... 18

4.3.4 For Age 6 Months to <5 Years: DILUTE PRIOR TO USE (Multiple Dose Vials with Maroon Cap and Maroon Label Border) ....................................................................... 21

4.4 Administration .......................................................................................................... 26

4.4.1 For 12 Years of Age and Older .............................................................................. 26

4.4.2 For Age 5 Years to <12 Years ................................................................................ 27

4.4.3 For Age 6 Months to <5 Years .............................................................................. 28

5 OVERDOSAGE ........................................................................................................ 29

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............................ 29

7 WARNINGS AND PRECAUTIONS ............................................................................. 32

7.1 Special Populations ................................................................................................... 33

7.1.1 Pregnant Women ................................................................................................. 33

7.1.2 Breast-feeding ...................................................................................................... 34

7.1.3 Pediatrics .............................................................................................................. 34

7.1.4 Geriatrics .............................................................................................................. 34

8 ADVERSE REACTIONS ............................................................................................ 34

8.1 Adverse Reaction Overview ...................................................................................... 34

8.1.1 COMIRNATY Original & Omicron BA.4/BA.5 (15 mcg/15 mcg) ............................ 34

8.1.2 COMIRNATY Original & Omicron BA.4/BA.5 (5 mcg/5 mcg) ................................ 35

8.1.3 COMIRNATY Original & Omicron BA.4/BA.5 (1.5 mcg/1.5 mcg) .......................... 35

8.1.4 COMIRNATY (30 mcg) ........................................................................................... 36

8.1.5 COMIRNATY (10 mcg) ........................................................................................... 37

8.1.6 COMIRNATY (3 mcg) ............................................................................................. 38

8.2 Clinical Trial Adverse Reactions ................................................................................ 38

8.2.1 COMIRNATY Original & Omicron BA.4/BA.5 (15 mcg/15 mcg) ............................ 39

8.2.2 COMIRNATY Original & Omicron BA.4/BA.5 (5 mcg/5 mcg) ................................ 41

8.2.3 COMIRNATY Original & Omicron BA.4/BA.5 (1.5 mcg/1.5 mcg) .......................... 43

8.2.4 COMIRNATY (30 mcg) ........................................................................................... 47

8.2.5 COMIRNATY (10 mcg) ........................................................................................... 56

8.2.6 COMIRNATY (3 mcg) ............................................................................................. 61

8.5 Post-Market Adverse Reactions ................................................................................ 65

9 DRUG INTERACTIONS ............................................................................................ 65

10 CLINICAL PHARMACOLOGY .................................................................................... 65

10.1 Mechanism of Action ................................................................................................ 65

11 STORAGE, STABILITY AND DISPOSAL ...................................................................... 65

12 SPECIAL HANDLING INSTRUCTIONS........................................................................ 68

PART II: SCIENTIFIC INFORMATION ..................................................................................... 69

13 PHARMACEUTICAL INFORMATION ........................................................................ 69

14 CLINICAL TRIALS .................................................................................................... 70

14.1 Trial Design and Study Demographics ...................................................................... 70

14.1.1 COMIRNATY Original & Omicron BA.4/BA.5 (15/15mcg) .................................... 70

14.1.2 COMIRNATY Original & Omicron BA.4/BA.5 (1.5/1.5 mcg) ................................. 70

14.1.3 COMIRNATY (30 mcg) ........................................................................................... 70

14.1.4 COMIRNATY (10 mcg) ........................................................................................... 72

14.2 Study Results ............................................................................................................. 74

14.2.1 COMIRNATY Original & Omicron BA.4/BA.5 (15/15mcg) .................................... 74

14.2.1.1 Immunogenicity in Participants 12 Years of Age and Older – After Second Booster Dose (Fourth Dose) ................................................................................... 74

14.2.2 COMIRNATY Original & Omicron BA.4/BA.5 (1.5/1.5 mcg) ................................. 78

14.2.2.1 Immunogenicity in Participants 6 Months Through <5 Years of Age – After Booster (Fourth Dose) ............................................................................................ 78

14.2.3 COMIRNATY (30 mcg) ........................................................................................... 79

14.2.3.1 Efficacy and Immunogenicity in Participants 16 Years of Age and Older ....... 79

14.2.3.1.1 Efficacy in Participants 16 Years of Age and Older – After Two Doses .... 79

14.2.3.1.2 Efficacy and Immunogenicity in Participants 16 Years of Age and Older – After Booster Dose ............................................................................................... 81

14.2.3.2 Efficacy and Immunogenicity in Adolescents 12 to 15 Years of Age .............. 84

14.2.3.2.1 Efficacy and Immunogenicity in Adolescents 12 to 15 Years of Age – After Two Doses ................................................................................................... 84

14.2.4 COMIRNATY (10 mcg) ........................................................................................... 86

14.2.4.1 Efficacy and Immunogenicity in Children 5 Years Through <12 Years of Age . 86

14.2.4.1.1 Efficacy and Immunogenicity in Children 5 Years Through <12 Years of Age – After Two Doses ......................................................................................... 86

14.2.4.2 Immunogenicity in Children 5 Years Through <12 Years of Age – After Booster Dose ........................................................................................................................ 88

14.2.5 COMIRNATY (3 mcg) ............................................................................................. 89

14.2.5.1 Immunogenicity in Children 6 Months Through <5 Years of Age ................... 89

14.2.5.1.1 Immunogenicity in Children 6 Months Through <5 Years of Age – After a 3-Dose Primary Series .......................................................................................... 89

15 MICROBIOLOGY .................................................................................................... 93

16 NON-CLINICAL TOXICOLOGY .................................................................................. 93

PATIENT MEDICATION INFORMATION ................................................................................ 94

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

COMIRNATY Omicron XBB.1.5 (COVID-19 mRNA Vaccine, Monovalent (Omicron XBB.1.5)) is indicated for active immunization against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) in individuals 6 months of age and older (see 4.2 Recommended Dose and Dosage Adjustment).

The safety and effectiveness of COMIRNATY Omicron XBB.1.5 for individuals 6 months of age and older are inferred from studies which evaluated the primary series and booster vaccination with COMIRNATY and supported by studies which evaluated a booster dose of COMIRNATY Original & Omicron BA.4/BA.5 in individuals 6 months of age and older.

1.1 Pediatrics

The safety and efficacy of COMIRNATY Omicron XBB.1.5 in children under 6 months of age have not yet been established.

1.2 Geriatrics

Clinical studies of COMIRNATY and COMIRNATY Original & Omicron BA.4/BA.5 included participants 65 years of age and older and their data contributes to the overall assessment of the safety and efficacy of COMIRNATY Omicron XBB.1.5 (see 8 ADVERSE REACTIONS and 14 CLINICAL TRIALS). The safety and efficacy of COMIRNATY Omicron XBB.1.5 in geriatric individuals have not yet been established in clinical trials.

2 CONTRAINDICATIONS

COMIRNATY Omicron XBB.1.5 is contraindicated in individuals who are hypersensitive to the active substance or to any ingredient in the formulation. For a complete listing see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

3 SERIOUS WARNINGS AND PRECAUTIONS

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

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

The storage, preparation and administration information differ depending on which presentation of the vaccine is considered. Careful attention should be paid to the vial cap and label border colour and information on the label, and the appropriate corresponding instructions must be followed under the subsections below.

For 12 Years of Age and Older

COMIRNATY Omicron XBB.1.5 is a suspension for intramuscular injection. DO NOT DILUTE (Single Dose or Multiple dose Vials with Gray Cap and Gray Label Border).

A single dose is 0.3 mL.

For Age 5 Years to <12 Years

There are two formulations of COMIRNATY Omicron XBB.1.5 for use in individuals 5 to <12 years of age, with different dosing.

DILUTE PRIOR TO USE: A suspension for intramuscular injection which must be diluted prior to administration (Multiple Dose Vials with Orange Cap and Orange Label Border).

• After preparation, a single dose is 0.2 mL.

DO NOT DILUTE: A ready to use suspension for intramuscular injection (Single Dose or Multiple Dose Vials with Blue Cap and Blue Label Border).

• A single dose is 0.3 mL.

For Age 6 Months to <5 Years

COMIRNATY Omicron XBB.1.5 is a suspension for intramuscular injection which must be diluted prior to administration. DILUTE PRIOR TO USE (Multiple Dose Vials with Maroon Cap and Maroon Label Border).

After preparation, a single dose is 0.2 mL.

4.2 Recommended Dose and Dosage Adjustment

4.2.1 Vaccination Schedule for Individuals 12 Years of Age and Older

COMIRNATY Omicron XBB.1.5 is administered intramuscularly as a single dose of 0.3 mL, regardless of prior COVID-19 vaccination status.

For individuals who have previously been vaccinated with a COVID-19 vaccine, COMIRNATY Omicron XBB.1.5 should be administered at least 3 to 6 months after the most recent dose of a COVID-19 vaccine.

Vials of COMIRNATY Omicron XBB.1.5 intended for individuals 12 years of age and older (gray cap/gray label border) cannot be used to prepare doses for individuals aged 6 months to <12 years of age.

4.2.2 Vaccination Schedule for Individuals Aged 5 Years to <12 Years

COMIRNATY Omicron XBB.1.5 is administered intramuscularly as a single dose, regardless of prior COVID-19 vaccination status.

• DILUTE PRIOR TO USE (Multiple Dose Vials with Orange Cap and Orange Label Border): After dilution, a single dose is 0.2 mL.
• DO NOT DILUTE (Single Dose or Multiple Dose Vials with Blue Cap and Blue Label Border): A single dose is 0.3 mL.

For individuals who have previously been vaccinated with a COVID-19 vaccine, COMIRNATY Omicron XBB.1.5 should be administered at least 6 months after the most recent dose of a COVID-19 vaccine.

Vials of COMIRNATY Omicron XBB.1.5 intended for individuals aged 5 years to <12 years (orange cap/orange label border or blue cap/blue label border) cannot be used to prepare doses for individuals 6 months to < 5 years or 12 years of age and older.

4.2.3 Vaccination Schedule for Individuals Aged 6 Months to <5 Years

Infants and children 6 months to <5 years of age without history of completion of a COVID-19 primary course

COMIRNATY Omicron XBB.1.5 is administered intramuscularly as a three-dose course (0.2 mL each). It is recommended to administer the second dose 3 weeks after the first dose, followed by a third dose administered at least 8 weeks after the second dose.

If an infant or child starts a primary vaccination course with COMIRNATY or COMIRNATY Original & Omicron BA.4/BA.5, they may complete the three-dose course with COMIRNATY Omicron XBB.1.5.

The interchangeability of COMIRNATY Omicron XBB.1.5 with COVID-19 vaccines from other manufacturers to complete the three-dose course has not been established. Individuals who have received a dose of COMIRNATY Omicron XBB.1.5 should receive COMIRNATY Omicron XBB.1.5 to complete the three-dose course.

Infants and children 6 months to <5 years of age with history of completion of a COVID-19 primary course

COMIRNATY Omicron XBB.1.5 is administered intramuscularly as a single dose of 0.2 mL for infants and children 6 months to <5 years of age.

For individuals who have previously been vaccinated with a COVID-19 vaccine, COMIRNATY Omicron XBB.1.5 should be administered at least 6 months after the most recent dose of a COVID-19 vaccine.

Vials of COMIRNATY Omicron XBB.1.5 intended for individuals aged 6 months to <5 years (maroon cap/maroon label border) cannot be used to prepare doses for individuals 5 years of age and older.

4.3 Reconstitution

4.3.1 For 12 Years of Age and Older: DO NOT DILUTE (Single Dose or Multiple Dose Vials with Gray Cap and Gray Label Border)

The COMIRNATY Omicron XBB.1.5 single dose or multiple dose vial with a gray cap and gray label border MUST NOT BE DILUTED prior to administration. Instructions on the handling and dose preparation of the vaccine prior to administration are provided below.

Preparation for Administration

Single Dose Vials

DO NOT DILUTE

• The COMIRNATY Omicron XBB.1.5 single dose vial with a gray cap and a gray label border is supplied as a frozen suspension that does not contain preservative. Each vial must be thawed prior to administration. DO NOT DILUTE prior to use.
• Single dose vials of COMIRNATY Omicron XBB.1.5 intended for 12 years of age or older with a gray cap/gray label border cannot be used to prepare doses for individuals aged 6 months to <12 years.
• Single dose vials may be thawed in the refrigerator (2°C to 8°C [35°F to 46°F]) or at room temperature (up to 25°C [77°F]) (see 11 STORAGE, STABILITY AND DISPOSAL).
• The thawed suspension may contain white to off-white opaque amorphous particles.
• One single dose vial contains 1 dose of 0.3 mL.
• Refer to thawing and dose preparation instructions in the panels below.

Multiple Dose Vials

DO NOT DILUTE

• The COMIRNATY Omicron XBB.1.5 multiple dose vial with a gray cap and a gray label border contains a volume of 2.25 mL, and is supplied as a frozen suspension that does not contain preservative. Each vial must be thawed prior to administration. DO NOT DILUTE prior to use.
• Multiple dose vials of COMIRNATY Omicron XBB.1.5 intended for 12 years of age or older with a gray cap/gray label border cannot be used to prepare doses for individuals aged 6 months to <12 years.
• Multiple dose vials may be thawed in the refrigerator (2°C to 8°C [35°F to 46°F]) or at room temperature (up to 25°C [77°F]) (see 11 STORAGE, STABILITY AND DISPOSAL).
• The thawed suspension may contain white to off-white opaque amorphous particles.
• One multiple dose vial contains 6^† doses of 0.3 mL.
• Refer to thawing and dose preparation instructions in the panels below.

^† Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract a 6^th dose from a single vial.

COMIRNATY Omicron XBB.1.5 Do not dilute

Can be stored in the refrigerator (2°C to 8°C) for up to 10 weeks prior to use within the expiry date Gently × 10

Withdraw 0.3 mL dose of vaccine COMIRNATY Omicron XBB.1.5 For 12 Years of Age and Older: DO NOT DILUTE (Single Dose & Multiple Dose Vials with Gray Cap and Gray Label Border)
	Multiple Dose Vial Only: Store between 2°C to 25°C (35°F to 77°F). Discard any unused vaccine 12 hours after first puncture. Record the discard time on the vial label.

4.3.2 For Age 5 Years to <12 Years: DILUTE PRIOR TO USE (Multiple Dose Vials with Orange Cap and Orange Label Border)

Preparation for Administration

Prior to Dilution:

• The COMIRNATY Omicron XBB.1.5 multiple dose vial (for ages 5 years to <12 years) has an orange cap and an orange label border and contains a volume of 1.3 mL. It is supplied as a frozen suspension that does not contain preservative. Each vial must be thawed and diluted prior to administration.
• Multiple dose vials of COMIRNATY Omicron XBB.1.5 intended for individuals aged 5 years to <12 years cannot be used to prepare doses for individuals aged 6 months to <5 years or 12 years and older.
• Multiple dose vials may be thawed in the refrigerator at 2°C to 8°C [35°F to 46°F] or at room temperature (up to 25°C [77°F]) (see 11 STORAGE, STABILITY AND DISPOSAL).
• Prior to dilution, the thawed suspension may contain opaque amorphous particles.
• Refer to thawing instructions in the panels below.

Dilution:

• Dilute the multiple dose vial contents using 1.3 mL of sterile 0.9% Sodium Chloride Injection, USP to form COMIRNATY Omicron XBB.1.5. Do not add more than 1.3 mL of diluent.
• ONLY use 0.9% Sodium Chloride Injection, USP as the diluent. This diluent is not packaged with the vaccine and must be sourced separately. Do not use bacteriostatic 0.9% Sodium Chloride Injection or any other diluent.

Record the discard time on the vial label. Use within 12 hours after first puncture.

• After dilution, one multiple dose vial contains 10* doses of 0.2 mL.
• After dilution, the vaccine will be a white to off-white suspension. Inspect vials to confirm there are no particulates and no discolouration is observed.
• Strict adherence to aseptic techniques must be followed.
• Refer to dilution and dose preparation instructions in the panels below.

* Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract 10 doses from a single vial.

Can be stored in the refrigerator (2°C to 8°C) for up to 10 weeks prior to use within the expiry date. COMIRNATY Omicron XBB.1.5 10 doses after dilution

COMIRNATY Omicron XBB.1.5 For Age 5 Years to <12 Years: DILUTE PRIOR TO USE (Multiple Dose Vials with Orange Cap and Orange Label Border)
			Record the discard time on the vial label. Use within 12 hours after dilution.	Store between 2°C to 25°C (35°F to 77°F). Do not freeze or shake the diluted vaccine. If refrigerated, allow the diluted vaccine to come to room temperature prior to use. Discard any unused vaccine 12 hours after dilution. Record the discard time on the vial label.
PREPARATION OF INDIVIDUAL 0.2 mL DOSES
			Withdraw 0.2 mL dose of vaccine	Using aseptic technique, cleanse the vial stopper with a single-use antiseptic swab, and withdraw 0.2 mL of COMIRNATY Omicron XBB.1.5 (for age 5 years to <12 years) preferentially using a low dead-volume syringe and/or needle. Each dose must contain 0.2 mL of vaccine. If the amount of vaccine remaining in the vial cannot provide a full dose of 0.2 mL, discard the vial and any excess volume. Administer immediately, and no later than 12 hours after dilution. Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. In order to ensure consistent withdrawal of 10 doses of 0.2 mL, it is important to adhere to minimizing volume loss during dose extraction.

4.3.3 For Age 5 Years to <12 Years: DO NOT DILUTE (Single Dose or Multiple Dose Vials with Blue Cap and Blue Label Border)

The COMIRNATY Omicron XBB.1.5 single dose or multiple dose vial with a blue cap and blue label border MUST NOT BE DILUTED prior to administration. Instructions on the handling and dose preparation of the vaccine prior to administration are provided below.

Preparation for Administration

Single Dose Vials

DO NOT DILUTE

• The COMIRNATY Omicron XBB.1.5 single dose vial with a blue cap and a blue label border is supplied as a frozen suspension that does not contain preservative. Each vial must be thawed prior to administration. DO NOT DILUTE prior to use.
• Single dose vials of COMIRNATY Omicron XBB.1.5 intended for individuals aged 5 years to <12 years of age cannot be used to prepare doses for individuals aged 6 months to <5 years or 12 years and older.
• Single dose vials may be thawed in the refrigerator (2°C to 8°C [35°F to 46°F]) or at room temperature (up to 25°C [77°F]) (see 11 STORAGE, STABILITY AND DISPOSAL).
• The thawed suspension may contain white to off-white opaque amorphous particles.
• One single dose vial contains 1 dose of 0.3 mL.
• Refer to thawing and dose preparation instructions in the panels below.

Multiple Dose Vials

DO NOT DILUTE

• The COMIRNATY Omicron XBB.1.5 multiple dose vial with a blue cap and a blue label border contains a volume of 2.25 mL, and is supplied as a frozen suspension that does not contain preservative. Each vial must be thawed prior to administration. DO NOT DILUTE prior to use.
• Multiple dose vials of COMIRNATY Omicron XBB.1.5 intended for individuals aged 5 years to <12 years of age cannot be used to prepare doses for individuals aged 6 months to <5 years or 12 years and older.
• Multiple dose vials may be thawed in the refrigerator (2°C to 8°C [35°F to 46°F]) or at room temperature (up to 25°C [77°F]) (see 11 STORAGE, STABILITY AND DISPOSAL).
• The thawed suspension may contain white to off-white opaque amorphous particles.
• One multiple dose vial contains 6^† doses of 0.3 mL.
• Refer to thawing and dose preparation instructions in the panels below.

^† Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract a 6^th dose from a single vial.

Can be stored in the refrigerator (2°C to 8°C) for up to 10 weeks prior to use within the expiry date. COMIRNATY Omicron XBB.1.5 Do not dilute

Withdraw 0.3 mL dose of vaccine Gently × 10 COMIRNATY Omicron XBB.1.5 For Age 5 Years to <12 Years: DO NOT DILUTE (Single Dose & Multiple Dose Vials with Blue Cap and Blue Label Border)
			important to adhere to minimizing volume loss during dose extraction.
	Multiple Dose Vial Only: Store between 2°C to 25°C (35°F to 77°F). Discard any unused vaccine 12 hours after first puncture. Record the discard time on the vial label.

4.3.4 For Age 6 Months to <5 Years: DILUTE PRIOR TO USE (Multiple Dose Vials with Maroon Cap and Maroon Label Border)

Preparation for Administration

Prior to Dilution:

• The COMIRNATY Omicron XBB.1.5 multiple dose vial (for age 6 months to <5 years) has a maroon cap and a maroon label border and contains a volume of 0.4 mL. It is supplied as a frozen suspension that does not contain preservative. Each vial must be thawed and diluted prior to administration.
• Multiple dose vials of COMIRNATY Omicron XBB.1.5 intended for individuals aged 6 months to <5 years cannot be used to prepare doses for individuals aged 5 years and older.
• Multiple dose vials may be thawed in the refrigerator at 2°C to 8°C [35°F to 46°F] or at room temperature (up to 25°C [77°F]) (see 11 STORAGE, STABILITY AND DISPOSAL).
• Prior to dilution, the thawed suspension may contain opaque amorphous particles.
• Refer to thawing instructions in the panels below.

Dilution:

• Dilute the multiple dose vial contents using 2.2 mL of sterile 0.9% Sodium Chloride Injection, USP to form COMIRNATY Omicron XBB.1.5. Do not add more than 2.2 mL of diluent.
• ONLY use 0.9% Sodium Chloride Injection, USP as the diluent. This diluent is not packaged with the vaccine and must be sourced separately. Do not use bacteriostatic 0.9% Sodium Chloride Injection or any other diluent.

Record the discard time on the vial label. Use within 12 hours after first puncture.

• After dilution, one multiple dose vial contains 10* doses of 0.2 mL.
• After dilution, the vaccine will be a white to off-white suspension. Inspect vials to confirm there are no particulates and no discolouration is observed.
• Strict adherence to aseptic techniques must be followed.
• Refer to dilution and dose preparation instructions in the panels below.

* Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract 10 doses from a single vial.

COMIRNATY Omicron XBB.1.5 10 doses after dilution

Can be stored in the refrigerator (2°C to 8°C) for up to 10 weeks prior to use

Add 2.2 mL of sterile 0.9% Sodium Chloride Injection, USP

Gently × 10 COMIRNATY Omicron XBB.1.5 For Age 6 Months to <5 Years: DILUTE PRIOR TO USE (Multiple Dose Vials with Maroon Cap and Maroon Label Border)
PREPARATION OF INDIVIDUAL 0.2 mL DOSES
			Withdraw 0.2 mL dose of vaccine	Using aseptic technique, cleanse the vial stopper with a single-use antiseptic swab, and withdraw 0.2 mL of COMIRNATY Omicron XBB.1.5 (for age 6 months to <5 years) preferentially using a low dead-volume syringe and/or needle. Each dose must contain 0.2 mL of vaccine. If the amount of vaccine remaining in the vial cannot provide a full dose of 0.2 mL, discard the vial and any excess volume. Administer immediately, and no later than 12 hours after dilution. Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. In order to ensure consistent withdrawal of 10 doses of 0.2 mL, it is important to adhere to minimizing volume loss during dose extraction.

4.4 Administration

4.4.1 For 12 Years of Age and Older

DO NOT DILUTE (Single Dose or Multiple Dose Vials with Gray Cap and Gray Label Border)

Administer a single 0.3 mL dose of COMIRNATY Omicron XBB.1.5 intramuscularly, preferably in the deltoid muscle.

Do not inject the vaccine intravascularly, subcutaneously or intradermally.

Visually inspect each dose in the dosing syringe prior to administration. The vaccine will be an off-white suspension. During the visual inspection:

• Verify the final dosing volume of 0.3 mL.
• Confirm there are no particulates and that no discolouration is observed.
• Do not administer if vaccine is discoloured or contains particulate matter.

Single Dose Vials

Single dose vials of COMIRNATY Omicron XBB.1.5 with gray caps and gray label borders contain 1 dose of 0.3 mL of vaccine.

• Withdraw a single 0.3 mL dose of vaccine.
• Discard the vial and any excess volume.
• Do not pool excess vaccine from multiple vials.

Multiple Dose Vials

Multiple dose vials of COMIRNATY Omicron XBB.1.5 with gray caps and gray label borders contain 6 doses of 0.3 mL of vaccine.

Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. In order to ensure consistent withdrawal of 6 doses of 0.3 mL, it is important to adhere to minimizing volume loss during dose extraction. If standard syringes and needles are used, there may not be sufficient volume to extract a 6^th dose from a single vial. Irrespective of the type of syringe and needle:

• Each dose must contain 0.3 mL of vaccine.
• If the amount of vaccine remaining in the vial cannot provide a full dose of 0.3 mL, discard the vial and any excess volume.
• Do not pool excess vaccine from multiple vials.

4.4.2 For Age 5 Years to <12 Years

DILUTE PRIOR TO USE (Multiple Dose Vial with Orange Cap and Orange Label Border)

Administer a single 0.2 mL dose of COMIRNATY Omicron XBB.1.5 intramuscularly, preferably in the deltoid muscle.

Do not inject the vaccine intravascularly, subcutaneously or intradermally.

DO NOT administer COMIRNATY Omicron XBB.1.5 with gray cap and gray label border or maroon cap and maroon label border to children 5 years to <12 years.

Visually inspect each dose in the dosing syringe prior to administration. The diluted vaccine will be a white to off-white suspension. During the visual inspection:

• Verify the final dosing volume of 0.2 mL.
• Confirm there are no particulates and that no discolouration is observed.
• Do not administer if vaccine is discoloured or contains particulate matter.

After dilution, multiple dose vials of COMIRNATY Omicron XBB.1.5 (for age 5 years to <12 years) contain 10 doses of 0.2 mL of vaccine. Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. In order to ensure consistent withdrawal of 10 doses of 0.2 mL, it is important to adhere to minimizing volume loss during dose extraction. If standard syringes and needles are used, there may not be sufficient volume to extract 10 doses from a single vial. Irrespective of the type of syringe and needle:

• Each dose must contain 0.2 mL of vaccine.
• If the amount of vaccine remaining in the vial cannot provide a full dose of 0.2 mL, discard the vial and any excess volume.
• Do not pool excess vaccine from multiple vials.

DO NOT DILUTE (Single Dose or Multiple Dose Vials with Blue Cap and Blue Label Border)

Administer a single 0.3 mL dose of COMIRNATY Omicron XBB.1.5 intramuscularly, preferably in the deltoid muscle.

Do not inject the vaccine intravascularly, subcutaneously or intradermally.

Visually inspect each dose in the dosing syringe prior to administration. The vaccine will be an off-white suspension. During the visual inspection:

• Verify the final dosing volume of 0.3 mL.
• Confirm there are no particulates and that no discolouration is observed.
• Do not administer if vaccine is discoloured or contains particulate matter.

Single Dose Vials

Single dose vials of COMIRNATY Omicron XBB.1.5 with blue caps and blue label borders contain 1 dose of 0.3 mL of vaccine.

• Withdraw a single 0.3 mL dose of vaccine.
• Discard the vial and any excess volume.
• Do not pool excess vaccine from multiple vials.

Multiple Dose Vials

Multiple dose vials of COMIRNATY Omicron XBB.1.5 with blue caps and blue label borders contain 6 doses of 0.3 mL of vaccine.

Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. In order to ensure consistent withdrawal of 6 doses of 0.3 mL, it is important to adhere to minimizing volume loss during dose extraction. If standard syringes and needles are used, there may not be sufficient volume to extract a 6^th dose from a single vial. Irrespective of the type of syringe and needle:

• Each dose must contain 0.3 mL of vaccine.
• If the amount of vaccine remaining in the vial cannot provide a full dose of 0.3 mL, discard the vial and any excess volume.
• Do not pool excess vaccine from multiple vials.

4.4.3 For Age 6 Months to <5 Years

Administer a single 0.2 mL dose of COMIRNATY Omicron XBB.1.5 intramuscularly. In individuals from 6 to less than 12 months of age, the recommended injection site is the anterolateral aspect of the thigh. In individuals 1 year of age and older, the recommended injection site is the anterolateral aspect of the thigh or the deltoid muscle.

Do not inject the vaccine intravascularly, subcutaneously or intradermally.

DO NOT administer COMIRNATY Omicron XBB.1.5 with gray cap and gray label border, blue cap and blue label or orange cap and orange label border to infants and children 6 months to <5 years.

DILUTE PRIOR TO USE (Multiple Dose Vial with Maroon Cap and Maroon Label Border).

Visually inspect each dose in the dosing syringe prior to administration. The diluted vaccine will be a white to off-white suspension. During the visual inspection:

• Verify the final dosing volume of 0.2 mL.
• Confirm there are no particulates and that no discolouration is observed.
• Do not administer if vaccine is discoloured or contains particulate matter.

After dilution, multiple dose vials of COMIRNATY Omicron XBB.1.5 (for age 6 months to <5 years) contain 10 doses of 0.2 mL of vaccine. Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. In order to ensure consistent withdrawal of 10 doses of 0.2 mL, it is important to adhere to minimizing volume loss during dose extraction. If standard syringes and needles are used, there may not be sufficient volume to extract 10 doses from a single vial. Irrespective of the type of syringe and needle:

• Each dose must contain 0.2 mL of vaccine.
• If the amount of vaccine remaining in the vial cannot provide a full dose of 0.2 mL, discard the vial and any excess volume.
• Do not pool excess vaccine from multiple vials.

5 OVERDOSAGE

In the event of suspected overdose, monitoring of vital functions and symptomatic treatment is recommended. Contact your regional poison control centre.

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.

For 12 Years of Age and Older: DO NOT DILUTE (Single Dose or Multiple Dose Vials with Gray Cap and Gray Label Border)

COMIRNATY Omicron XBB.1.5 is supplied as a frozen suspension in single dose or multiple dose vials with gray caps and labels with gray borders. Do not dilute. Each single dose vial contains 1 dose of 0.3 mL and each multiple dose vial contains 6^† doses of 0.3 mL. Each 0.3 mL dose of COMIRNATY Omicron XBB.1.5 contains 30 mcg of a nucleoside modified messenger RNA (modRNA) encoding the viral spike (S) protein of SARS-CoV-2 Omicron variant lineage XBB.1.5 (Omicron XBB.1.5). Each dose also includes the non-medicinal ingredients listed in Table 1.

COMIRNATY Omicron XBB.1.5 does not contain preservative. The vial stoppers are not made with natural rubber latex.

COMIRNATY Omicron XBB.1.5 single dose or multiple dose vials (with gray cap and gray label border) are supplied in a carton containing 10 single dose or multiple dose vials.

^† Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract a 6^th dose from a single vial.

For Age 5 Years to <12 Years: DILUTE PRIOR TO USE (Vials with Orange Cap and Orange Label Border)

COMIRNATY Omicron XBB.1.5 is supplied as a frozen suspension in multiple dose vials with an orange cap and an orange label border. Each multiple dose vial must be diluted with 1.3 mL of sterile 0.9% Sodium Chloride Injection, USP prior to use to form the vaccine, and contains 10* doses of 0.2 mL after dilution. Each 0.2 mL dose of COMIRNATY Omicron XBB.1.5 contains 10 mcg of a nucleoside modified messenger RNA (modRNA) encoding the viral spike (S) protein of SARS-CoV-2 Omicron variant lineage XBB.1.5 (Omicron XBB.1.5) and the non-medicinal ingredients listed in Table 2. COMIRNATY Omicron XBB.1.5 does not contain preservative. The vial stoppers are not made with natural rubber latex.

COMIRNATY Omicron XBB.1.5 multiple dose vials (with orange cap and orange label border) are

^† Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract a 6^th dose from a single vial.

* Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract 10 doses from a single vial.

supplied in a carton containing 10 multiple dose vials.

For Age 5 Years to <12 Years: DO NOT DILUTE (Single Dose or Multiple Dose Vials with Blue Cap and Blue Label Border)

COMIRNATY Omicron XBB.1.5 is supplied as a frozen suspension in single dose or multiple dose vials with blue caps and labels with blue borders. Do not dilute. Each single dose vial contains 1 dose of 0.3 mL and each multiple dose vial contains 6^† doses of 0.3 mL. Each 0.3 mL dose of COMIRNATY Omicron XBB.1.5 contains 10 mcg of a nucleoside modified messenger RNA (modRNA) encoding the viral spike (S) protein of SARS-CoV-2 Omicron variant lineage XBB.1.5 (Omicron XBB.1.5). Each dose also includes the non-medicinal ingredients listed in Table 1.

COMIRNATY Omicron XBB.1.5 does not contain preservative. The vial stoppers are not made with natural rubber latex.

COMIRNATY Omicron XBB.1.5 single dose or multiple dose vials (with blue cap and blue label border) are supplied in a carton containing 10 single dose or multiple dose vials.

Table 2: Dosage Forms, Strengths, Composition and Packaging (DILUTE PRIOR TO USE: For Age 5 Years to <12 Years and For Age 6 Months to <5 Years)

^† Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract a 6^th dose from a single vial.

* Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract 10 doses from a single vial.

For Age 6 Months to <5 Years: DILUTE PRIOR TO USE (Vials with Maroon Cap and Maroon Label Border)

COMIRNATY Omicron XBB.1.5 is supplied as a frozen suspension in multiple dose vials with a maroon cap and a maroon label border. Each multiple dose vial must be diluted with 2.2 mL of sterile 0.9% Sodium Chloride Injection, USP prior to use to form the vaccine, and contains 10* doses of 0.2 mL after dilution. Each 0.2 mL dose of COMIRNATY Omicron XBB.1.5 contains 3 mcg of a nucleoside modified messenger RNA (modRNA) encoding the viral spike (S) protein of SARS-CoV-2 Omicron variant lineage XBB.1.5 (Omicron XBB.1.5) and the non-medicinal ingredients listed in Table 2. COMIRNATY Omicron XBB.1.5 does not contain preservative. The vial stoppers are not made with natural rubber latex.

COMIRNATY Omicron XBB.1.5 multiple dose vials (with maroon cap and maroon label border) are supplied in a carton containing 10 multiple dose vials.

7 WARNINGS AND PRECAUTIONS

General

The administration of COMIRNATY Omicron XBB.1.5 should be postponed in individuals suffering from acute severe febrile illness.

Fainting may occur in association with administration of injectable vaccines. Individuals should be advised to bring symptoms (e.g., dizziness, increases in heart rate, feeling short of breath, tingling sensations or sweating) to the attention of the vaccination provider for evaluation. Procedures should be in place to avoid injury from fainting.

As with any vaccine, vaccination with COMIRNATY Omicron XXB.1.5 may not protect all recipients.

Acute Allergic Reactions

Anaphylaxis has been reported. As with all vaccines, training for immunizers, appropriate medical treatment and supervision after immunization should always be readily available in case of a rare anaphylactic event following the administration of this vaccine.

Vaccine recipients should be kept under observation for at least 15 minutes after immunization; 30 minutes is a preferred interval when there is a specific concern about a possible vaccine reaction.

COMIRNATY Omicron XBB.1.5 should not be given to those who have experienced anaphylaxis after a prior dose of COMIRNATY, COMIRNATY Original/Omicron BA.1, or COMIRNATY Original & Omicron BA.4/BA.5.

* Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract 10 doses from a single vial.

Cardiovascular

Myocarditis and Pericarditis

Very rare cases of myocarditis and/or pericarditis following vaccination with COMIRNATY have been reported during post-authorization use. These cases occurred more commonly after the second dose and in adolescents and young adults. Typically, the onset of symptoms has been within a few days following receipt of COMIRNATY. Based on accumulating data, the reporting rates of myocarditis and pericarditis after COMIRNATY primary series in children ages 5 through <12 years are lower than in ages 12 through 17 years. Available short-term follow-up data suggest that the symptoms resolve in most individuals, but information on long-term sequelae is lacking. The decision to administer COMIRNATY Omicron XBB.1.5 to an individual with a history of myocarditis or pericarditis should take into account the individual’s clinical circumstances.

Healthcare professionals are advised to consider the possibility of myocarditis and/or pericarditis in their differential diagnosis if individuals present with chest pain, shortness of breath, palpitations or other signs and symptoms of myocarditis and/or pericarditis following immunization with a COVID-19 vaccine. This could allow for early diagnosis and treatment. Cardiology consultation for management and follow up should be considered.

Driving and Operating Machinery

COMIRNATY Omicron XBB.1.5 has no or negligible influence on the ability to drive and use machines. However, some of the effects mentioned under 8 ADVERSE REACTIONS may temporarily affect the ability to drive or use machines.

Fertility

It is unknown whether this vaccine 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).

Hematologic

Individuals receiving anticoagulant therapy or those with a bleeding disorder that would contraindicate intramuscular injection should not be given the vaccine unless the potential benefit clearly outweighs the risk of administration.

Immune

The efficacy and safety of the vaccine has not been assessed in immunocompromised individuals, including those receiving immunosuppressant therapy. Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished immune response to the vaccine.

7.1 Special Populations

7.1.1 Pregnant Women

No data are available yet regarding the use of COMIRNATY Omicron XBB.1.5 during pregnancy.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/ fetal development, parturition, or post-natal development (see 16 NON-CLINICAL TOXICOLOGY).

7.1.2 Breast-feeding

No data are available yet regarding the use of COMIRNATY Omicron XBB.1.5 during breast- feeding.

It is unknown whether COMIRNATY Omicron XBB.1.5 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 COMIRNATY Omicron XBB.1.5 in children under 6 months of age have not yet been established.

7.1.4 Geriatrics

Clinical studies of COMIRNATY and COMIRNATY Original & Omicron BA.4/BA.5 included participants 65 years of age and older and their data contributes to the overall assessment of the safety and efficacy of COMIRNATY Omicron XBB.1.5 (See 8 ADVERSE REACTIONS and 14 CLINICAL TRIALS). The safety and efficacy of COMIRNATY Omicron XBB.1.5 in geriatric individuals have not yet been established in clinical trials.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The safety of COMIRNATY Omicron XBB.1.5 is inferred from safety data of the prior COMIRNATY and COMIRNATY Original & Omicron BA.4/BA.5 vaccines.

Safety data accrued with the COMIRNATY and COMIRNATY Original & Omicron BA.4/BA.5 formulations are relevant to the COMIRNATY Omicron XBB.1.5 vaccine because these vaccines are manufactured using the same process.

8.1.1 COMIRNATY Original & Omicron BA.4/BA.5 (15 mcg/15 mcg)

Participants ≥12 Years of Age – After a Dose of COMIRNATY Original & Omicron BA.4/BA.5 as a Second Booster (4^th Dose)

Study C4591044 (Study 5) is an ongoing Phase 2/3 study to evaluate the safety, tolerability, and immunogenicity of new bivalent vaccines including COMIRNATY Original & Omicron BA.4/BA.5. In Cohorts 2 and 3 of the study 317 participants 12 years and older and 410 participants 18 years and older, respectively, received COMIRNATY Original & Omicron BA.4/BA.5 30 mcg (15/15 mcg) as a second booster dose following a previous primary series and one booster dose of COMIRNATY. The safety evaluation of participants in the study is ongoing. All participants were monitored for solicited local and systemic reactions and use of antipyretic medication after vaccination with an electronic diary during the 7 days following the dose of vaccination. Participants continue to be monitored for unsolicited adverse events (AEs), including serious adverse events (SAEs), throughout the study [from Dose 1 to 1 month after the last dose (all AEs) and 6 months (SAEs) after the last vaccination].

In a substudy from Study 5, 108 participants 12 to 17 years of age, 313 participants 18 to 55 years of age and 306 participants ≥56 years of age who had completed 3 doses of COMIRNATY, received a booster (fourth dose) of COMIRNATY Original & Omicron BA.4/BA.5 (15/15 mcg) 5.4 to 16.9 months after receiving Dose 3. Participants who received a booster (fourth dose) of COMIRNATY Original & Omicron BA.4/BA.5 had a median follow-up time of at least 1.5 months.

The overall safety profile for the COMIRNATY Original & Omicron BA.4/BA.5 booster (fourth dose) was similar to that seen after 3 doses of COMIRNATY. The most frequent adverse reactions in participants 12 years of age and older were injection site pain (>60%), fatigue (>50%), headache (>40%), muscle pain (>20%), chills (>10%), and joint pain (>10%).

8.1.2 COMIRNATY Original & Omicron BA.4/BA.5 (5 mcg/5 mcg)

Participants 5 to <12 Years of Age – After a Dose of COMIRNATY Original & Omicron BA.4/BA.5 as a Second Booster (4^th Dose)

Study C4591048 (Study 6) is an ongoing study to evaluate the safety, tolerability, and immunogenicity of new bivalent vaccines including COMIRNATY Original & Omicron BA.4/BA.5.

In a subset from Study 6 (Phase 3), 113 participants 5 to <12 years of age who had completed 3 doses of COMIRNATY, received a booster (fourth dose) of COMIRNATY Original & Omicron BA.4/BA.5 (5/5 mcg) 2.6 to 8.5 months after receiving Dose 3. Participants who received a booster (fourth dose) of COMIRNATY Original & Omicron BA.4/BA.5 had a median follow-up time of at least 1.6 months.

The overall safety profile for the COMIRNATY Original & Omicron BA.4/BA.5 booster (fourth dose) was similar to that seen after 3 doses of COMIRNATY. The most frequent adverse reactions in participants 5 to <12 years were injection site pain (>60%), fatigue (>40%), headache (>20%), and muscle pain (>10%).

8.1.3 COMIRNATY Original & Omicron BA.4/BA.5 (1.5 mcg/1.5 mcg)

Study C4591048 (Study 6) is an ongoing study evaluating the safety, tolerability and immunogenicity of COMIRNATY Original & Omicron BA.4/BA.5. The safety of a 3-dose primary series of COMIRNATY Original & Omicron BA.4/BA.5 at 1.5 mcg/1.5 mcg in children 6 months to < 5 years of age is inferred primarily from the safety profile of COMIRNATY at 3 mcg administered as a 3-dose primary series in this age bracket. Safety data from study 6 in children 6 months to <5 years of age using the COMIRNATY Original & Omicron BA.4/BA.5 formulation at 1.5 mcg/1.5 mcg administered as a booster (fourth) dose are considered supportive.

Participants 2 Years Through <5 Years of Age – After a Dose of COMIRNATY Original & Omicron BA.4/BA.5 as a Booster (4^th Dose)

In a subset from Study 6 (Phase 3), 124 participants 2 through <5 years of age who had completed 3 doses of COMIRNATY, received a booster of COMIRNATY Original & Omicron BA.4/BA.5 (1.5/1.5 mcg) 2.2 to 8.6 months after receiving Dose 3. Participants who received a booster of COMIRNATY Original & Omicron BA.4/BA.5 had a median follow-up time of at least 1.8 months up to a data cut-off date of 30 Nov 2022.

The overall safety profile for the COMIRNATY Original & Omicron BA.4/BA.5 booster was similar to that seen after 3 doses of COMIRNATY. The most frequent adverse reactions in participants 2 through <5 years of age were injection site pain (>30%) and fatigue (>20%).

Participants 6 months Through <2 Years of Age – After a Dose of COMIRNATY Original & Omicron BA.4/BA.5 as a Booster (4^th Dose)

In a subset from Study 6 (Phase 3), 39 participants 6 months to <2 years of age who had completed 3 doses of COMIRNATY, received a booster of COMIRNATY Original & Omicron BA.4/BA.5 (1.5/1.5 mcg)

2.1 to 8.6 months after receiving Dose 3. Participants who received a booster of COMIRNATY Original & Omicron BA.4/BA.5 had a median follow-up time of at least 1.7 months up to data cut-off of 30 Nov 2022.

The overall safety profile for the COMIRNATY Original & Omicron BA.4/BA.5 booster was similar to that seen after 3 doses of COMIRNATY. The most frequent adverse reactions in participants 6 months to <2 years of age were irritability (>20%) and decreased appetite (>10%).

8.1.4 COMIRNATY (30 mcg)

Study BNT162-01 (Study 1) was a Phase 1/2, two-part dose-escalation trial that enrolled 60 participants 18 through 55 years of age and 36 participants 56 through 85 years of age.

Study C4591001 (Study 2) is a Phase 1/2/3, multicenter, multinational, randomized, saline placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection (Phase 1) and efficacy (Phase 2/3) study that has enrolled approximately 46,000 participants, 12 years of age or older. Of these, approximately 44,047 participants (22,026 COMIRNATY; 22,021 placebo) in Phase 2/3 are 16 years of age or older (including 378 and 376 adolescents 16 and 17 years of age in the vaccine and placebo groups, respectively) and 2,260 adolescents are 12 to 15 years of age (1,131 and 1,129 in the vaccine and placebo groups, respectively). Of the total number of COMIRNATY recipients in the study, 20.7% were 65 years of age and older. Study 2 also included 200 participants with confirmed stable human immunodeficiency virus (HIV) infection. HIV-positive participants are included in safety population disposition but are summarized separately in safety analyses.

Additionally, 306 existing Phase 3 participants 18 through 55 years of age received a booster dose of COMIRNATY approximately 6 months (range of 4.8 to 8.0 months) after completing the second dose in the non-placebo-controlled booster dose portion of Study 2. The overall safety profile for the booster dose was similar to that seen after 2 doses.

In Study C4591031 (Study 4), a placebo-controlled booster study, 5,081 participants 16 years of age and older were recruited from Study 2 to receive a booster dose of COMIRNATY at least 6 months after the second dose. The overall safety profile for the booster dose was similar to that seen after 2 doses.

The safety evaluation of participants in Study 2 and Study 4 is ongoing. In Study 2, all participants 12 to 15 years of age and 16 years of age and older in the reactogenicity subset, and a subset of 306 participants 18 through 55 years of age who received a booster dose in Study 2, were monitored for solicited local and systemic reactions and use of antipyretic medication after each vaccination with an electronic diary during the 7 days following any dose of vaccination. Participants, including those who received a booster in Study 4, continue to be monitored for unsolicited adverse events (AEs), including serious adverse events (SAEs), throughout the study [from Dose 1 to 1 month after the last dose (all AEs) and 6 months (SAEs) after the last vaccination].

Participants 12 Years of Age and Older

At the time of the analysis of Study 2 (data accrued through March 13, 2021), a total of 25,651 (58.2%) participants (13,031 in vaccine group and 12,620 in placebo group) 16 years of age and older had been followed up for at least 4 months, with 3,082 (7.0%) participants (1,778 in vaccine group and 1,304 in placebo group) followed up for at least 6 months after the second dose during the blinded placebo-controlled follow-up period. A total of 12,006 (54.5%) participants originally randomized to the vaccine group in Study 2 had been followed up for at least 6 months after the second dose including the blinded and open-label periods.

In an analysis of Study 2, based on data up to the cut-off date of March 13, 2021, a total of 2,260 adolescents (1,131 COMIRNATY; 1,129 placebo) were 12 to 15 years of age. Of these,1,559 (786 COMIRNATY and 773 placebo) adolescents have been followed for ≥4 months after the second dose of COMIRNATY.

In clinical studies with a data cut-off of March 13, 2021, and where 2 doses were administered 3 weeks apart, the most common adverse reactions in the reactogenicity subset (n=4,924) of participants 16 years of age and older after any dose included injection site pain (84.3%), fatigue (64.7%), headache (57.1%), muscle pain (40.2%), chills (34.7%), joint pain (25.0%), fever (15.2%), injection site swelling (11.1%), and injection site redness (9.9%). Additional AEs reported in the safety population (n=21,926) of participants 16 years of age and older from dose 1 to 1 month after dose 2 included nausea (1.2%), malaise (0.6%), lymphadenopathy (0.4%), asthenia (0.3%), decreased appetite (0.2%), hyperhidrosis (0.1%), lethargy (0.1%), and night sweats (0.1%). Adverse reactions were usually mild or moderate in intensity and resolved within a few days after vaccination.

The safety profile in 545 participants receiving COMIRNATY that were seropositive for SARS-CoV-2 at baseline was similar to that seen in the general population.

In a clinical study with a data cut-off date of 02 September 2021, the most commonly reported (≥8%) adverse reactions in adolescents 12 through 15 years of age following any dose were pain at the injection site (90.5%), fatigue (77.5%), headache (75.5%), chills (49.2%), muscle pain (42.2%), fever (24.3%), joint pain (20.2%), injection site swelling (9.2%), and injection site redness (8.6%).

In a clinical study of participants 18 through 55 years of age (N=306), 289 participants (94%) completed the e-diary recording adverse reactions. The most commonly reported adverse reactions (≥10%) following administration of a booster dose were pain at the injection site (83.0%), fatigue (63.7%), headache (48.4%), muscle pain (39.1%), chills (29.1%), and joint pain (25.3%).

In a clinical study of approximately 10,000 participants 16 years of age and older, unsolicited adverse reactions following administration of a booster dose included headache (5%), fever (4.8%), lymphadenopathy (2.8%), pain in extremity (1.1%), nausea (0.9%), malaise (0.7%), and decreased appetite (0.2%).

8.1.5 COMIRNATY (10 mcg)

Study C4591007 (Study 3) is a Phase 1/2/3 study comprised of an open-label vaccine dose-finding portion (Phase 1) and a multicenter, multinational, randomized, saline placebo-controlled, observer-blind immunogenicity and efficacy portion (Phase 2/3) that has enrolled approximately 4,600 participants 5 years through <12 years of age. Of these, approximately 3,100 participants received COMIRNATY 10 mcg and approximately 1,500 participants received placebo in the Phase 2/3 part of the study. Study 3 also enrolled 1,776 participants 6 months through <2 years of age (1,178 COMIRNATY 3 mcg; 598 placebo), and 2,750 participants 2 through <5 years of age (1,835 COMIRNATY 3 mcg; 915 placebo) in Phase 2/3.

In a subset of Study 3 Phase 2/3 participants, 401 participants 5 years through <12 years of age received a booster dose of COMIRNATY at least 5 months (range 5 to 9 months) after completing the primary series. The overall safety profile for the booster dose was similar to that seen after the primary series. The analysis of the Study 3 Phase 2/3 subset is based on data up to the cut-off date of March 22, 2022 (median follow-up time of 1.3 months).

Participants 5 Years Through <12 Years of Age

In an analysis of Study 3 Phase 2/3, based on data up to the cut-off date of October 8, 2021, 2,268 participants (initial enrolment group: 1,518 COMIRNATY 10 mcg and 750 placebo) were 5 years through <12 years of age. Of these, 2,171 (95.7%) (1,456 COMIRNATY 10 mcg and 715 placebo) participants have been followed for at least 3 months after Dose 2. An analysis of Study 3 Phase 2/3 adverse event data also included another 2,379 participants (safety expansion group: 1,591 COMIRNATY 10 mcg and 788 placebo), of whom 71.2% had a follow-up period for at least 2 weeks after Dose 2. The safety evaluation in Study 3 is ongoing.

Adverse reactions following administration of any dose in the initial enrolment safety population (n = 1,518) of children 5 years through <12 years of age included pain at the injection site (84.3%), fatigue (51.7%), headache (38.2%), injection site redness (26.4%), injection site swelling (20.4%), muscle pain (17.5%), chills (12.4%), fever (8.3%), joint pain (7.6%), lymphadenopathy (0.9%), rash (0.5%), nausea (0.4%), malaise (0.1%), and decreased appetite (0.1%).

The most frequent adverse reactions in participants 5 years through <12 years of age following the booster dose (data cut-off date of March 22, 2022; median follow-up time of 1.3 months) were injection site pain (73.9%), fatigue (45.6%), headache (34.0%), myalgia (18.3%), chills (10.5%), injection site redness (15.6%), and swelling (16.4%). The most frequently reported unsolicited adverse event was lymphadenopathy (2.5%).

8.1.6 COMIRNATY (3 mcg)

Participants 2 Through <5 Years of Age

Study 3 (Phase 2/3) enrolled 2,750 participants 2 through <5 years of age (1,835 COMIRNATY 3 mcg; 915 placebo). Of these, 2,726 participants (1,819 COMIRNATY 3 mcg; 907 placebo) received 2 doses and 1,369 (50.2%; 910 COMIRNATY 3 mcg and 459 placebo) participants have been followed for at least 4 months after the second dose; 886 participants received a 3-dose primary series (606 COMIRNATY 3 mcg; 280 placebo) and have been followed for a median of 1.4 months after the third dose, based on data in the blinded, placebo-controlled follow-up period up to the cut-off date of April 29, 2022. Adverse reactions following administration of any dose included pain at the injection site (47.0%), fatigue (44.8%), injection site redness (18.9%), fever (10.5%), headache (8.7%), injection site swelling (8.4%), chills (5.7%), muscle pain (5.0%), joint pain (2.4%), and lymphadenopathy (0.1%).

Participants 6 Months Through <2 Years of Age

Study 3 (Phase 2/3) also enrolled 1,776 participants 6 months through <2 years of age (1,178 COMIRNATY 3 mcg; 598 placebo). Of these, 1,762 participants (1,166 COMIRNATY 3 mcg; 596 placebo) received 2 doses and 1,207 (68.5%; 801 COMIRNATY 3 mcg and 406 placebo) participants have been followed for at least 4 months after the second dose; 570 participants received a 3-dose primary series (386 COMIRNATY 3 mcg; 184 placebo) and have been followed for a median of 1.3 months after the third dose, based on data in the blinded, placebo-controlled follow-up period up to the cut-off date of April 29, 2022. Adverse reactions following administration of any dose included irritability (68.4%), decreased appetite (38.6%), tenderness at the injection site (26.4%), injection site redness (17.8%), fever (14.4%), injection site swelling (7.3%), and lymphadenopathy (0.2%).

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 drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

8.2.1 COMIRNATY Original & Omicron BA.4/BA.5 (15 mcg/15 mcg)

Participants 12 Years of Age and Older

Solicited Local Adverse Reactions

Table 3 presents the frequency of reported solicited local reactions within 7 days of a second booster dose with COMIRNATY Original & Omicron BA.4/BA.5.

Most local reactions were mild or moderate in severity and no Grade 4 local reactions were reported in any group. The median onset for all local reactions was 1 to 3 days, and all events resolved within a median duration of 1 to 3 days after onset.

a. N = number of participants reporting at least 1 yes or no response for the specified reaction after the study vaccination.

b. n = Number of participants with the specified characteristic.

c. Mild: >2.0 to 5.0 cm; moderate: >5.0 to 10.0 cm; severe: >10.0 cm; Grade 4: necrosis (redness and swelling categories) or exfoliative dermatitis (redness category only).

d. Mild: does not interfere with activity; moderate: interferes with activity; severe: prevents daily activity; Grade 4: emergency room visit or hospitalization for severe pain at the injection site.

e. N=301

f. Any local reaction: any redness >2.0 cm, any swelling >2.0 cm, or any pain at the injection site.

Solicited Systemic Adverse Reactions

Table 4 presents the frequency of reported systemic reactions within 7 days of a second booster dose of COMIRNATY Original & Omicron BA.4/BA.5. Most systemic reactions were mild or moderate in severity and no Grade 4 systemic reactions were reported in any group. The median onset for all systemic reactions was 2 to 4 days, and all events resolved within a median duration of 1 to 2 days after onset.

a. N = number of participants reporting at least 1 yes or no response for the specified event after the study vaccination.

b. n = Number of participants with the specified characteristic.

c. Mild: does not interfere with activity; moderate: some interference with activity; severe: prevents daily activity; Grade 4: emergency room visit or hospitalization for severe fatigue, severe headache, severe chills, severe muscle pain, or severe joint pain.

d. N=301

e. Mild: 1 to 2 times in 24 hours; moderate: >2 times in 24 hours; severe: requires intravenous hydration; Grade 4: emergency room visit or hospitalization for severe vomiting.

f. Mild: 2 to 3 loose stools in 24 hours; moderate: 4 to 5 loose stools in 24 hours; severe: 6 or more loose stools in 24 hours; Grade 4: emergency room visit or hospitalization for severe diarrhea.

g. Any systemic event: any fever, any fatigue, any vomiting, any chills, any diarrhea, any headache, any new or worsened muscle pain, or any new or worsened joint pain.

h. Severity was not collected for use of antipyretic or pain medication.

Unsolicited Adverse Events

Among participants 12 years of age and older, unsolicited adverse events were reported by 48 (6.6%) participants who received a second booster dose through 1 month after the booster dose. Lymphadenopathy occurred in 7 (1.0%) participants.

8.2.2 COMIRNATY Original & Omicron BA.4/BA.5 (5 mcg/5 mcg)

Participants 5 to <12 Years of Age

Solicited Local Adverse Reactions

Table 5 presents the frequency of reported solicited local reactions within 7 days of a second booster dose with COMIRNATY Original & Omicron BA.4/BA.5.

All local reactions were mild or moderate in severity. The median onset for all local reactions was 1 to 2 days, and all events resolved within a median duration of 2 days after onset.

a. N = number of participants reporting at least 1 yes or no response for the specified reaction after the study vaccination.

b. n = Number of participants with the specified characteristic.

c. Mild: ≥0.5 to 2.0 cm; moderate: >2.0 to 7.0 cm; severe: >7.0 cm; Grade 4: necrosis (redness and swelling categories) or exfoliative dermatitis (redness category only).

d. Mild: does not interfere with activity; moderate: interferes with activity; severe: prevents daily activity; Grade 4: emergency room visit or hospitalization for severe pain at the injection site.

e. Any local reaction: any redness ≥0.5 cm, any swelling ≥0.5 cm, or any pain at the injection site.

Solicited Systemic Adverse Reactions

Table 6 presents the frequency of reported solicited systemic reactions within 7 days of a second booster dose with COMIRNATY Original & Omicron BA.4/BA.5.

Most systemic events were mild or moderate in severity, and no Grade 4 systemic events were reported. The median onset for all systemic events was 2 to 4 days, and all events resolved within a median duration of 1 to 2 days after onset.

a. N = number of participants reporting at least 1 yes or no response for the specified event after the study vaccination.

b. n = Number of participants with the specified characteristic.

c. Mild: does not interfere with activity; moderate: some interference with activity; severe: prevents daily activity; Grade 4: emergency room visit or

hospitalization for severe fatigue, severe headache, severe chills, severe muscle pain, or severe joint pain.

d. Mild: 1 to 2 times in 24 hours; moderate: >2 times in 24 hours; severe: requires intravenous hydration; Grade 4: emergency room visit or hospitalization

for severe vomiting.

e. Mild: 2 to 3 loose stools in 24 hours; moderate: 4 to 5 loose stools in 24 hours; severe: 6 or more loose stools in 24 hours; Grade 4: emergency room visit

or hospitalization for severe diarrhea.

f. Any systemic event: any fever ≥38.0℃, any fatigue, any vomiting, any chills, any diarrhea, any headache, any new or worsened muscle pain, or any new

or worsened joint pain.

g. Severity was not collected for use of antipyretic or pain medication.

Unsolicited Adverse Events

Among participants 5 to <12 years of age, unsolicited adverse events were reported by 4 (3.5%) participants who received a second booster dose through 1 month after the booster dose. Lymphadenopathy occurred in 1 (0.9%) participant.

8.2.3 COMIRNATY Original & Omicron BA.4/BA.5 (1.5 mcg/1.5 mcg)

Participants 2 Through <5 Years of Age – After a Dose of COMIRNATY Original & Omicron BA.4/BA.5 as a Booster (4^th Dose)

Solicited Local Adverse Reactions

Table 7 presents the frequency of solicited local reactions within 7 days of a booster (fourth) dose with COMIRNATY Original & Omicron BA.4/BA.5. Most local reactions were mild or moderate in severity. No severe or Grade 4 local reactions were reported. The onset for all local reactions was 1 to 2 days, and all events resolved within 1 to 3 days after onset.

a. N = number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose.

b. n = Number of participants with the specified characteristic.

c. Mild: ≥0.5 to 2.0 cm; moderate: >2.0 to 7.0 cm; severe: >7.0 cm; Grade 4: necrosis (redness and swelling categories) or exfoliative dermatitis (redness category only).

d. Mild: does not interfere with activity; moderate: interferes with activity; severe: prevents daily activity; Grade 4: emergency room visit or hospitalization for severe pain at the injection site.

e. Any local reaction: any redness ≥0.5 cm, any swelling ≥0.5 cm, or any pain at the injection site.

Solicited Systemic Adverse Reactions

Table 8 presents the frequency of solicited systemic reactions within 7 days of a booster (fourth) dose with COMIRNATY Original & Omicron BA.4/BA.5. Most systemic reactions were mild or moderate in severity. No severe or Grade 4 systemic reactions were reported. The median onset for most systemic reactions was 1 to 6 days, and most events resolved within a median duration of 1 to 2 days after onset.

a. N = number of participants reporting at least 1 yes or no response for the specified event after the study vaccination.

b. n = Number of participants with the specified characteristic.

c. N = 124

d. Mild: does not interfere with activity; moderate: some interference with activity; severe: prevents daily activity; Grade 4: emergency room visit or hospitalization for severe fatigue, severe headache, severe chills, severe new or worsened muscle pain, or severe new or worsened joint pain.

e. Mild: 1 to 2 times in 24 hours; moderate: >2 times in 24 hours; severe: requires intravenous hydration; Grade 4: emergency room visit or hospitalization for hypotensive shock.

f. Mild: 2 to 3 loose stools in 24 hours; moderate: 4 to 5 loose stools in 24 hours; severe: 6 or more loose stools in 24 hours; Grade 4: emergency room visit or hospitalization for severe diarrhea.

g. Any systemic event: any fever ≥38.0℃, any fatigue, any vomiting, any chills, any diarrhea, any headache, any new or worsened muscle pain, or any new or worsened joint pain.

h. Severity was not collected for use of antipyretic or pain medication.

Participants 6 Months Through <2 Years of Age

Solicited Local Adverse Reactions

Table 9 presents the frequency of solicited local reactions within 7 days of a booster (fourth) dose with COMIRNATY Original & Omicron BA.4/BA.5. All local reactions were mild in severity. No moderate, severe or Grade 4 local reactions were reported. The onset for all local reactions was 1 day, and all events resolved within 1 day after onset.

a. N = number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose.

b. n = Number of participants with the specified characteristic.

c. Mild: ≥0.5 to 2.0 cm; moderate: >2.0 to 7.0 cm; severe: >7.0 cm; Grade 4: necrosis (redness and swelling categories) or exfoliative dermatitis (redness category only).

d. Mild: hurts if gently touched; moderate: hurts if gently touched with crying; severe: causes limitation of limb movement; Grade 4: emergency room visit or hospitalization for severe pain (tenderness) at the injection site.

e. N = 38

f. Any local reaction: any redness ≥0.5 cm, any swelling ≥0.5 cm, or any pain at the injection site.

Solicited Systemic Adverse Reactions

Table 10 presents the frequency of solicited systemic reactions within 7 days of a booster (fourth) dose with COMIRNATY Original & Omicron BA.4/BA.5. Most systemic reactions were mild or moderate in severity. No severe or Grade 4 systemic reactions were reported. The median onset for all systemic reactions was 2 to 6 days, and most events resolved within a median duration of 1 to 3 days after onset.

a. N = number of participants reporting at least 1 yes or no response for the specified event after the study vaccination.

b. n = Number of participants with the specified characteristic.

c. Mild: decreased interest in eating; Moderate: decreased oral intake; Severe: refusal to feed; Grade 4: emergency room visit or hospitalization for severe decreased appetite (loss of appetite). d. N=37

e. Mild: increased or prolonged sleeping bouts; Moderate: slightly subdued interfering with daily activity; Severe: disabling; not interested in usual daily activity; Grade 4: emergency room visit or hospitalization for severe drowsiness (increased sleep).

f. Mild: easily consolable; moderate: requiring increased attention; severe: inconsolable; crying cannot be comforted; Grade 4: emergency room visit or hospitalization for severe irritability (fussiness).

g. Any systemic event: any fever ≥38.0℃, any decreased appetite, any drowsiness, or any irritability.

h. Severity was not collected for use of antipyretic or pain medication.

Unsolicited Adverse Events

The safety population included 39 participants ≥6 months to <2 years of age and 124 participants ≥2 years to <5 years of age who received a fourth dose of COMIRNATY Original & Omicron BA.4/BA.5 at 3 mcg. Overall, median (min, max) follow-up time after study vaccination was 1.8 (1.3, 2.5) months.

Overall, AEs were reported by 6 (15.4%) and 6 (4.8%) participants in the ≥6 months to <2 years of age group and ≥2 to <5 years of age group, respectively. No severe AEs, life-threatening AEs, SAEs, or AEs leading to withdrawal or death were reported from study vaccination to 1 month after study vaccination.

From study vaccination through 1-month postvaccination, no AEs of lymphadenopathy, rash, anaphylaxis/hypersensitivity, appendicitis, Bell’s palsy, and myo/pericarditis were reported.

8.2.4 COMIRNATY (30 mcg)

Participants 16 Years of Age and Older – Primary Series (Two Doses)

Solicited Adverse Reactions

Tables 11 through 14 present the frequency and severity of solicited local and systemic reactions, respectively, within 7 days following each dose of COMIRNATY and placebo in the subset of participants 16 years of age and older (n=9,839) in the safety population who were monitored for reactogenicity with an electronic diary.

*Randomized participants in the safety analysis population who received at least 1 dose of the study intervention.

a. N = Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. No Grade 4 solicited local reactions were reported in participants 16-55 years of age.

b. n = Number of participants with the specified reaction.

c. Any local reaction: any redness >2.0 cm, any swelling >2.0 cm, or any pain at the injection site.

d. Severe: >10.0 cm.

e. Severe: prevents daily activity.

*Randomized participants in the safety analysis population who received at least 1 dose of the study intervention.

a. N =Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. No Grade 4 solicited systemic reactions were reported in participants 16-55 years of age.

b. n = Number of participants with the specified reaction.

c. Any systemic reaction: any fever ≥38.0°C, any fatigue, any vomiting, any chills, any diarrhea, any headache, any new or worsened muscle pain, or any new or worsened joint pain.

d. Severe: prevents daily activity.

e. Severe: requires intravenous hydration.

f. Severe: 6 or more loose stools in 24 hours.

*Randomized participants in the safety analysis population who received at least 1 dose of the study intervention.

a. N = Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. No Grade 4 solicited local reactions were reported in participants 56 years of age and older.

b. n = Number of participants with the specified reaction.

c. Any local reaction: any redness >2.0 cm, any swelling >2.0 cm, or any pain at the injection site.

d. Severe: >10.0 cm.

e. Severe: prevents daily activity.

*Randomized participants in the safety analysis population who received at least 1 dose of the study intervention.

a. N = Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. The only Grade 4 solicited systemic reaction reported in participants 56 years of age and older was fatigue.

b. n = Number of participants with the specified reaction.

c. Any systemic reaction: any fever ≥38.0°C, any fatigue, any vomiting, any chills, any diarrhea, any headache, any new or worsened muscle pain, or any new or worsened joint pain.

d. Severe: prevents daily activity.

e. Severe: requires intravenous hydration.

f. Severe: 6 or more loose stools in 24 hours.

g. Grade 4: emergency room visit or hospitalization.

Study 2 also included 200 participants with confirmed stable human immunodeficiency virus

(HIV) infection. The safety profile of the participants with stable HIV infection receiving COMIRNATY (n = 100) was similar to that seen in the general population.

Unsolicited Adverse Events

The participants were unblinded to offer placebo participants COMIRNATY when they became locally eligible under regulatory approval in December 2020. A total of 25,651 (58.2%) participants (13,031 in vaccine group and 12,620 in placebo group) 16 years of age and older had been followed up for at least 4 months, with 3,082 (7.0%) participants (1,778 in vaccine group and 1,304 in placebo group) followed up for at least 6 months after the second dose during the blinded placebo-controlled follow-up period in Study 2. Adverse events detailed below for participants 16 years of age and older are for the placebo-controlled blinded follow-up period up to the participants’ unblinding dates.

Among participants 16 through 55 years of age who received at least one dose of study vaccine, 12,995 of whom received COMIRNATY and 13,026 of whom received placebo, unsolicited adverse events were reported by 4,396 (33.8%) participants in the COMIRNATY group and 2,136 (16.4%) participants in the placebo group. In a similar analysis in participants 56 years of age and older that included 8,931 COMIRNATY recipients and 8,895 placebo recipients, unsolicited adverse events were reported by 2,551 (28.6%) participants in the COMIRNATY group and 1,432 (16.1%) participants in the placebo group. Among participants with confirmed stable HIV infection that included 100 COMIRNATY recipients and 100 placebo recipients, unsolicited adverse events were reported by 29 (29%) participants in the COMIRNATY group and 15 (15%) participants in the placebo group.

Lymphadenopathy was reported in 87 (0.4%) participants in the vaccine group compared to 8 (<0.1%) participants in the placebo group. Bell’s palsy (facial paralysis and facial paresis) was reported by four participants in the vaccine group and two in the placebo group. In the four vaccinated participants, events began from 3 to 48 days after their last dose, were mild to moderate in severity, and duration ranged from 3 to 68 days. Currently available information is insufficient to determine a causal relationship with the vaccine. There were no other notable patterns or numerical imbalances between treatment groups for specific categories of non-serious adverse events (including other neurologic or neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to COMIRNATY. Cumulative safety follow-up to at least 6 months after Dose 2 for approximately 12,000 participants who received COMIRNATY showed no other safety signals arising from longer-term follow-up of the study.

Serious Adverse Events

In Study 2, among participants 16 through 55 years of age who had received at least 1 dose of vaccine or placebo (COMIRNATY = 12,995; placebo = 13,026), serious adverse events from Dose 1 up to the participant unblinding date in ongoing follow-up were reported by 103 (0.8%) COMIRNATY recipients and 117 (0.9%) placebo recipients. In a similar analysis, in participants 56 years of age and older (COMIRNATY = 8,931; placebo = 8,895), serious adverse events were reported by 165 (1.8%) COMIRNATY recipients and 151 (1.7%) placebo recipients who received at least 1 dose of COMIRNATY or placebo, respectively. Among participants with confirmed stable HIV infection serious adverse events from Dose 1 up to the participant unblinding date in ongoing follow-up were reported by 2 (2%) COMIRNATY recipients and 2 (2%) placebo recipients.

Pericarditis was reported for one participant in the vaccine group, and no case was reported in the placebo group. Appendicitis was reported as a serious adverse event for 27 participants, 15 vaccine participants and 12 placebo participants. Currently available information is insufficient to determine a causal relationship with the vaccine. There were no other notable patterns or numerical imbalances between treatment groups for specific categories of serious adverse events (including neurologic, neuro-inflammatory, thrombotic events, myocarditis or anaphylactic reaction to the vaccine) reported during the blinded placebo-controlled follow-up period of the study.

Participants 16 Years of Age and Older – After Booster Dose

A subset from Study C4591001 (Study 2) Phase 2/3 participants, of 306 adults 18 through 55 years of age who completed the original COMIRNATY 2-dose series, received a booster dose of COMIRNATY approximately 6 months (range of 4.8 to 8.0 months) after receiving Dose 2.

In Study C4591031 (Study 4), a placebo-controlled booster study, participants 16 years of age and older recruited from Study C4591001 (Study 2) received a booster dose of COMIRNATY (5,081 participants), or placebo (5,044 participants) at least 6 months after the second dose of COMIRNATY. Overall, participants who received a booster dose, had a median follow-up time of 2.5 months after the booster dose to the cut-off date (5 October 2021). Among the participants, the median age was 53.0 years

(range 16 through 87 years of age), including 1,175 booster dose recipients (23.1%) who were ≥65 years of age, 49.1% were male and 50.9% were female, 79.0% were White, 14.9% were Hispanic/Latino, 9.2% were Black or African American, 5.5% were Asian, and 1.7% were American Indian/Alaska Native.

Solicited Local and Systemic Adverse Reactions

Overall, among participants who received a booster dose in a subset from Study C4591001 (Study 2), the median age was 42 years (range 19 through 55 years of age), 45.8% were male and 54.2% were female, 81.4% were White, 27.8% were Hispanic/Latino, 9.2% were Black or African American, 5.2% were Asian, and 0.7% were American Indian/Alaska Native.

In participants who received a booster dose the mean duration of pain at the injection site after the booster dose was 2.6 days (range 1 to 8 days), for redness 2.2 days (range 1 to 15 days), and for swelling 2.2 days (range 1 to 8 days).

Unsolicited Adverse Events

Overall, participants who received a booster dose in Study C4591031 (Study 4), had a median follow-up time of 2.5 months after the booster dose to the cut-off date (October 5, 2021).

In an analysis of all unsolicited adverse events reported following the booster dose of COMIRNATY, through 1 month after the booster dose, in participants 16 through 87 years of age (N = 5,055), adverse reactions included headache (5%), fever (4.8%), lymphadenopathy (2.8%), decreased appetite (0.2%), malaise (0.7%), nausea (0.9%), and pain in extremity (1.1%).

Serious Adverse Events

Of the participants who received a booster dose of COMIRNATY or placebo (COMIRNATY = 5,055; placebo = 5,020) to the cut-off date (October 5, 2021), serious adverse events were reported by 0.3% of COMIRNATY recipients and 0.5% by placebo recipients. There were no notable patterns or numerical imbalances between treatment groups for specific categories of serious adverse events that would suggest a causal relationship to COMIRNATY. A 17-year-old male in Study 2 was diagnosed with myocarditis three days after receiving the booster dose (Dose 3). The participant was treated and recovered.

Adolescents 12 to 15 Years of Age – Primary Series (Two Doses)

Solicited Adverse Reactions

Table 17 and Table 18 present the frequency and severity of solicited local and systemic reactions, respectively, within 7 days following each dose of COMIRNATY and placebo in adolescents 12 to 15 years of age included in the safety population who were monitored for reactogenicity with an electronic diary.

Unsolicited Adverse Events

In the analysis of Study 2 of all unsolicited adverse events reported following any dose, through 1 month after Dose 2, in adolescents 12 to 15 years of age (N=2260; 1,131 COMIRNATY group vs. 1,129 placebo group), those assessed as adverse reactions not already captured by solicited local and systemic reactions were lymphadenopathy (9 (0.8%) vs. 2 (0.2%)), and nausea (5 (0.4%) vs. 1 (0.1%)).

In analyses of all unsolicited adverse events in Study 2 from Dose 1 up to the participant unblinding date, 69.0% of study participants 12 through 15 years of age had at least 4 months of follow-up after Dose 2. Among participants 12 through 15 years of age who received at least one dose of study vaccine, 1,131 of whom received COMIRNATY and 1,129 of whom received placebo, unsolicited adverse events were reported by 95 (8.4%) participants in the COMIRNATY group and 113 (10.0%) participants in the placebo group.

Non-serious adverse events from Dose 1 through up to 30 days after Dose 2 in ongoing follow-up were reported by 5.8% of COMIRNATY recipients and by 5.8% of placebo recipients. From Dose 1 through 30 days after Dose 2, reports of lymphadenopathy plausibly related to the study intervention were imbalanced, with notably more cases in the COMIRNATY group (7) vs. the placebo group (1). In the analysis of blinded, placebo-controlled follow-up, there were no other notable patterns or numerical imbalances between treatment groups for specific categories of non-serious adverse events (including other neurologic or neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to COMIRNATY. In the analysis of unblinded follow-up, there were no notable patterns of specific categories of non-serious adverse events that would suggest a causal relationship to COMIRNATY.

Serious Adverse Events

In Study 2, among participants 12 through 15 years of age who had received at least 1 dose of vaccine or placebo (COMIRNATY = 1,131; placebo = 1,129), serious adverse events from Dose 1 up to the participant unblinding date in ongoing follow-up were reported by 10 (0.9%) COMIRNATY recipients and 2 (0.2%) placebo recipients. In these analyses, 69.0% (786 COMIRNATY and 773 placebo) of study participants had at least 4 months of follow-up after Dose 2. In the analysis of blinded, placebo-controlled follow-up, there were no notable patterns between treatment groups for specific categories of serious adverse events (including neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to COMIRNATY. In the analysis of unblinded follow-up, there were no notable patterns of specific categories of serious adverse events that would suggest a causal relationship to COMIRNATY. In study 2, a 16-year-old male was diagnosed with myopericarditis 3 days after his 2nd dose. The participant was treated and recovered.

8.2.5 COMIRNATY (10 mcg)

Children 5 Years Through <12 Years of Age – Primary Series (Two Doses)

Solicited Adverse Reactions

Table 19 and Table 20 present the frequency and severity of solicited local and systemic reactions, respectively, within 7 days following each dose of COMIRNATY and placebo in children 5 years through <12 years of age included in the initial enrolment safety population who were monitored for reactogenicity with an electronic diary.

Table 19: Study 3 – Frequency of Solicited Local Reactions Within 7 Days After Each Dose – Children 5 Years Through <12 Years of Age – Safety Population*

Table 20: Study 3 – Frequency of Solicited Systemic Reactions Within 7 Days After Each Dose – Children 5 Years Through <12 Years of Age – Safety Population*

Unsolicited Adverse Events

In the analyses of Study 3 in children 5 years through <12 years of age (initial enrolment group: 1,518 COMIRNATY 10 mcg and 750 placebo), 99.5% of participants had at least 30 days and 95.7% of participants had at least 3 months follow-up after Dose 2.

Serious adverse events from Dose 1 through up to 30 days after Dose 2 in ongoing follow-up in the initial enrolment group were reported by 1 participant (0.1%) in each group after receiving the vaccine or placebo through the data cut-off date. No serious adverse events were reported that were considered related to vaccination.

Non-serious adverse events from Dose 1 through up to 30 days after Dose 2 in ongoing follow-up in the initial enrolment group were reported by 10.9% of COMIRNATY 10 mcg recipients and by 9.1% of placebo recipients. Lymphadenopathy was reported in 13 (0.9%) participants in the COMIRNATY 10 mcg group vs. 1 (0.1%) in the placebo group. All cases were considered to be mild, with a median onset of 3 days after Dose 1, and 2 days after Dose 2 in the vaccine group. The median duration was 3.5 days (ranged from 1 to 14 days) in the vaccine group. Skin and subcutaneous tissue disorders (including skin rash, dermatitis, eczema and urticaria) were reported in 17 (1.1%) participants in the vaccine group and 5 (0.7%) participants in the placebo group. Most of the events began from 3-11 days after the second dose and were characterized as mild and self-limited. There were no other notable patterns between treatment groups for specific categories of non-serious adverse events that would suggest a causal relationship to COMIRNATY. There were no reports of myocarditis/pericarditis or anaphylaxis by the study cut-off date.

Children 5 Years Through ˂12 Years of Age – After Booster Dose

A subset of Phase 2/3 participants 5 years through ˂12 years of age received a booster dose of COMIRNATY at least 5 months after completing the primary series (range 5 to 9 months, 86.8% of participants received the booster dose at least 8 months after Dose 2). Those participants vaccinated prior to February 22, 2022 provided the safety database (n=401), and had a median safety follow-up of 1.3 months from vaccination through the data cut-off date of March 22, 2022.

The median age of these 401 participants was 8.0 years (range 5 years through ˂12 years of age), 52.4% were male and 47.6% were female, 70.1% were White, 7.2% were Black or African American, 22.9% were Hispanic/Latino, 7.7% were Asian, and 2.0% were American Indian/Alaska Native.

Solicited Local and Systemic Adverse Reactions

Table 21 and Table 22 present the frequency and severity of reported solicited local and systemic reactions, respectively, within 7 days of a booster dose of COMIRNATY for Phase 2/3 participants 5 years through ˂12 years of age.

In participants who received a booster dose, the mean duration of pain at the injection site after the booster dose was 2.4 days (range 1 to 35 days), for redness 2.3 days (range 1 to 12 days), and for swelling 2.3 days (range 1 to 9 days).

Table 21: Study 3 – Frequency and Percentages of Participants With Solicited Local Reactions, By Maximum Severity, Within 7 Days After the Booster Dose of COMIRNATY– Children 5 Years through ˂12 Years of Age – Safety Population*

Unsolicited Adverse Events

Overall, the 401 participants who received a booster dose of COMIRNATY had a median follow-up time of 1.3 months after the booster dose through the cut-off date.

In an analysis of all unsolicited adverse events reported in participants 5 years through ˂12 years of age (N = 401) through up to 1 month after the booster dose, lymphadenopathy (n = 10, 2.5%) was an adverse reaction not already captured by solicited local and systemic reactions.

Serious Adverse Events

No serious adverse events were reported after the booster dose of COMIRNATY through the cut-off date.

8.2.6 COMIRNATY (3 mcg)

Children 2 Through <5 Years of Age – Primary Series (Three Doses)

Solicited Adverse Reactions

Table 23 and Table 24 present the frequency of solicited local and systemic reactions, respectively, within 7 days following each dose of COMIRNATY and placebo in children 2 through <5 years of age who were monitored for reactogenicity with an electronic diary.

Unsolicited Adverse Events

In the analyses of Study 3 in participants 2 through <5 years of age (606 COMIRNATY; 280 placebo), 76.6% of participants had at least 30 days of follow-up after Dose 3.

Serious adverse events from Dose 1 through 1 month after Dose 3, with an overall median of 1.4 months follow-up after Dose 3, were reported by 0.7% of COMIRNATY recipients and by 0.9% of placebo recipients. One serious adverse event of fever (maximum temperature 40.3°C) on Day 3 after Dose 2 in a 4-year-old was considered possibly related to vaccination.

Non-serious adverse events from Dose 1 through up to 30 days after Dose 3, in ongoing follow-up were reported by 18.5% of COMIRNATY recipients and by 18.5% of placebo recipients.

From Dose 1 through 30 days after Dose 3, lymphadenopathy was reported in 1 (0.1%) of COMIRNATY recipients vs. 0 (0.0%) of placebo recipients. There were no other notable patterns between treatment groups for specific categories of non-serious adverse events that would suggest a causal relationship to COMIRNATY.

Children 6 Months Through <2 Years of Age – Primary Series (Three Doses)

Solicited Adverse Reactions

Table 25 and Table 26 present the frequency of solicited local and systemic reactions, respectively, within 7 days following each dose of COMIRNATY and placebo in children 6 months through <2 years of age who were monitored for reactogenicity with an electronic diary.

Unsolicited Adverse Events

In the analyses of Study 3 in participants 6 months through 2 years of age (386 COMIRNATY; 184 placebo), 83.7% of participants had at least 30 days of follow-up after Dose 3.

Serious adverse events from Dose 1 through 1 month after Dose 3, with an overall median of 1.3 months follow-up after Dose 3, were reported by 1.4% of COMIRNATY recipients and by 2.3% of placebo recipients. No serious adverse events were reported that were considered related to vaccination.

Non-serious adverse events from Dose 1 through up to 1 month after Dose 3, in ongoing follow-up were reported by 29.1% of COMIRNATY recipients and by 26.3% of placebo recipients.

From Dose 1 through 30 days after Dose 3, lymphadenopathy was reported in 2 (0.2%) of COMIRNATY recipients vs. 0 (0%) of placebo recipients. There were no other notable patterns between treatment groups for specific categories of non-serious adverse events that would suggest a causal relationship to COMIRNATY.

8.5 Post-Market Adverse Reactions

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

Cardiac disorders: myocarditis and/or pericarditis (see 7 WARNING AND PRECAUTIONS)

Immune system disorders: severe allergic reactions, including anaphylaxis

Musculoskeletal and connective tissue disorders: pain in extremity (arm)

Nervous system disorders: Facial paralysis / Bell’s Palsy, hypoesthesia, paresthesia, dizziness

Skin and subcutaneous tissue disorders and other hypersensitivity reactions: skin rash, pruritus, urticaria, angioedema, erythema multiforme

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. They are included because: a) they represent reactions that are known to occur following immunizations generally; b) they are potentially serious; or c) on the basis of their frequency of reporting.

9 DRUG INTERACTIONS

No interaction studies have been performed. There is no information on the co-administration of COMIRNATY Omicron XBB.1.5 with other vaccines.

Do not mix COMIRNATY Omicron XBB.1.5 with other vaccines/products in the same syringe.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

The nucleoside-modified messenger RNA in raxtozinameran encodes for the viral spike (S) protein of SARS-CoV-2 Omicron variant lineage XBB.1.5. The mRNA is formulated in lipid nanoparticles, which enable delivery of the RNA into host cells to allow expression of the SARS-CoV-2 S antigen. The vaccine elicits both neutralizing antibody and cellular immune responses to the spike (S) antigen, which may contribute to protection against COVID-19 disease.

11 STORAGE, STABILITY AND DISPOSAL

During storage, minimize exposure to room light, and avoid exposure to direct sunlight and ultraviolet light.

Do not refreeze thawed vials.

For 12 Years and Older: DO NOT DILUTE (Single Dose or Multiple Dose Vials with Gray Cap and Gray Label Border)

And

For Age 5 Years to <12 Years: DO NOT DILUTE (Single Dose or Multiple Dose Vials with Blue Cap and Blue Label Border)

Single Dose or Multiple Dose Vial Storage Prior to Use

Cartons of COMIRNATY Omicron XBB.1.5 single dose or multiple dose vials (for 12 years and older: DO NOT DILUTE) and single dose or multiple dose vials (for 5 years to <12 years): DO NOT DILUTE) may arrive frozen at ultra-cold conditions in thermal containers with dry ice.

Once received, frozen single dose or multiple dose vials may be immediately transferred to the refrigerator [2°C to 8°C (35°F to 46°F)], thawed and stored for a single period of up to 10 weeks within the 18-month shelf-life. The 10-week refrigerated expiry date should be recorded on the carton at the time of transfer.

A carton of 10 single dose vials may take up to 2 hours to thaw at this temperature.

A carton of 10 multiple dose vials may take up to 6 hours to thaw at this temperature.

Alternatively, frozen single dose or multiple dose vials may be stored in an ultra-low temperature freezer at -90°C to -60°C (-130°F to -76°F) within the expiry date printed on the single dose or multiple dose vials and cartons. Do not store single dose or multiple dose vials at -25°C to -15°C (-13°F to 5°F). Once single dose or multiple dose vials are thawed they should not be refrozen.

Cartons of COMIRNATY Omicron XBB.1.5 single dose or multiple dose vials (for 12 years and older: DO NOT DILUTE) and single dose or multiple dose vials (for 5 years to <12 years): DO NOT DILUTE) may also arrive at 2°C to 8°C (35°F to 46°F). If received at 2°C to 8°C, they should be stored at 2°C to 8°C. Check that the carton has been updated to reflect the 10-week refrigerated expiry date.

Regardless of storage condition, vaccine should be used within the expiry date printed on the single dose or multiple dose vials and cartons.

Single Dose or Multiple Dose Vial Storage During Use

If not previously thawed at 2°C to 8°C (35°F to 46°F), allow single dose or multiple dose vials to thaw at room temperature [up to 25°C (77°F)] for 30 minutes.

COMIRNATY Omicron XBB.1.5 single dose or multiple dose vials (for 12 years and older: DO NOT DILUTE) and single dose or multiple dose vials (for 5 years to <12 years): DO NOT DILUTE) may be stored at room temperature up to 25°C (77°F) for a total of 12 hours prior to the first puncture.

DO NOT DILUTE PRIOR TO USE.

After first puncture, the single dose or multiple dose vial should be stored at 2°C to 25°C (35°F to 77°F). Vials should be discarded 12 hours after first puncture.

Thawed single dose or multiple dose vials can be handled in room light conditions.

Transportation of Single Dose or Multiple Dose Vials

If local redistribution is needed, full cartons containing unpunctured single dose or multiple dose vials may be transported at -90°C to -60°C (-130°F to -76°F); full cartons or individual unpunctured single dose or multiple dose vials may also be transported at 2°C to 8°C (35°F to 46°F).

For Age 5 Years to <12 Years: DILUTE PRIOR TO USE (Multiple Dose Vials with Orange Cap and Orange Label Border)

And

For Age 6 Months to <5 Years: DILUTE PRIOR TO USE (Multiple Dose Vials with Maroon Cap and Maroon Label Border)

Multiple Dose Vial Storage Prior to Use

Cartons of COMIRNATY Omicron XBB.1.5 multiple dose vials (for age 5 years to <12 years) and COMIRNATY Omicron XBB.1.5 multiple dose vials (for age 6 months to <5 years) may arrive frozen at ultra-cold conditions in thermal containers with dry ice.

Once received, frozen multiple dose vials may be immediately transferred to the refrigerator [2°C to 8°C (35°F to 46°F)], thawed and stored for a single period of up to 10 weeks within the 18-month shelf-life. The 10-week refrigerated expiry date should be recorded on the carton at the time of transfer.

• COMIRNATY Omicron XBB.1.5 (for age 5 years to <12 years): A carton of 10 multiple dose vials may take up to 4 hours to thaw at this temperature.
• COMIRNATY Omicron XBB.1.5 (for age 6 months to <5 years): A carton of 10 multiple dose vials may take up to 2 hours to thaw at this temperature.

Alternatively, frozen multiple dose vials may be stored in an ultra-low temperature freezer at -90°C to -60°C (-130°F to -76°F) within the expiry date printed on the single dose or multiple dose vials and cartons. Do not store multiple dose vials at -25°C to -15°C (-13°F to 5°F). Once multiple dose vials are thawed they should not be refrozen.

Cartons of COMIRNATY Omicron XBB.1.5 (for age 5 years to <12 years) and COMIRNATY Omicron XBB.1.5 (for age 6 months to <5 years) may also arrive at 2°C to 8°C (35°F to 46°F). If multiple dose vials are received at 2°C to 8°C, they should be stored at 2°C to 8°C. Check that the carton has been updated to reflect the 10-week refrigerated expiry date.

Regardless of storage condition, vaccines should be used within the expiry date printed on the vial and cartons.

Multiple Dose Vial Storage During Use

If not previously thawed at 2°C to 8°C (35°F to 46°F), allow multiple dose vials to thaw at room temperature [up to 25°C (77°F)] for 30 minutes.

Multiple dose vials of COMIRNATY Omicron XBB.1.5 (for age 5 years to <12 years) and COMIRNATY Omicron XBB.1.5 (for age 6 months to <5 years) may be stored at temperatures up to 25°C (77°F) for a total of 12 hours prior to dilution.

After dilution the multiple dose vials should be stored at 2°C to 25°C (35°F to 77°F). Vials should be discarded 12 hours after dilution (i.e., the first puncture).

Thawed vials can be handled in room light conditions.

Transportation of Multiple Dose Vials

If local redistribution is needed, full cartons containing undiluted multiple dose vials may be transported at -90°C to -60°C (-130°F to -76°F); full cartons or individual undiluted multiple dose vials may also be transported at 2°C to 8°C (35°F to 46°F).

12 SPECIAL HANDLING INSTRUCTIONS

COMIRNATY Omicron XBB.1.5 single dose and multiple dose vials contain a frozen suspension that does not contain preservative and must be thawed and may require dilution prior to administration.

Careful attention should be paid to the vial cap colour and label border and information on the label, and the appropriate corresponding instructions must be followed. For important information on handling and preparation for administration, please refer to 11 STORAGE, STABILITY AND DISPOSAL and 4 DOSAGE AND ADMINISTRATION.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance:

Proper name: COVID-19 Vaccine, mRNA

International nonproprietary name: Raxtozinameran (Omicron XBB.1.5 strain)

Product Characteristics:

COMIRNATY Omicron XBB.1.5 (COVID-19 mRNA Vaccine, Monovalent (Omicron XBB.1.5)) contains highly purified single-stranded, 5’-capped messenger RNA (mRNA) produced using a cell-free in vitro transcription from the corresponding DNA template encoding the viral spike (S) protein of the SARS-CoV-2 Omicron variant lineage XBB.1.5 (Omicron XBB.1.5).

This vaccine is a white to off-white frozen suspension.

For 12 Years and Older: DO NOT DILUTE (Single Dose Vials with Gray Cap and Gray Label Border)

One single dose vial contains 1 dose of 0.3 mL. Do not dilute prior to use. One dose (0.3 mL) contains 30 micrograms of COVID-19 mRNA (30 mcg Omicron XBB.1.5), embedded in lipid nanoparticles.

For 12 Years and Older: DO NOT DILUTE (Multiple Dose vials with Gray Cap and Gray Label Border)

One multiple dose vial (2.25 mL) contains 6^† doses of 0.3 mL. Do not dilute prior to use. One dose (0.3 mL) contains 30 micrograms of COVID-19 mRNA (30 mcg Omicron XBB.1.5), embedded in lipid nanoparticles.

For Age 5 Years to <12 Years: DILUTE PRIOR TO USE (Multiple Dose Vials with Orange Cap and Orange Label Border)

One multiple dose vial (1.3 mL) contains 10* doses of 0.2 mL after dilution. One dose (0.2 mL) contains 10 micrograms of COVID-19 mRNA Vaccine (10 mcg Omicron XBB.1.5), embedded in lipid nanoparticles.

For Age 5 Years to <12 Years: DO NOT DILUTE (Single Dose Vials with Blue Cap and Blue Label Border)

One single dose vial contains 1 dose of 0.3 mL. Do not dilute prior to use. One dose (0.3 mL) contains 10 micrograms of COVID-19 mRNA (10 mcg Omicron XBB.1.5), embedded in lipid nanoparticles.

For Age 5 Years to <12 Years: DO NOT DILUTE (Multiple Dose Vials with Blue Cap and Blue Label Border)

One multiple dose vial (2.25 mL) contains 6† doses of 0.3 mL. Do not dilute prior to use. One dose (0.3 mL) contains 10 micrograms of COVID-19 mRNA (10 mcg Omicron XBB.1.5), embedded in lipid nanoparticles.

For Age 6 Months to <5 Years: DILUTE PRIOR TO USE (Multiple Dose Vials with Maroon Cap and Maroon Label Border)

One multiple dose vial (0.4 mL) contains 10* doses of 0.2 mL after dilution. One dose (0.2 mL) contains 3 micrograms of COVID-19 mRNA Vaccine (3 mcg Omicron XXB.1.5), embedded in lipid nanoparticles.

^† Low dead volume syringes and/or needles can be used to extract 6 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract a 6^th dose from a single vial.

* Low dead-volume syringes and/or needles can be used to extract 10 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract 10 doses from a single vial.

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

The safety and effectiveness of COMIRNATY Omicron XBB.1.5 for individuals 6 months of age and older are inferred from studies which evaluated the primary series and booster vaccination with COMIRNATY and supported by studies which evaluated a booster dose of COMIRNATY Original & Omicron BA.4/BA.5 in individuals 6 months of age and older.

14.1.1 COMIRNATY Original & Omicron BA.4/BA.5 (15/15mcg)

Relative vaccine immunogenicity in participants greater than 12 years of age – after a second booster dose of COMIRNATY bivalent vaccine

Study C4591044 (Study 5) is an ongoing Phase 2/3 study to evaluate the safety, tolerability, and immunogenicity of new bivalent vaccines including COMIRNATY Original & Omicron BA.4/BA.5. A subset of 107 Study 5 Phase 2/3 participants 12 through 17 years of age, 313 participants 18 through 55 years of age and 306 participants 56 years of age and older previously vaccinated with a 2-dose primary series and 1 booster dose of COMIRNATY (original vaccine), went on to receive a second booster dose with COMIRNATY Original & Omicron BA.4/BA.5 (15/15 mcg, bivalent vaccine). Participants received a second booster dose 11.1 months (median time; range 5.4 to 16.9 months) after receiving the first booster dose and had a median follow up time of 1.5 months up to a data cut-off date of 31 October 2022. The median age was 48.0 years, 42.7% were male, 57.3% were female, 80.6% were White, 11.4% were Hispanic/Latino, 5.9% were Asian, and 11.4% were Black or African American.

14.1.2 COMIRNATY Original & Omicron BA.4/BA.5 (1.5/1.5 mcg)

Relative vaccine Immunogenicity in children 6 months through ˂5 years of age – after the booster (fourth dose)

Study C4591048 (Study 6) is a Phase 1/2/3 master study investigating the safety, tolerability, and immunogenicity of COMIRNATY Original & Omicron BA.4/BA.5 bivalent vaccine. In Study 6, a subset of 60 participants 6 months through <5 years of age received a booster dose (fourth dose) of COMIRNATY Original & Omicron BA.4/BA.5 (1.5 mcg/1.5 mcg) after receiving 3 prior doses of COMIRNATY (3 mcg), with their last dose 60 to 240 days prior to enrollment. The evaluable immunogenicity population (with or without evidence of infection up to 1month post-Dose 4) included 58 participants ≥6 months through <5 years of age (23 were ≥6 months through <2 years of age and 35 were 2 through <5 years of age). A total of 50.0% of participants were male. Most participants were White (58.6%), with 5.2% Black or African American participants, 15.5% Asian participants, and 20.7% multiracial participants. There were 25.9% Hispanic/Latino participants. Median age at the fourth dose was 19.0 months for the ≥6 months through <2 years of age group and 2.0 years for the 2 through <5 years of age group. Overall, 8.6% of participants reported comorbidities. A total of 27.6% of participants had evidence of prior SARS-CoV-2 infection at the time of Dose 4 (“baseline positive”).

14.1.3 COMIRNATY (30 mcg)

The safety and efficacy of COMIRNATY were evaluated in Study 2, a multicenter, multinational, Phase 1/2/3, randomized, placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection and efficacy study in participants 12 years of age and older. Randomization was stratified by age: 12 through 15 years of age, 16 through 55 years of age, or 56 years of age and older, with a minimum of 40% of participants in the ≥56 year stratum. The study excluded participants who were

immunocompromised and those who had previous clinical or microbiological diagnosis of COVID-19. Participants with pre-existing stable disease, defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 6 weeks before enrollment, were included as were participants with known stable infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV).

In the Phase 2/3 portion of Study 2, based on data accrued through November 14, 2020, approximately 44,000 participants 12 years of age and older were randomized equally and received 2 doses of COMIRNATY or placebo. The efficacy analyses included participants that received their second vaccination within 19 to 42 days after their first vaccination. The majority (93.1%) of vaccine recipients received the second dose 19 days to 23 days after Dose 1. Participants are planned to be followed for up to 24 months, for assessments of safety and efficacy against COVID-19.

The population for the analysis of the primary efficacy endpoint included 36,621 participants 12 years of age and older (18,242 in the COMIRNATY group and 18,379 in the placebo group) who did not have evidence of prior infection with SARS-CoV-2 through 7 days after the second dose. Table 27 presents the specific demographic characteristics in the studied population.

To assess boostability, a subset of Study 2 participants were enrolled in selected sites, and 306 participants aged 18 to 55 years were re-randomized to receive a booster dose approximately 6 months after completion of the two-dose regimen (median interval between dose 2 and booster dose – 6.8 months; range 4.8 to 8.0 months). The median age at the time of booster vaccination was 42.0 years, and 46.3% of participants were male.

In Study 4, a placebo-controlled booster study, 5,081 participants 16 years of age and older were recruited from Study 2 to receive a booster dose of COMIRNATY at least 6 months after the second dose. The median age at the time of booster vaccination was 53 years, and 49% of the participants were male.

14.1.4 COMIRNATY (10 mcg)

Participants 5 Through <12 Years of Age

Study 3 is a Phase 1/2/3 study comprised of an open-label vaccine dose finding portion (Phase 1) and a multicentre, multinational, randomized, saline placebo-controlled, observer-blind immunogenicity and efficacy portion (Phase 2/3) that has enrolled participants 6 months to <12 years of age.

Participants 5 Through <12 Years of Age: Demographic characteristics in Study 3 were generally similar with regard to age, gender, race, and ethnicity among participants 5 years through <12 years of age who received COMIRNATY 10 mcg and those who received placebo. Among the 1,518 participants (initial enrolment group) 5 years through <12 years of age who received at least 1 dose of COMIRNATY 10 mcg, 52.6% were male and 47.4% were female, 79.3% were White, 5.9% were Black or African American, 21.0% were Hispanic/Latino, 5.9% were Asian, and 0.8% were American Indian/Alaska Native.

A descriptive efficacy analysis of Study 3 has been performed in 1,968 children 5 years through ˂12 years of age without evidence of infection prior to 7 days after Dose 2. This analysis evaluated confirmed symptomatic COVID-19 cases accrued up to a data cut-off date of October 8, 2021.

Table 28 presents the specific demographic characteristics in participants who did not have evidence of prior infection with SARS-CoV-2 through 7 days after the second dose.

Table 28: Demographics Characteristics – Participants Without Evidence of Infection Prior to 7 Days After Dose 2 – Phase 2/3 – 5 Years Through ˂12 Years of Age – Evaluable Efficacy Population (Data Accrued Through October 8, 2021)

14.2 Study Results

14.2.1 COMIRNATY Original & Omicron BA.4/BA.5 (15/15mcg)

14.2.1.1 Immunogenicity in Participants 12 Years of Age and Older – After Second Booster Dose (Fourth Dose)

In an analysis of a subset from Study 5, 105 participants 12 to 17 years of age, 297 participants 18 to 55 years of age, and 286 participants 56 years of age and older who had previously received a 2-dose primary series and 1 booster dose with COMIRNATY (original vaccine) received a second booster (fourth) dose of COMIRNATY Original & Omicron BA.4/BA.5 (15/15 mcg, bivalent vaccine). In participants 12 to 17 years of age, 18 to 55 years of age, and 56 years of age and older, 75.2%, 71.7% and 61.5% were positive for SARS-CoV-2 at baseline, respectively.

Analyses of 50% neutralizing antibody titers (NT50) against Omicron BA.4/BA.5 and against reference strain among participants 56 years of age and older who received a second booster dose of COMIRNATY Original & Omicron BA.4/5 in Study 5 compared to a subset of participants from Study 4 who received a second booster dose of COMIRNATY demonstrated superiority of COMIRNATY Original & Omicron BA.4/BA.5 to COMIRNATY based on geometric mean ratio (GMR) and noninferiority based on difference in seroresponse rates with respect to anti-Omicron BA.4/BA.5 response, and noninferiority of anti-reference strain immune response based on GMR (Table 29 and Table 30).

Analyses of NT50 against Omicron BA.4/BA.5 among participants 18 through 55 years of age compared to participants 56 years of age and older who received a second booster dose of COMIRNATY Original & Omicron BA.4/BA.5 in Study 5 demonstrated noninferiority of anti-Omicron BA.4/BA.5 response among participants 18 through 55 years of age compared to participants 56 years of age and older for both GMR and difference in seroresponse rates (Table 29 and Table 30).

The study also assessed the level of NT50 of the anti-Omicron BA.4/BA.5 SARS-COV-2 strains pre-vaccination and 1 month after vaccination in participants who received a second booster dose (Table 31).

14.2.2 COMIRNATY Original & Omicron BA.4/BA.5 (1.5/1.5 mcg)

14.2.2.1 Immunogenicity in Participants 6 Months Through <5 Years of Age – After Booster (Fourth Dose)

In Study 6, a subset of 60 participants 6 months through <5 years of age received a booster (fourth dose) of COMIRNATY Original & Omicron BA.4/BA.5 (1.5/1.5 mcg) after receiving 3 prior doses of COMIRNATY 3 mcg. Neutralizing antibody levels following the fourth dose are presented in Table 32. Data from a subset of participants 6 months through <5 years of age in Study 3 who received 3 doses of COMIRNATY 3 mcg are included as a reference.

At 1 month after a booster dose (fourth dose), COMIRNATY Original & Omicron BA.4/BA.5 (1.5/1.5 mcg) elicited higher Omicron BA.4/BA.5 specific neutralizing titers (regardless of baseline SARS-CoV-2 status) compared with the titers in the comparator group who received 3 doses of COMIRNATY 3 mcg. COMIRNATY Original & Omicron BA.4/BA.5 (1.5/1.5 mcg) also elicited similar reference strain-specific titers compared with the titers in the comparator group.

14.2.3 COMIRNATY (30 mcg)

14.2.3.1 Efficacy and Immunogenicity in Participants 16 Years of Age and Older

14.2.3.1.1 Efficacy in Participants 16 Years of Age and Older – After Two Doses

Primary Vaccine Efficacy Analysis (Based on Cut-off Date of November 14, 2020)

At the time of the primary efficacy analysis, participants had been followed for symptomatic COVID-19 for at least 2,214 person-years in the COMIRNATY group and at least 2,222 person-years in the placebo group.

There were no meaningful clinical differences in overall vaccine efficacy in participants who were at risk of severe COVID-19 including those with 1 or more comorbidities that increase the risk of severe COVID-19 [e.g., asthma, body mass index (BMI) ≥30 kg/m², chronic pulmonary disease, diabetes mellitus, hypertension]. The primary endpoint was defined as any symptomatic COVID-19 case¹ confirmed by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). The population for the analysis of the primary efficacy endpoint included participants who did not have evidence of prior infection with SARS-CoV-2 through 7 days after the second dose (first primary efficacy endpoint), as well as participants with and without evidence of prior infections with SARS-CoV-2 through 7 days after the second dose (second primary efficacy endpoint). The pre-specified success criterion for vaccine efficacy was met. The vaccine efficacy information is presented in Table 33.

¹ Case definition defined by Study 2 protocol: (at least 1 of) fever, new or increased cough, new or increased shortness of breath, chills, new or increased muscle pain, new loss of taste or smell, sore throat, diarrhea or vomiting.

Updated Vaccine Efficacy (Based on Cut-off Date of March 13, 2021)

Updated efficacy analyses were performed with additional confirmed COVID-19 cases accrued during blinded placebo-controlled follow-up through March 13, 2021, representing up to 6 months of follow-up after Dose 2 for participants in the efficacy population. There were 77 confirmed COVID-19 cases identified in the COMIRNATY and 850 in the placebo groups, respectively. In this analysis, compared to placebo, the vaccine efficacy of COMIRNATY in participants without evidence of SARS-CoV-2 infection prior to 7 days after Dose 2 was 91.3% (95% confidence interval of 89.0% to 93.2%); in participants 65 years of age and older without evidence of prior infection vaccine efficacy was 94.5% (two-sided 95% confidence interval 88.3% to 97.8%). The vaccine efficacy of COMIRNATY in participants with or without evidence of prior infection was 91.1% (95% confidence interval: 88.8% to 93.0%) with 81 COVID-19 cases in the COMIRNATY group compared to 873 cases in the placebo group.

Efficacy Against Severe COVID-19 (Based on Cut-off Date of March 13, 2021)

Secondary efficacy analyses in Study 2 supported benefit of COMIRNATY in preventing severe COVID-19. During blinded placebo-controlled follow-up through March 13, 2021, the vaccine efficacy against severe COVID 19 (as defined by the study protocol) in participants with or without evidence of SARS-CoV-2 infection prior to 7 days after Dose 2 was 95.3% (95% CI: 70.9%, 99.9%) with 1 and 21 cases in the vaccine and placebo groups, respectively. The COVID-19 case counts in participants without prior SARS-CoV-2 infection were the same as those in participants with or without prior SARS-CoV-2 infection in both the COMIRNATY and placebo groups.

14.2.3.1.2 Efficacy and Immunogenicity in Participants 16 Years of Age and Older – After Booster Dose

Immunogenicity in Participants 18 to 55 Years of Age – After Booster Dose

Noninferiority of immune responses 1 month after a COMIRNATY booster dose compared to 1 month after completion of the primary 2-dose series was assessed, in a subset of participants enrolled at selected sites in the US, by evaluating SARS-CoV-2 50% neutralizing titers (NT50) against the reference strain. Immunogenicity was evaluated in subjects who had no serological or virological evidence of past SARS-CoV-2 infection up to 1 month after the booster vaccination. The analysis demonstrated noninferior immune responses 1 month after a booster dose compared to 1 month after Dose 2 in individuals 18 through 55 years of age (Table 34).

Relative Vaccine Efficacy in Participants 16 Years of Age and Older – After Booster Dose

An interim efficacy analysis of Study 4, a placebo-controlled booster study was performed in approximately 10,000 participants 16 years of age and older who were recruited from Study 2 and evaluated confirmed COVID-19 cases accrued from at least 7 days after booster vaccination up to a data cut-off date of 5 October 2021, which represents a median of 2.5 months post-booster follow-up. Vaccine efficacy of the COMIRNATY booster dose after the primary series relative to the placebo booster group who only received the primary series dose was assessed. The relative vaccine efficacy information for participants 16 years of age and older is presented in Table 35.

14.2.3.2 Efficacy and Immunogenicity in Adolescents 12 to 15 Years of Age

14.2.3.2.1 Efficacy and Immunogenicity in Adolescents 12 to 15 Years of Age – After Two Doses

Efficacy

The vaccine efficacy in participants 12 to 15 years of age was evaluated on a subgroup analysis of Study 2 based on a cut-off date of March 13, 2021 (Table 36).

An updated efficacy analysis of Study 2 has been performed in approximately 2,260 adolescents 12 through 15 years of age evaluating confirmed COVID-19 cases accrued up to a data cut-off date of September 2, 2021, representing up to 6 months of follow-up after Dose 2 for participants in the efficacy population.

In the adolescent group, in efficacy analyses in the evaluable efficacy population based on cases reported from at least 7 days after Dose 2 through the data cut-off date (02 September 2021), representing a median of 4.4 (range 0-10.8) months of follow-up after Dose 2, there were 0 confirmed COVID-19 cases identified in the COMIRNATY and 28 in the placebo groups, respectively. In this analysis, compared to placebo, the estimated VE against confirmed COVID-19 was 100% (95% CI: 86.8%, 100%) for individuals without evidence of prior SARS-CoV-2 infection before and during vaccination regimen. The estimated VE against confirmed COVID-19 was 100% (2-sided 95% CI: 87.5%, 100%) for those with or without evidence of prior SARS-CoV-2 infection before and during vaccination regimen, with 0 COVID-19 cases in the COMIRNATY group compared to 30 cases in the placebo group.

Among participants without and with or without evidence of SARS-CoV-2 infection before and during the vaccination regimen (evaluable efficacy population), VE against COVID-19 occurring at least 7 days after Dose 2 was evaluated for demographic and risk subgroups, and the estimated VE was 100.0% for all subgroups.

Immunogenicity – After Two Doses

In Study 2, an analysis of SARS-CoV-2 50% neutralizing titers (NT50) 1 month after Dose 2 in a randomly selected subset of participants demonstrated non-inferior immune responses (within 1.5-fold) comparing adolescents 12 through 15 years of age to participants 16 through 25 years of age who had no serological or virological evidence of past SARS-CoV-2 infection up to 1 month after Dose 2 (Table 37).

Table 37: Summary of Geometric Mean Ratio for 50% Neutralizing Titer – Comparison of Adolescents 12 Through 15 Years of Age to Participants 16 Through 25 Years of Age (Immunogenicity Subset) –Participants Without Evidence of Infection up to 1 Month After Dose 2 – Dose 2 Evaluable Immunogenicity Population

14.2.4 COMIRNATY (10 mcg)

14.2.4.1 Efficacy and Immunogenicity in Children 5 Years Through <12 Years of Age

14.2.4.1.1 Efficacy and Immunogenicity in Children 5 Years Through <12 Years of Age – After Two Doses

Immunogenicity

In Study 3, an analysis of SARS-CoV-2 50% neutralizing titers (NT50) 1 month after Dose 2 in a randomly selected subset of participants demonstrated effectiveness by immunobridging of immune responses. Children 5 years through <12 years of age in the Phase 2/3 part of Study 3 were compared to participants 16 through 25 years of age in the Phase 2/3 part of Study 2 who had no serological or virological evidence of past SARS-CoV-2 infection up to 1 month after Dose 2. The study met the prespecified immunobridging criteria for both the geometric mean ratio (GMR) and the seroresponse difference with seroresponse defined as achieving at least 4-fold rise in SARS-CoV-2 NT50 from baseline (before Dose 1). The ratio of the SARS-CoV-2 NT50 in children 5 years through <12 years of age to that of young adults 16 to 25 years of age was 1.04 (2-sided 95% CI: 0.93, 1.18), meeting the 1.5-fold noninferiority criterion (the lower bound of the 2-sided 95% CI for the geometric mean ratio [GMR] >0.67). Results are presented in Table 38.

Among participants without prior evidence of SARS-CoV-2 infection up to 1 month after Dose 2, 99.2% of children 5 years through <12 years of age and 99.2% of participants 16 through 25 years of age had a seroresponse from before vaccination to 1 month after Dose 2. The difference in proportions of participants who had seroresponse between the 2 age groups (children – young adult) was 0.0% (2-sided 95% CI: -2.0%, 2.2%), meeting the -10% noninferiority criterion (the lower bound of the 2-sided 95% CI for the difference in seroresponse rate>-10%). Results are presented in Table 38.

Efficacy

An exploratory efficacy analysis (based on a cut-off date of October 8, 2021) in participants 5 to less than 12 years of age without evidence of SARS-CoV-2 infection prior to Dose 2 showed that the observed vaccine efficacy against confirmed COVID-19 occurring at least 7 days after Dose 2 was 90.7% (95% CI: 67.7%, 98.3%), with 3 COVID-19 cases in the vaccine group compared to 16 in the placebo group (2:1 randomization in vaccine group to placebo group).

No severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) were reported in children 5 to less than 12 years of age, as of the data cut-off date (October 8, 2021).

14.2.4.2 Immunogenicity in Children 5 Years Through <12 Years of Age – After Booster Dose

Immunogenicity of a booster dose administered 7 to 9 months after the second primary series dose was evaluated in a subset of 67 evaluable study participants with no evidence of prior SARS-CoV-2 infection up to 1 month after the booster dose, and descriptively compared to 96 subjects in the same age group (67 participants randomly selected from the 2-dose analysis set and 29 participants in the 3-dose analysis set) with evaluable immunogenicity data following 2 doses of 10 mcg BNT162b2.

Vaccine effectiveness of a booster dose of COMIRNATY was inferred based on a descriptive analysis of NT50 against the reference strain of SARS-CoV-2 (USA_WA1/2020). The NT50 GMT at 1 month after the booster dose was increased compared to before the booster dose and after dose 2. See Table 39.

14.2.5 COMIRNATY (3 mcg)

14.2.5.1 Immunogenicity in Children 6 Months Through <5 Years of Age

14.2.5.1.1 Immunogenicity in Children 6 Months Through <5 Years of Age – After a 3-Dose Primary Series

Effectiveness in individuals 6 months through <5 years of age is based on a comparison of immune responses in this age group to individuals 16 through 25 years of age.

Immunogenicity in Children 2 Through <5 Years of Age

Immunogenicity analyses have been performed in the immunobridging subset of 143 Study 3 participants 2 through <5 years of age without evidence of infection up to 1 month after Dose 3 based on a data cut-off date of April 29, 2022.

SARS-CoV-2 50% neutralizing antibody titers (NT50) were compared between an immunogenicity subset of Phase 2/3 participants 2 through <5 years of age from Study 3 at 1 month after the 3-dose primary course and a randomly selected subset from Study 2 Phase 2/3 participants 16 through 25 years of age at 1 month after the 2-dose primary series, using a microneutralization assay against the reference strain (USA_WA1/2020). The primary immunobridging analyses compared the geometric mean titers (using a geometric mean ratio [GMR]) and the seroresponse (defined as achieving at least 4-fold rise in SARS-CoV-2 NT50 from before Dose 1) rates in the evaluable immunogenicity population of participants without evidence of prior SARS-CoV-2 infection up to 1 month after Dose 3 in participants 2 through <5 years of age and up to 1 month after Dose 2 in participants 16 through 25 years of age. The prespecified immunobridging criteria were met for both the GMR and the seroresponse difference (Table 40).

Using a non-validated fluorescence focus reduction neutralization test assay against the Omicron variant of SARS-CoV-2 (BA.1), the NT50 GMT at 1 month after Dose 3 among a subset of 34 study participants without evidence of prior SARS-CoV-2 infection (82.5 [2-sided 95% CI: 55.4, 122.9]) was increased compared to the NT50 GMT before Dose 3 (14.0 [2-sided 95% CI: 10.6, 18.5]).

Immunogenicity in Children 6 Months Through <2 Years of Age

Immunogenicity analyses have been performed in the immunobridging subset of 82 Study 3 participants 6 months through <2 years of age without evidence of infection up to 1 month after Dose 3 based on a data cut-off date of 29 April 2022.

SARS-CoV-2 50% neutralizing antibody titers (NT50) 1 month after the vaccination series were compared between an immunogenicity subset of Phase 2/3 participants 6 months through <2 years of age from Study 3 and a randomly selected subset from Study 2 Phase 2/3 participants 16 through 25 years of age, using a microneutralization assay against the reference strain (USA_WA1/2020). The primary immunobridging analyses compared the geometric mean titers (using a GMR) and the seroresponse (defined as achieving at least 4-fold rise in SARS-CoV-2 NT50 from before Dose 1) rates in the evaluable immunogenicity population of participants without evidence of prior SARS-CoV-2 infection up to 1 month after Dose 3 in participants 6 months through < 2 years of age and up to 1 month after Dose 2 in participants 16 through 25 years of age. The prespecified immunobridging criteria were met for both the GMR and the seroresponse difference (Table 41).

Table 41: SARS-CoV-2 GMTs (NT50) at 1 Month after Vaccination Series and Difference in Percentages of Participants With Seroresponse at 1 Month After Vaccination Series – Immunobridging Subset – Participants 6 Months Through <2 Years of Age (Study 3) 1 Month After Dose 3 and Participants 16 Through 25 Years of Age (Study 2) 1 Month After Dose 2 – Without Evidence of SARS-CoV-2 Infection– Evaluable Immunogenicity Population

Using a non-validated fluorescence focus reduction neutralization test assay against the Omicron variant of SARS-CoV-2 (BA.1), the NT50 GMT at 1 month after Dose 3 among a subset of 32 study participants without evidence of prior SARS-CoV-2 infection (127.5 [2-sided 95% CI: 90.2, 180.1]) was increased compared to the NT50 GMT before Dose 3 (16.3 [2-sided 95% CI: 12.8, 20.8]).

15 MICROBIOLOGY

No microbiological information is required for this product.

16 NON-CLINICAL TOXICOLOGY

Non-clinical data reveal no special hazard for humans based on conventional studies of repeat dose toxicity.

General Toxicology:

In a repeat-dose toxicity study, rats were administered three once weekly doses of 30 mcg/animal (0.06 mL of a vaccine formulation containing the same quantity of nucleoside-modified messenger ribonucleic acid (mRNA) and other ingredients included in a single human dose) of COMIRNATY by intramuscular injection. Vaccine administration resulted in transient erythema and edema at the site of injection, as well as increased cellularity in draining and inguinal lymph nodes, spleen, and bone marrow, along with transiently increased body temperature, increased white blood counts, and decreased reticulocyte counts coupled with decreased red blood cell mass. Clinical chemistry changes (e.g., increased acute phase protein levels) indicated an acute phase response. These changes are consistent with an expected immunostimulatory response following intramuscular administration of a vaccine. Transient periportal hepatocyte vacuolation was also observed without evidence of liver injury. Full or partial recovery from all findings was observed following a 3-week recovery period.

Carcinogenicity:

Carcinogenic potential was not assessed, as carcinogenicity studies were not considered relevant to this vaccine.

Genotoxicity:

Genotoxic potential was not assessed, as genotoxicity studies were not considered relevant to this vaccine.

Reproductive and Developmental Toxicology:

In a reproductive and developmental toxicity study, 30 mcg/animal (0.06 mL of a vaccine formulation containing the same quantity of nucleoside-modified messenger ribonucleic acid (mRNA) and other ingredients included in a single human dose) of COMIRNATY was administered to female rats by the intramuscular route on four occasions: 21 and 14 days prior to mating, and on gestation days 9 and 20. No vaccine-related adverse effects on female fertility, fetal development, or postnatal development were reported in the study.