Vaccines and Related Biological Products Advisory Committee June 14-15, 2022 Meeting Presentation.pdf

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ModernaTX, Inc.

mRNA-1273 Vaccines and Related Biological Products Advisory Committee

mRNA-1273 PRIMARY SERIES 6 MONTHS TO 17 YEARS SPONSOR BRIEFING DOCUMENT VACCINES AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE

MEETING DATES: JUNE 14–15, 2022

ModernaTX, Inc.

mRNA-1273 Vaccines and Related Biological Products Advisory Committee

TABLE OF CONTENTS Table of Contents.................................................................................................................... 2 List of Tables....................................................................................................................... 5 List of Figures...................................................................................................................... 7 List of Abbreviations ............................................................................................................ 9 1 Executive Summary .......................................................................................................... 11 1.1

Introduction............................................................................................................ 11

1.2

Background and Unmet Need................................................................................. 11

1.3

Clinical Development of mRNA-1273 in Adolescents, Children, Toddlers and Infants13

1.3.1

Study Design..................................................................................................... 13

1.3.2

Dose Selection .................................................................................................. 14

1.3.3

Exposure and Duration of Follow-up................................................................... 15

1.4

Effectiveness and Efficacy of mRNA-1273 Primary Series in Participants 6 Months to 17 Years................................................................................................................ 16

1.5

Safety and Tolerability of mRNA-1273 Primary Series in Participants 6 Months to 17 Years of Age.......................................................................................................... 17

1.6

Ongoing Follow-up ................................................................................................. 18

1.7

Benefit-Risk Conclusions........................................................................................ 19

2 COVID-19 Background...................................................................................................... 21 2.1

Clinical/Pathophysiology of Condition...................................................................... 21

2.2

Currently Available COVID-19 Vaccines.................................................................. 22

2.3

Unmet Medical Need.............................................................................................. 23

3 Overview of Clinical Development of mRNA-1273 for Adolescents, Children, Toddlers, and Infants............................................................................................................................... 26 3.1

Studies Supporting Pediatric Development of mRNA-1273...................................... 26

3.1.1

Study mRNA-1273-P203.................................................................................... 26

3.1.2

Study mRNA-1273-P204.................................................................................... 27

3.1.3

Study mRNA-1273-P301: Immunogenicity Cohort Used as Control Group for Inference of Efficacy .......................................................................................... 30

3.2

Study Endpoints and Analysis Sets......................................................................... 30

3.2.1

Immunogenicity Endpoints................................................................................. 30

3.2.2

Efficacy Endpoints............................................................................................. 31

3.2.3

Safety Endpoints ............................................................................................... 32

3.2.4

Analysis Sets..................................................................................................... 32 2

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3.3

Evaluation of Myocarditis and Pericarditis in Clinical Trials of Infants, Toddlers, Children, and Adolescents ..................................................................................... 34

3.4

Enrolled Participants............................................................................................... 34

3.4.1

Study 203 Study Populations (12 to 17 Years).................................................... 34

3.4.2

Study 204 Study Populations (6 to 11 Years)...................................................... 37

3.4.3

Study 204 Study Populations (2 to 5 Years) ....................................................... 39

3.4.4

Study 204 Study Populations (6 to 23 Months) ................................................... 40

4 Overview of Immunogenicity and Efficacy.......................................................................... 43 4.1

Immunogenicity in Participants 6 Months to 17 Years of Age................................... 43

4.1.1

Immunogenicity (12 to 17 Years) ...................................................................... 44

4.1.2

Immunogenicity (6 to 11 Years) ........................................................................ 45

4.1.3

Immunogenicity (2 to 5 Years) .......................................................................... 46

4.1.4

Immunogenicity (6 to 23 Months)...................................................................... 47

4.2

Efficacy in Participants 6 Months to 17 Years of Age............................................... 47

4.2.1

SARS-CoV-2 Landscape During mRNA-1273 Trials........................................... 47

4.2.2

Efficacy (12 to 17 Years).................................................................................... 48

4.2.3

Efficacy (6 to 11 Years)...................................................................................... 50

4.2.4

Efficacy (2 to 5 Years)........................................................................................ 51

4.2.5

Efficacy (6 to 23 Months) ................................................................................... 53

4.3

Immunogenicity Against Variants of Concern .......................................................... 53

4.4

Immunogenicity and Efficacy Conclusions............................................................... 56

5 Overview of Safety............................................................................................................ 58 5.1

Safety Data Presentation from Study 203................................................................ 58

5.2

Overview of Safety in Study 203 Participants 12 to 17 Years of Age........................ 59

5.2.1

Duration of Follow-Up and Data Cutoff Dates for Analyses ................................. 59

5.2.2

Solicited Adverse Reactions (12 to 17 Years)..................................................... 59

5.2.3

Unsolicited Adverse Events Within 28 Days (12 to 17 Years).............................. 62

5.2.4

Unsolicited Adverse Events in the Entire Study Period (12 to 17 Years).............. 63

5.3

Safety Data Presentation from Study 204................................................................ 67

5.4

Overview of Safety in Study 204 Participants 6 to 11 Years of Age.......................... 68

5.4.1

Duration of Follow-Up and Data Cutoff Dates..................................................... 68

5.4.2

Solicited Adverse Reactions (6 to 11 Years)....................................................... 68

5.4.3

Unsolicited Adverse Events within 28 Days (6 to 11 Years)................................. 71

5.4.4

Unsolicited Adverse Events in the Entire Study Period (6 to 11 Years)................ 72 3

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Overview of Safety in Study 204 Participants 2 to 5 Years of Age............................ 76

5.5.1

Duration of follow-Up and Data Cutoff Dates ...................................................... 76

5.5.2

Solicited Adverse Reactions (2 to 5 Years)......................................................... 76

5.5.3

Unsolicited Adverse Events within 28 Days (2 to 5 Years) .................................. 81

5.5.4

Unsolicited Adverse Events in the Entire Study Period (2 to 5 Years).................. 82

5.6

Overview of Safety in Study 204 Participants 6 to 23 Months of Age........................ 87

5.6.1

Duration of Follow-up and Data Cutoff Date ....................................................... 87

5.6.2

Solicited Adverse Reactions............................................................................... 87

5.6.3

Unsolicited Adverse Events within 28 Days (6 to 23 Months).............................. 91

5.6.4

Unsolicited Adverse Events in the Entire Study Period (6 to 23 Months).............. 93

5.7

Safety Conclusions................................................................................................. 99

6 Post-Authorization Safety Update.................................................................................... 101 6.1

Summary of Post-Authorization Myocarditis Data.................................................. 102

7 Pharmacovigilance and Risk Management Plan............................................................... 104 8 Path Forward: Continued follow-Up ................................................................................. 106 9 Benefits and Risks Conclusions....................................................................................... 107 9.1

Benefit-Risk Analysis Evaluation........................................................................... 107

9.2

Conclusions ......................................................................................................... 110

10References ..................................................................................................................... 111 11Appendices..................................................................................................................... 115 11.1

Appendix: Specified Adverse Events of Special Interest........................................ 115

11.2

Appendix: Benefit-Risk Assessment Methodology................................................. 117

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List of Tables Table 1: Number of COVID-19 Cases and Associated Deaths in the US in Infants, Children, and Adolescents.................................................................................................... 12 Table 2: mRNA-1273 Dose Selection by Age Range............................................................ 15 Table 3: Number of Participants Receiving ≥ 1 Injection of mRNA-1273 (Safety Set)............ 15 Table 4: Median Follow-Up in Each mRNA-1273 Age Group................................................ 16 Table 5: Studies 203 and 204 Summary of Serum Antibody Level and Seroresponse at Day 57 (PP Immunogenicity Subsets, 6 Months to 17 Years).............................................. 16 Table 6: Studies 203 and 204 Summary of Efficacy in CDC Case Definition (6 Months to 17 Years) ................................................................................................................... 17 Table 7: Overview of Bioassays for the Assessment of Clinical Endpoints............................ 31 Table 8: Key Analysis Sets for Studies 203 and 204 ............................................................ 33 Table 9: Study 203 Participant Disposition (Randomization Set, 12 to 17 Years) ..................

35 Table 10: Study 203 Participant Demographics and Baseline Characteristics (Safety Set, 12 to 17 Years) .............................................................................................................. 36 Table 11: Study 204 Participant Disposition (Randomization Set, 6 to 11 Years) .................... 37 Table 12: Study 204 Participant Demographics and Baseline Characteristics (Safety Set, 6 to 11 Years) .............................................................................................................. 38 Table 13: Study 204 Participant Disposition (Randomization Set, 2 to 5 Years) ...................... 39 Table 14: Study 204 Participant Demographics and Baseline Characteristics (Safety Set, 2 to 5 Years) ................................................................................................................... 40 Table 15: Study 204 Participant Disposition (Randomization Set; 6 to 23 Months).................. 41 Table 16: Study 204 Participant Demographics and Baseline Characteristics (Safety Set, 6 to 23 Months)............................................................................................................ 42 Table 17: Study 203 Analysis of Serum Antibody Level and Seroresponse at Day 57 (PP Immunogenicity Subset, 12 to 17 Years) ................................................................

44 Table 18: Study 204 Co-primary Immunobridging Comparison to Study 301 (PP Immunogenicity Subset, 6 to 11 Years)........................................................................................... 45 Table 19: Study 204 Co-primary Immunobridging Comparison to Study 301 (PP Immunogenicity Subset, 2 to 5 Years)............................................................................................. 46 Table 20: Study 204 Co-primary Immunobridging Comparison to Study 301 (PP Immunogenicity Subset, 6 to 23 Months)......................................................................................... 47 Table 21: Study 203 Blinded Efficacy Analysis (PP Set for Efficacy, 12 to 17 Years)............... 49 Table 22: Study 204 Secondary Efficacy Endpoint Analysis Results Starting 14 Days after Dose 1 (mITT1 Population, 6 to 11 Years)....................................................................... 51 5

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mRNA-1273 Vaccines and Related Biological Products Advisory Committee

Table 23: Study 204 Efficacy Endpoint Analysis Results Starting 14 Days After Dose 2 (PP Set for Efficacy, 2 to 5 Years)....................................................................................... 52 Table 24: Study 204 Efficacy Endpoint Analysis Results Starting 14 Days After Dose 2 (PP Set for Efficacy, 6 to 23 Months)................................................................................... 53 Table 25: Efficacy of mRNA-1273 in Pediatric Age Groups is Consistent with that Observed in Adults During Each SARS-CoV-2 Variant Wave ..................................................... 57 Table 26: Study 203 Proportion of Participants with Unsolicited AEs within 28 Days after Any Dose (Safety Set, 12 to 17 Years).......................................................................... 63 Table 27: Study 203 Proportion of Participants Reporting Unsolicited AEs in the Entire Study after Any Dose (Safety Set, 12 to 17 Years) ........................................................... 64 Table 28: Serious Adverse Events within 28 Days of Any Injection (Safety Set, 12 to 17 Years) .............................................................................................................................

65 Table 29: Study 204 Participants Reporting ≥ 1 Unsolicited Adverse Event within 28 Days after Any Dose (Safety Set, 6 to 11 Years) ..................................................................... 72 Table 30: Study 204 mRNA-1273 Recipients Reporting Unsolicited AEs in the Entire Study after Any Dose (Safety Set, 6 to 11 Years) ..................................................................... 73 Table 31: Study 204 SAEs within 28 Days of Any Injection (Safety Set, 6 to 11 Years) ........... 74 Table 32: Study 204 Participants Reporting Fever > 40°C (2 to 5 Years) ................................ 80 Table 33: Study 204 Participants Reporting ≥ 1 Unsolicited Adverse Event within 28 Days after Any Dose (Safety Set, 2 to 5 Years)....................................................................... 82 Table 34: Study 204 Unsolicited AEs in the Entire Study after Any Dose in Participants (Safety Set, 2 to 5 Years)................................................................................................... 83 Table 35: Study 204 SAEs within 28 Days of any Injection (Safety Set, 2 to 5 Years) ............. 84 Table 36: Study 204 Serious Adverse Events Beyond 28 days after Any injection (2 to 5 Years) .............................................................................................................................

85 Table 37: Study 204 Participants Reporting a Fever > 40 C (6 to 23 Months) ......................... 90 Table 38: Participants Reporting ≥ 1 Unsolicited Adverse Event within 28 Days after Any Dose (Safety Set, 6 to 23 Months)................................................................................... 92 Table 39: Study 204 Time to Onset of Reported Febrile Seizures (Safety Set, 6 to 23 Months)93 Table 40: Study 204 Unsolicited AEs in the Entire Study Period after Any Dose in Participants (Safety Set, 6 to 23 Months)................................................................................... 94 Table 41: Study 204 Serious Adverse Events within 28 Days of Any Injection (6 to 23 Months) ............................................................................................................................. 95 Table 42: Study 204 SAEs Beyond 28 Days After Any Injection (6 to 23 Months) ................... 97 Table 43: Post-Authorization Commitment Studies .............................................................. 104

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mRNA-1273 Vaccines and Related Biological Products Advisory Committee

List of Figures Figure 1: Immunogenicity of mRNA-1273 1 Month after 2-Dose Primary Series Across Age Groups .................................................................................................................. 20 Figure 2: Daily Cases of SARS-CoV-2 Infections and Predominant Circulating Variants Over Time...................................................................................................................... 22 Figure 3: Rate of Severe COVID-19 Hospitalizations in Vaccinated and Unvaccinated Adults (≥ 18 Years) .............................................................................................................. 23 Figure 4: Weekly COVID-19–Associated Hospitalization Rates in the United States among Children and Adolescents by Age Group and Variant ............................................. 24 Figure 5: Study 203 Study Design Schematic ....................................................................... 27 Figure 6: Study 204 Part 1 Design Schematic ....................................................................... 28 Figure 7: Study 204 Part 2 Design Schematic ....................................................................... 29 Figure 8: Clinical Studies Conducted During Different Periods of COVID-19 Pandemic..........

48 Figure 9: Long-term Analysis of Incidence Rate of COVID-19 (Study 301 Case Definition) Starting 14 Days After Second Injection by Calendar Month, mRNA-1273 Group (Combined Blinded and Open-Label Phases) – Based on RT-PCR only ................. 50 Figure 10:Study 204 nAb Against Delta Variant (6 to 11 Years).............................................. 54 Figure 11:Neutralization of Original Viral Strain (D614G) and Omicron SARS-CoV-2 Pseudoviruses by Sera from mRNA-1273 Primary Vaccination Recipients.............. 55 Figure 12:MesoScale Discovery Results for Original, Beta, Delta, and Omicron Variants at Day 1 and Day 57 of the Primary Series........................................................................ 56 Figure 13:Solicited Local Adverse Reactions in Study 203 Participants 12 to 17 Years and Study 301 Participants 18 to 25 Years (Solicited Safety Set)................................... 60 Figure 14:Solicited Systemic Adverse Reactions in Study 203 Participants 12 to 17 Years and Study 301 Participants 18 to 25 Years (Solicited Safety Set)................................... 61 Figure 15:Study 203 Solicited Systemic Adverse Reactions by Baseline Serostatus (12 to 17 Years) ...................................................................................................................

62 Figure 16:Study 204 Solicited Local Adverse Reactions (Solicited Safety Set, 6 to 11 Years).. 69 Figure 17:Study 204 Solicited Systemic Adverse Reactions (Solicited Safety Set, 6 to 11 Years) ............................................................................................................................. 70 Figure 18:Study 204 Solicited Systemic Adverse Reactions by Baseline Serostatus (Solicited Safety Set, 6 to 11 Years) ...................................................................................... 71 Figure 19:Study 204 Solicited Local Adverse Reactions (Solicited Safety Set, 2 to 5 Years) ... 77 Figure 20:Study 204 Solicited Systemic Adverse Reactions Other than Fever (Solicited Safety Set, 37 months to 5 Years ).................................................................................... 78 Figure 21:Study 204 Solicited Systemic Adverse Reactions Other than Fever (Solicited Safety Set, 24 to 36 Months)............................................................................................. 78 7

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Figure 22:Study 204 Fevers within 7 days (Solicited Safety Set, 2 to 5 Years) ........................ 79 Figure 23:Study 204 Fevers by Day and Temperature Post-Dose 2 (Safety Set, 2 to 5 Years) 79 Figure 24:Study 204 Solicited Local Adverse Reactions (Solicited Safety Set, 6 to 23 Months) 88 Figure 25:Study 204 Solicited Systemic Adverse Reactions (Solicited Safety Set, 6 to 23 Months)................................................................................................................. 88 Figure 26:Study 204 Fevers within 7 Days (Solicited Safety Set, 6 to 23 Months) ................... 89 Figure 27:Study 204 Percentage of Participants Reporting Fevers by Temperature over Time after Dose 2 (Safety Set, 6 to 23 Months)............................................................... 90 Figure 28:Reporting Rates of Myocarditis within 7 Days After Dose 1 and 2 per Million Doses Administered of mRNA-1273 Stratified by Age and Sex – Moderna Global Safety Database............................................................................................................. 102 Figure 29:Reporting Rates of Myocarditis Associated with SARS-CoV-2 Infections............... 103 Figure 30:mRNA-1273 Benefit-Risk Assessment ................................................................. 110

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mRNA-1273 Vaccines and Related Biological Products Advisory Committee

List of Abbreviations Acronym Ab AE AESI AR BLA CDC CEAC CI COVID-19 CoV DSMB EKG ELISA EUA FDA GM GMC GMT GMR LFT LLOQ MedDRA MAAE MIS-C mITT mRNA MSD nAb PASS PP PsVNA PT RSV RT-PCR RTI SAE SARS SARS-CoV-2 SMQ SOC

Definition antibody adverse event adverse events of special interest adverse reaction Biologics License Application Centers f or Disease Control and Prevention Cardiac Endpoint Adjudication Committee conf idence interval Coronavirus disease 2019 Coronavirus Data Saf ety Monitoring Board electrocardiogram enzyme-linked immunosorbent assay Emergency Use Authorization Food and Drug Administration geometric mean geometric mean concentration geometric mean titer geometric mean ratio liver f unction test lower limit of quantification Medical Dictionary for Regulatory Activities medically attended adverse events Multisystem Inflammatory Syndrome in Children modified Intent-to-Treat messenger ribonucleic acid MesoScale Discovery neutralizing antibody Post-authorization safety study Per-Protocol pseudovirus neutralizing antibody assay pref erred term respiratory syncytial virus reverse transcription polymerase chain reaction respiratory tract infection serious adverse event Severe Acute Respiratory Syndrome Severe Acute Respiratory Syndrome Coronavirus-2 Standardized Medical Dictionary for Regulatory Activities Query System organ class

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ModernaTX, Inc. Acronym SRR Study 203 Study 204 Study 301 TEAE URI US VE

mRNA-1273 Vaccines and Related Biological Products Advisory Committee

Definition seroresponse rate Study mRNA-1273-P203, the pivotal Phase 2/3 safety and effectiveness study in adolescents 12–17 years of age Study mRNA-1273-P204, the pivotal Phase 2/3 safety and effectiveness study in children 6 months to 11 years of age Study mRNA-1273-P301, the pivotal Phase 3 safety, efficacy, and immunogenicity study in adults ≥ 18 years of age treatment-emergent adverse event Upper respiratory infection United States vaccine efficacy

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ModernaTX, Inc. 1

EXECUTIVE SUMMARY

1.1

Introduction

mRNA-1273 Vaccines and Related Biological Products Advisory Committee

Following the outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ModernaTX, Inc. (Moderna) applied its messenger ribonucleic acid (mRNA) vaccine platform and coronavirus research experience to rapidly develop the mRNA-1273 vaccine against SARS-CoV-2. The safety and efficacy of mRNA-1273 to prevent COVID-19 was demonstrated in adults 18 years and older in Study mRNA-1273-P301 (Study 301), leading to Emergency Use Authorization (EUA) in the United States (US) on 18 Dec 2020 and licensure on 31 Jan 2022. As of 15 Apr 2022, more than 1 billion doses of mRNA-1273 have been distributed globally. Approximately 633 million doses of the mRNA-1273 (Moderna COVID-19 vaccine) have been administered to individuals in more than 100 countries, with over 220 million individuals fully vaccinated (Centers for Disease Control and Prevention 2022; Moderna 2022; New York Times 2022). Based on robust pre-authorization data, which now includes > 10,800 children and adolescents aged 6 months to 17 years who received at least 1 dose of mRNA-1273, Moderna is seeking EUA for: •

a 100 µg dose level of mRNA-1273 for use in individuals 12 to 17 years of age as a two-dose primary series given 1 month apart

•

a 50 µg dose level of mRNA-1273 for use in individuals 6 to 11 years of age as a two-dose primary series given 1 month apart

•

a 25 µg dose level of mRNA-1273 for use in individuals 6 months to 5 years of age as a two-dose primary series given 1 month apart

The safety, immunogenicity, and efficacy data from the pediatric clinical development program presented here support the favorable benefit-risk profile of mRNA-1273 for individuals 6 months to 17 years of age and fulfill the recommendations outlined in the Food and Drug Administration (FDA) guidance for EUA for Vaccines to Prevent COVID19 (Food and Drug Administration 2022). 1.2

Background and Unmet Need

As of 02 Jun 2022, confirmed COVID-19 mortality has surpassed 1 million deaths in the US with 1,086 deaths in children 0–17 years of age (Table 1). As of 17 May 2022 there have been more than 84 million COVID-19 cases in the US with 10.7 million cases reported in children 0 to 17 years (CDC). While vaccinated adults continue to benefit from clinically meaningful levels of protection against COVID-19, children and adolescents continue to be disproportionately at risk (Figure 2 and Figure 3). Since March 2020, approximately 1 in 4 hospitalized children and adolescents (0 to 17 years old) with COVID-19 have required intensive care (Delahoy et al 2021). While rates of severe disease have not 11

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mRNA-1273 Vaccines and Related Biological Products Advisory Committee

increased since the start of the pandemic, the increase in absolute numbers of cases has added substantial burden, including the number of children requiring ICU admissions (Marks et al 2022a; Shen et al 2020). Table 1: Number of COVID-19 Cases and Associated Deaths in the US in Infants, Children, and Adolescents Age Group (Years) 12 to 17 5 to 11 0 to 4 Total

# Cases 5.5 million 4.9 million 2.4 million 10.7 million

*# Cases as of 17 May 2022; # Deaths as of 02 Jun 2022 Source: https://covid.cdc.gov/covid-data-tracker/#demographicsovertime

# Deaths 449 195 442 1086

An evaluation of COVID-19 incidence over time indicates marked increases in children ages 0 to 4 years old during the Delta and Omicron variant waves. Prior to the Delta wave, in June 2021, there were 14.1 incident cases of COVID-19 per 100,000 population among ages 0 to 4 years. Peak incidence among 0 to 4 years of age was 187.0 incident cases per 100,000 population in August 2021 during the Delta wave and increased to 894.6 cases per 100,000 population during the Omicron wave in January 2022 (Centers for Disease Control and Prevention). After the onset of the Omicron wave, the demographics of hospitalized patients with COVID-19 shifted to younger age groups (Abdullah et al 2022; Goga et al 2021; United Kingdom Health Security Agency 2021). Furthermore, peak hospitalizations during Omicron were nearly four times that observed during the Delta variant wave (Delahoy et al 2021; Marks et al 2022a; Marks et al 2022b). In addition to the increased incidence and hospitalizations observed, COVID-19 disease in children and adolescents can include a unique complication in conjunction with severe disease called Multisystem Inflammatory Syndrome in Children (MIS-C) (Vogel et al 2021).

MIS-C shares some common features with Kawasaki disease, and is defined as fever, laboratory evidence of inflammation, and involvement of ≥ 2 organ systems in an individual < 21 years of age with no plausible alternative diagnosis and evidence of current or recent SARS-CoV-2 infection. MIS-C is also associated with cardiac complications. Through 31 May 2022, 8,525 cases of MIS-C have been reported in the US, with 69 MIS-C related deaths reported. The median age of patients with MIS-C was 9 years (range 5 to 13 years) (Centers for Disease Control and Prevention). Myocarditis has been well described as a complication of pediatric COVID-19. Children under 16 years of age with COVID-19 are at an almost 37-fold higher risk of myocarditis than the uninfected age- and gender-matched control population (Boehmer et al 2021). Of note, the frequency of myocarditis due to COVID-19 is higher than that of vaccineassociated myocarditis. Additionally, the clinical syndrome of COVID-19 related 12

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myocarditis is more severe and clinically meaningful than vaccine-associated myocarditis. Patients with vaccine-associated myocarditis generally have a milder clinical course than patients with classic myocarditis or MIS-C myocarditis, with a lower likelihood of cardiac dysfunction at presentation and more rapid recovery (Patel et al 2022). Long COVID, a sequela of COVID-19, which affects up to 20% of persons infected with SARS-CoV-2, has been described in children as well, including in those with mild infection. This syndrome is manifested by symptoms that can include fatigue, muscle and joint pain, insomnia, concentration difficulties, respiratory problems, persistence anosmia and ageusia, and cardiac palpitations that may occur within 6 months after infection (Buonsenso et al 2022; Buonsenso et al 2021; Dembinski et al 2021). Although the primary focus on COVID-19 in all age groups has been upon the physical consequences of SARS-CoV-2 infection, the pandemic also has had a detrimental impact on the mental health of children. Studies show that a combination of school disruptions, social isolation, and family loss/illness has led to a rise in depression, particularly among adolescents.

As the pandemic continues, vaccination coverage in pediatric populations has not reached the level in adults, leaving a group of individuals vulnerable to both COVID-19 as well as severe COVID-19 and downstream complications. Since May 2021, approximately 60% of the eligible adolescent population and approximately 30% of the 5 to 11 year old population has completed a primary vaccination series in the US. There is no vaccine option currently available for children under 5 years of age, leaving this vulnerable population without access to the protection afforded by a safe and efficacious vaccine. Immunization with safe and effective COVID-19 vaccines is a critical component of the strategy to reduce COVID-19-related illnesses, complications, hospitalizations, and deaths in all age groups, prevent interruptions in school and work attendance, and enable normal social interactions. 1.3

Clinical Development of mRNA-1273 in Adolescents, Children, Toddlers and Infants

1.3.1 Study Design

Data to support the EUA are derived from two studies: •

Study 203, a Phase 2/3, randomized, observer-blind, placebo-controlled study to evaluate mRNA-1273 in participants 12 to 17 years of age (study start: 09 Dec 2020; blinded efficacy data through 31 May 2021, and safety data through 31 Jan 2022).

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•

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Study 204, a Phase 2/3, two-part, open-label, dose-escalation, age de-escalation and randomized, observer-blind, placebo-controlled expansion study to evaluate mRNA-1273 in participants 6 months to 11 years of age o 6 to 11 year old age group – study start: 15 Mar 2021; randomized, blinded portion start 09 Aug 2021, safety data through 21 Feb 2022 o 2 to 5 year old age group – 21 Apr 2021; randomized, blinded portion start 18 Oct 2021, efficacy and safety data through 21 Feb 2022 o 6 to 23 months old age group – study start: 20 May 2021; randomized, blinded portion start 18 Oct 2021, efficacy and safety data through 21 Feb 2022

In both studies, the primary safety objective was to evaluate the safety and reactogenicity of mRNA-1273 administered as 2 doses given 28 days apart. Vaccine effectiveness was successfully inferred by meeting the primary immunogenicity objectives, which were consistent with FDA recommendations as outlined at the 10 Jun 2021 VRBPAC meeting. In each age group, immune responses were compared to the immunogenicity subset of vaccine recipients 18–25 years of age from Study 301 where efficacy of mRNA-1273 against COVID-19 infection was demonstrated. The co-primary immunogenicity objectives included assessments of neutralizing antibody geometric mean titer (GMT) ratio and difference in seroresponse rates (SRR) after dose 2 (Day 57). In addition, while the study was not designed with vaccine efficacy (VE) as a primary objective, incidence of COVID-19 was included as a pre-specified secondary objective, based on two different case definitions requiring symptomatology of COVID19 along with a positive reverse transcription polymerase chain reaction (RT-PCR) test. Safety endpoints were consistent with those evaluated in Study 301, with some modifications in specific solicited systemic adverse reactions (ARs) and in grading scales for local and systemic solicited ARs for young children.

Solicited ARs were collected within 7 days after any dose, all unsolicited adverse events (AEs) were collected within 28 days after any dose, and medically attended adverse events (MAAEs), serious adverse events (SAEs), adverse events of special interest (AESIs), and adverse events leading to discontinuation were collected for the duration of the study. Based on the post-authorization awareness of cases of myocarditis observed following receipt of an mRNA vaccine, an independent Cardiac Endpoint Adjudication Committee (CEAC), composed of external experts, was established and was responsible for adjudication of potential cases of myocarditis emerging in the studies. See Section 3 for complete descriptions of study designs and enrolled participants. 1.3.2 Dose Selection

Table 2 describes the doses evaluated and selected for the various age groups in Studies 203 and 204. Dose selection for blinded, placebo-controlled evaluation of in 14

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Study 204 was based on evaluation of the reactogenicity profile in combination with the observed immune response in the open-label, dose-escalation phase of the study. If a dose was eliminated in an older age group, it was not evaluated in the subsequent age groups. Table 2:

mRNA-1273 Dose Selection by Age Range

Study 203

Age Range 12–17 years 6–11 years 2–5 years 6–23 months

204

Doses Evaluated 100 µg* 50 µg and 100 µg 50 µg and 25 µg 25 µg

Selected 2-Dose Primary Series 100 µg 50 µg 25 µg 25 µg

*selected to match the dose used in adult population of Study 301

1.3.3 Exposure and Duration of Follow-up

Studies 203 and 204 enrolled more than 14,000 individuals who received either mRNA1273 or placebo across the 4 age groups (Table 3). More than 10,800 participants have received at least one injection of mRNA-1273 at the dose selected for authorization in their respective age group. The median duration of follow-up in each study group exceeds the median 2-month recommendation as outlined in EUA guidance (Food and Drug Administration 2022). The median duration of follow-up for the different age groups ranges from 2.4 months to 11.1 months (Table 4). Table 3:

Number of Participants Receiving ≥ 1 Injection of mRNA-1273 (Safety Set)

Study

Age Range

Dose Selected

203

12–17 years 6–11 years 2–5 years 6–23 months

100 μg 50 μg 25 μg 25 μg Total

204

Participants Receiving ≥ 1 Injection mRNA-1273 2,486 3,387 3,100 1,911* 10,884

Placebo 1,240 995 1,007 589* 3,831

Total 3,726 4,382 4,107 2,500 14,715

*Enrollment ongoing.

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mRNA-1273 Vaccines and Related Biological Products Advisory Committee

ModernaTX, Inc. Table 4:

Median Follow-Up in Each mRNA-1273 Age Group

Study Age Range 203 204

Part

Dose

12–17 years Blinded, Randomized 6–11 years Dose-Ranging

2–5 years

Blinded, Randomized Dose-Ranging

Blinded, Randomized 6–23 months Dose-Ranging Blinded, Randomized

100 µg 50 µg 100 µg 50 µg 25 µg 50 µg 25 µg 25 µg 25 µg

mRNA1273 (N) 2,486 380 371 3,007 75 149 3,031 150 1,760

Median Follow-Up Post-Dose 2 (Months*) 11.1 8.9 8.7 5.6 7.4 8.5 2.5 8.3 2.4

*1 month=28 days

1.4

Effectiveness and Efficacy of mRNA-1273 Primary Series in Participants 6 Months to 17 Years

The immune response to mRNA-1273, both in terms of GMT and SRR, is remarkably consistent across age groups from 6 months through 17 years of age. In all age groups, the pre-specified co-primary immunogenicity objectives were met (GMT Ratio: Lower 95% confidence interval [CI] ≥ 0.67 and Point Estimate ≥ 0.8; Difference in SRR: 95% CI > -10% and Point Estimate > -5%). Immune responses in terms of GMT ratio and SRR rates were non-inferior as compared to the young adults from Study 301, where efficacy was demonstrated (Table 5). Therefore, vaccine effectiveness was successfully inferred based on immunobridging. Table 5: Studies 203 and 204 Summary of Serum Antibody Level and Seroresponse at Day 57 (PP Immunogenicity Subsets, 6 Months to 17 Years)

Study, Age Group Study 203, 12 – 17 Years (100 µg) Study 204, 6 – 11 Years (50 µg) Study 204, 2– 5 Years (25 µg) Study 204, 6 – 23 Months (25 µg)

Day 57 Analysis, Part 2 PsVNA Geometric Mean Ratio Seroresponse Difference (vs Study 301 Young Adults) (vs Study 301 Young Adults) 95% CI 95% CI 1.1 0.2 (0.9, 1.2) (-1.8, 2.4) 0.1 1.2 (1.1, 1.4) (-1.9, 2.1) 1.0 -0.4 (0.9, 1.2) (-2.7,1.5) 1.3 0.7 (1.1, 1.5) (-1.0, 2.5)

Abbreviations: CI=confidence interval; PP=per-protocol; PsVNA =pseudovirus neutralizing antibody assay GMR & seroresponse difference based on comparison to young adults, 18–25 years of age in Study 301

Efficacy results per Centers for Disease Control (CDC) case definitions, pre-specified as secondary objectives in Studies 203 and 204, provide additional support for the EUA of 16

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mRNA-1273 (Table 6). In all age groups, there was evidence of efficacy against COVID19 conferred after completion of a primary series of mRNA-1273 administered as 2 doses given 28 days apart during the randomized blinded phase of each study. Assessment of VE in the 6 to 11 age group was limited due to a relatively short, blinded follow-up period (as another COVID-19 vaccine was authorized and participants were unblinded [to offer them access to the authorized vaccine] per protocol). The number of COVID-19 cases accrued 14 days post-dose 2 were too few to perform meaningful analysis, therefore a similar analysis of VE using cases accrued starting 14 days postdose 1 was conducted (modified Intent-to-Treat 1 [mITT1] set). VE in children 6 to 17 years of age (with 2-dose 50 µg primary series of mRNA-1273 for 6- to 11 years and 2-dose 100 µg primary series of mRNA-1273 for 12 to 17 years) was comparable to the efficacy observed in adults against the original strain in Study 301 (original strain) as well as real-world effectiveness demonstrated against Delta. Although the VE following 2-dose 25 µg primary series of mRNA-1273 in children 6 months to 5 years is lower than that observed in the pivotal adult or older pediatric studies, it is highly consistent with real-world vaccine effectiveness observed against Omicron in adults.

Real-world effectiveness data continue to provide reassuring evidence that mRNA-1273 remains highly effective against hospitalizations and death in adults, even during the Omicron wave (Andrews et al 2022; Tseng et al 2022b). Table 6: Studies 203 and 204 Summary of Efficacy in CDC Case Definition (6 Months to 17 Years) Study, Age Group, Major Circulating Variants Study 203, 12 – 17 Years (100 µg), Original, Alpha Study 204, 6 – 11 Years (50 µg), Delta Study 204, 2– 5 Years (25 µg), Omicron Study 204, 6 – 23 Months (25 µg), Omicron

Parameter Cases, n/N (%) VE (95% CI) Cases, n/N (%) VE (95% CI) Cases, n/N (%) VE (95% CI) Cases, n/N (%) VE (95% CI)

mRNA-1273

Placebo

2/2139 (< 0.1) 7/1045 (0.7) 93.3% (47.9, 99.9) 7/2680 (0.3) 18/875 (2.1) 88.0% (70.0, 95.8)* 119/2594 (4.6) 61/858 (7.1) 36.8% (12.5, 54.0) 51/1511 (3.4) 34/513 (6.6) 50.6% (21.4, 68.6)

Abbreviations: VE=vaccine efficacy CDC case definition: 1 systemic or respiratory symptom + PCR positive *mITT1 population

1.5

Safety and Tolerability of mRNA-1273 Primary Series in Participants 6 Months to 17 Years of Age

Overall, mRNA-1273 was generally well tolerated in children 6 months to 17 years, and the safety profile is consistent with that seen in young adults. No new safety concerns have been identified.

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In all age groups, the most common solicited local AR was pain. Local ARs were mostly Grade 1–2 in severity and lasted 2–3 days. Solicited systemic ARs were more common post-dose 2 than post-dose 1 in all age groups. Among adolescents and children, the most common solicited systemic ARs were headache and fatigue; among young children fatigue was most common. ARs were mostly Grade 1–2 in severity with a median duration of 2–3 days. Among infants and toddlers, the most common solicited systemic ARs were irritability/crying; events were mostly Grades 1–2 in severity with a median duration of 2–3 days. Solicited systemic ARs in infants/toddlers 6 to 23 months were similar to placebo. Fever was observed in 12% of adolescents and ~25% of infants, toddlers, and children (6 months to 11 years) who received vaccine. Most fevers occurred within 2 days of vaccination, with a median duration of 1 day. Fevers > 40°C were rare, occurring only in the 2 to 5 year (0.4%) and the 6 to 23 month (0.2%) age groups. Fever > 40°C also was of short duration, and the children often had symptoms of concurrent viral infections.

In the participants randomized to mRNA-1273, there were no deaths, cases of MIS-C, or myocarditis/pericarditis observed in any age group; within 28 days of vaccination, no related SAEs were observed in children or adolescents; 1 related SAE of fever/seizure was reported in the 6 to 23 month age group. 1.6

Ongoing Follow-up

The long-term safety and effectiveness of mRNA-1273 in Studies 203 and 204 will continue to be captured until study completion. As the pandemic has continued to evolve, Study 203 was amended to offer a 50 µg booster dose to all study participants (~1,400 participants have been boosted). In addition, all Study 204 participants 6 to 11 years have been offered a booster dose with mRNA-1273 (~1700 participants have been boosted) and participants < 6 years will be offered a booster at least 4 months after their second dose (~100 participants 2 to 5 years of age and ~80 participants 6 to 23 months of age have been boosted as of 03 Jun 2022). The boosters for < 6 years will either be mRNA-1273 or mRNA-1273.214, an Omicron-containing vaccine. Follow-up will continue for all participants in these studies through 12 months after last dose. Several post-authorization safety studies (PASS) in the US and EU are included in the Risk Management Plan addressing long-term safety information as well as characterization of important and potential identified risks included in the safety profile of mRNA-1273. The previously endorsed PASS assessing the risk of multiple AESI (US PASS protocol mRNA-1273-P903 and EU PASS mRNA-1273-P904) have been expanded to capture any use of mRNA-1273 observed, including subgroups of children and adolescents.

Analyses in these studies will quantify the incidence of vaccineassociated myocarditis by age, sex, and dose of mRNA-1273, and will utilize both historical cohort and self-controlled risk interval methods to assess absolute and relative 18

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risk. Further, new analyses currently in development will characterize the natural history, clinical course, short and long-term outcomes, and risk factors for myocarditis temporally associated with mRNA-1273. 1.7

Benefit-Risk Conclusions

As the pandemic persists, and new, highly transmissible variants of concern, such as Omicron, emerge, real-world data continue to demonstrate that COVID-19 vaccines provide protection against severe disease and reduce COVID-19-associated hospitalizations in adults. However, there has also been a substantial increase in the number of COVID-19 infections and hospitalizations among infants, toddlers, children and adolescents. As hospitalizations have increased in this age group, so have severe complications of COVID-19, including admissions to ICUs, cases of MIS-C, and deaths in the pediatric population. As only 60% and 30%, respectively, of US populations of children 12 to 17 and 5 to 11 years of age have been vaccinated against COVID-19, and as there are currently no available vaccines in children between 6 months and 4 years of age, an unmet medical need for safe and effective vaccines to prevent SARSCoV-2 remains. The totality of safety, immunogenicity, and efficacy data from the clinical development program meet recommendations outlined by EUA guidance and support a favorable benefit-risk profile in all age groups evaluated. This data package supports the EUA of mRNA-1273 in children 6 months to 17 years of age: •

> 10,800 children and adolescents received at least 1 dose of mRNA-1273.

•

Median duration of follow-up was > 2 months in each study group.

•

mRNA-1273 was well tolerated in all age groups with a safety profile consistent with young adults. No new safety concerns have been identified.

•

The doses selected met pre-specified co-primary immunogenicity objectives compared to young adults 18 to 25 years of age and is remarkably consistent across age strata (Figure 1). Therefore, vaccine effectiveness of mRNA-1273 is successfully inferred based on immunobridging.

•

Protection from COVID-19 was conferred after completion of a primary series of mRNA-1273 administered as 2 doses given 28 days apart. The VE observed is consistent with efficacy/effectiveness in individuals ≥ 18 years of age. In all age groups, there was direct evidence of efficacy observed with mRNA-1273 during the circulation of the original strain (in ages 12 to 17), Delta (in ages 6 to 11), and Omicron variants (in ages 6 months to 5 years) after a two-dose primary series.

•

Moderna has established plans for safety and effectiveness follow-up postauthorization. 19

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Figure 1: Immunogenicity of mRNA-1273 1 Month after 2-Dose Primary Series Across Age Groups 10000

1391

1402

1610

1410

1781

295

340

320

264

230

Study 301 Young Adults (18-25 Years)

Study 203 Adolescents (12-17 Years)

Study 204 Children (6-11 Years)

Study 204 Young Children (2-5 Years)

Study 204 Infants/Toddlers (6-23 Months)

100 µg

100 µg

50 µg

25 µg

25 µg

1.1

1.2

1.01

1.28

1000 Neutralizing Ab Geometric 100 Mean Titer/ Concentration 10 1

Dose

N=

Geometric Mean Ratio (vs Young Adults)

Abbreviation: Ab=antibody Geometric mean titer displayed for 12 to 17 and 6 to 11 year age groups Geometric mean concentration displayed for 18 to 25 year, 2 to 5 year, and 6 to 23 months age groups

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COVID-19 BACKGROUND

Summary •

COVID-19 has been a significant public health issue since early 2020.

•

As of 02 Jun 2022 in the US, confirmed COVID-19 mortality has surpassed 1 million deaths, with more than 84 million cases of COVID-19. o 5.5 million cases of COVID-19 and 449 deaths reported among ages 12 to 17 years o 4.9 million cases of COVID-19 and 195 deaths reported among ages 5 to 11 years o 2.4 million cases of COVID-19 and 442 deaths reported among ages 0 to 4 years

2.1

•

Hospitalization rates among children 0 to 4 years of age were approximately five times higher during the Omicron-predominant peak period than the Delta predominant period.

•

Since March 2020, approximately 1 in 4 hospitalized infants, children and adolescents with COVID-19 have required intensive care.

•

Through 31 May 2022, 8,525 cases of MIS-C have been reported in the US, including 69 MIS-C related deaths; the median age of patients with MIS-C was 9 years.

•

There is no vaccine option currently available for children under 5 years of age, leaving this vulnerable population without access to the protection afforded by a safe and efficacious vaccine.

•

Immunization with safe and effective COVID-19 vaccines is a critical component of the strategy to reduce COVID-19-related illnesses, complications, hospitalizations, and deaths in all age groups.

Clinical/Pathophysiology of Condition

Early in 2020, the World Health Organization declared COVID-19 to represent a Public Health Emergency of International Concern, denoting its highest level of public health emergency. Confirmed COVID-19 mortality has surpassed 6.3 million deaths worldwide and more than 1 million deaths in the US as of 02 Jun 2022, with COVID-19 cases numbered over 532 million worldwide and more than 84 million in the US (Centers for Disease Control and Prevention). Figure 2 shows the daily new cases of SARS-CoV-2 infection in the US over time. Several highly transmissible variants of concern, including the Delta and Omicron variants, have resulted in continued viral transmission and an ongoing public health emergency.

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Figure 2: Daily Cases of SARS-CoV-2 Infections and Predominant Circulating Variants Over Time

Abbreviations: SAR-CoV-2=Severe Acute Respiratory Syndrome Coronavirus-2; US=United StatesSource: Data as of 14 May 2022 –https://covid.cdc.gov/covid-data-tracker/#trends_dailycases

2.2

Currently Available COVID-19 Vaccines

It is widely acknowledged that the key to controlling this pandemic and mitigating its impact is primary prevention through vaccination. Currently available COVID-19 vaccines in the US for adults 18 years of age and older include mRNA-1273 (EUA: December 2020; Biologics License Application [BLA]: January 2022) and BNT162b2 (EUA: December 2020; BLA: August 2021) and Ad26.COV2.S (EUA: February 2021). BNT 162b2 is also available for children and adolescents, 5 to 17 years of age, in the US. Outside of the US, mRNA-1273 is indicated for use in adolescents 12 to 17 years of age and children 6 to 11 years of age in over 40 countries, as of 03 Jun 2022. As the pandemic persists, and new, highly transmissible variants of concern, like Omicron, emerge – the data continue to demonstrate that COVID-19 vaccines provide protection against severe disease and reduce COVID-19-associated hospitalizations. Vaccinated adults have fewer COVID-19 associated hospitalizations as compared to unvaccinated adults (Figure 3).

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Figure 3: Rate of Severe COVID-19 Hospitalizations in Vaccinated and Unvaccinated Adults (≥ 18 Years)

Fully Vaccinated=2-dose primary series Data as of 14 May 2022 Source: https://covid.cdc.gov/covid-data-tracker/#covidnet-hospitalizations-vaccination

2.3

Unmet Medical Need

Since the beginning of the COVID-19 pandemic, severe disease and deaths associated with COVID-19 have occurred more frequently in adults (Ayoub et al 2020; Hay 2020); however, COVID-19 can also lead to severe outcomes in children and adolescents (Havers et al 2021; Kim et al 2020). An evaluation of COVID-19 incidence over time indicates marked increases in the ages 0 to 4 years with the Delta and Omicron variant waves. Prior to the Delta wave, in June 2021, there were 14.1 incident cases of COVID-19 per 100,000 population among children ages 0 to 4 years. Peak incidence among children 0 to 4 years reached 187.0 incident cases per 100,000 population in August 2021 during the Delta wave and increased further to 894.6 cases per 100,000 population during the Omicron wave in January 2022 (Centers for Disease Control and Prevention). Initial data suggest that the demographics of hospitalized patients with COVID-19 shifted to younger age groups after the onset of the Omicron wave (Abdullah et al 2022; Goga et al 2021; United Kingdom Health Security Agency 2021). The weekly hospitalization rates in the pre-Delta, Delta, and Omicron periods are shown in Figure 4.

During the Omicron variant wave, peak COVID-19-related hospitalizations amongst older children were nearly four times that observed during the Delta variant wave and in children 0 to 4 years old were approximately five times higher than the rates observed during the Delta wave. 23

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mRNA-1273 Vaccines and Related Biological Products Advisory Committee

Since March 2020, approximately 1 in 4 hospitalized children, and adolescents (0 to 17 years) with COVID-19 have required intensive care (Delahoy et al 2021). While rates of severe disease in children have not increased since the start of the pandemic, the increase in absolute numbers of cases has added substantial burden overall, including the number of children requiring ICU admissions (Marks et al 2022a; Shen et al 2020). According to the Coronavirus Disease 2019 Associated Hospitalization Surveillance Network, a population-based surveillance system in the US that collects laboratoryconfirmed COVID-19-associated hospitalizations among children and adults through a network of over 250 acute-care hospitals in 14 states, there were 3,606 hospitalized children between 0 to 4 years of age through 16 Apr 2022, with an estimated 24.1% of these children requiring ICU interventions, and with 21 related in-hospital deaths reported. Additionally, approximately 6% of children 0 to 17 years of age hospitalized due to COVID-19 required mechanical ventilation (COVID-NET 2022). Figure 4: Weekly COVID-19–Associated Hospitalization Rates in the United States among Children and Adolescents by Age Group and Variant

COVID-19; Coronavirus disease 2019; ICU: Intensive Care Unit Data as of 14 May 2022 Source: https://gis.cdc.gov/grasp/covidnet/covid19 3.html; 1. Delahoy, et al., Clin Infect Dis 20212; 73:336-340. Doi: 10.1093/cid/ciac388/6589788

MIS-C is amongst the most severe complications of COVID-19 in children and adolescents. While the long-lasting cardiovascular effects of MIS-C are still unknown, patients may suffer both acute and sub-acute complications from disease and cardiovascular manifestations range from mild to severe (Chin et al 2022). It has been reported that between 50 and 70% of patients with MIS-C have myocarditis. In a study evaluating hospitalized pediatric patients diagnosed with MIS-C (Son et al 2021), 47% required vasopressor support, 41% had depressed left ventricular systolic dysfunction, 24

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12% developed coronary artery aneurysm, and 3% required extracorporeal membrane oxygenation. While short-term cardiac outcomes in these patients are reassuring, with almost all patients fully recovering at 2-week follow-up, there is some evidence that diastolic dysfunction may persist in a small subset of patients six months after acute illness (Capone et al 2021). Through 31 May 2022, there were a total of 8,525 cases of COVID-19 related MIS-C reported in the US, including 69 MIS-C related deaths. The median age of patients with MIS-C was 9 years (range 5 to 13 years). COVID-19 is a strong and significant risk factor for myocarditis, with risk varying by age group. A large cohort study found that children under 16 years of age with COVID-19 are at 37 times higher risk of myocarditis than the uninfected age and gender-matched control population (Boehmer et al 2021). Manifestations of viral myocarditis can range from subclinical disease to sudden death, with new-onset atrial or ventricular arrhythmias, complete heart block, or an acute myocardial infarction–like syndrome. Cardiac symptoms are variable and may include fatigue, decreased exercise tolerance, palpitations, precordial chest pain, and syncope. Chest pain in acute myocarditis can result from an associated pericarditis or, occasionally, from coronary-artery spasm.

The long-term sequalae of COVID-19 related myocarditis in children are not well understood, however, the major long-term sequela of general viral myocarditis is dilated cardiomyopathy with chronic heart failure (Cooper 2009). There is also evidence of chronic sequelae known as “long-COVID-19” in children even after mild infection; this includes fatigue, muscle and joint pain, insomnia, concentration difficulties, respiratory problems, persistence anosmia and ageusia, and cardiac palpitations that may persist 6 months or more after infection (Dembinski et al 2021). Immunization with a safe and effective COVID-19 vaccine is a critical component of the strategy to reduce COVID-19related illnesses, hospitalizations, and deaths in all age groups and to help restore societal functioning. Overall, the evidence suggests that the burden of COVID-19 has increased in younger age groups over time based on the number and proportion of cases. Vaccination is expected to prevent most of the morbidity and mortality consequences in children 6 months to 17 years of age. Currently, there is only one authorized COVID-19 vaccine for the 5 to 11 and 12 to 17 year old age groups. Since May 2021, about 60% of eligible adolescent population and about 30% of eligible participants 5 to 11 years old have completed primary vaccination with this vaccine.

As the pandemic continues, it is evident that the vaccination coverage in pediatric and adolescent populations has not reached the level in adults, leaving a group of individuals vulnerable to both COVID-19 as well as severe COVID-19 and sequelae. For children and adolescents who remain unvaccinated, especially those less than 5 years of age for whom there is no authorized COVID-19 vaccine, there remains an urgent unmet need for a safe and effective vaccine that can reduce COVID-19-associated morbidity and mortality. 25