Vaccine Information: Moderna COVID-19 Vaccine, Bivalent (Page 4 of 11)

5.3 Syncope

Syncope (fainting) may occur in association with administration of injectable vaccines. Procedures should be in place to avoid injury from fainting.

5.4 Altered Immunocompetence

Immunocompromised persons, including individuals receiving immunosuppressive therapy, may have a diminished response to Moderna COVID-19 Vaccine, Bivalent.

5.5 Limitations of Vaccine Effectiveness

Moderna COVID-19 Vaccine, Bivalent may not protect all vaccine recipients.

6 OVERALL SAFETY SUMMARY

It is MANDATORY for vaccination providers to report to the Vaccine Adverse Event Reporting System (VAERS) all vaccine administration errors, all serious adverse events, cases of myocarditis, cases of pericarditis, cases of Multisystem Inflammatory Syndrome (MIS) in adults and children, and hospitalized or fatal cases of COVID-19 following vaccination with Moderna COVID-19 Vaccine, Bivalent. To the extent feasible, provide a copy of the VAERS form to ModernaTX, Inc. Please see the REQUIREMENTS AND INSTRUCTIONS FOR REPORTING ADVERSE EVENTS AND VACCINE ADMINISTRATION ERRORS section for details on reporting to VAERS and ModernaTX, Inc.

The safety of a booster dose of Moderna COVID-19 Vaccine, Bivalent is based on:

safety data from a clinical study which evaluated a booster dose of Moderna’s bivalent COVID-19 vaccine (Original and Omicron BA.1), not authorized or approved in the U.S., hereafter referred to as bivalent vaccine (Original and Omicron BA.1),
safety data from clinical trials which evaluated primary and booster vaccination with Moderna COVID-19 Vaccine,3 and
postmarketing safety data with Moderna COVID-19 Vaccine

The safety data accrued with the bivalent vaccine (Original and Omicron BA.1) and with Moderna COVID-19 Vaccine are relevant to Moderna COVID-19 Vaccine, Bivalent because these vaccines are manufactured using the same process. The bivalent vaccine (Original and Omicron BA.1) contained 25 mcg of nucleoside-modified messenger RNA (mRNA) encoding the pre-fusion stabilized S-glycoprotein of SARS-CoV-2 Wuhan-Hu-1 strain (Original) and 25 mcg of mRNA encoding the S-glycoprotein of SARS-CoV-2 Omicron variant lineage BA.1, for a total of 50 mcg mRNA per dose. This is the same total quantity of mRNA per dose as a dose of Moderna COVID-19 Vaccine, Bivalent for individuals 12 years of age and older and as a booster dose of Moderna COVID-19 Vaccine (previously but no longer authorized for booster vaccination in individuals 18 years of age and older), and half the total quantity of mRNA as a primary series dose of Moderna COVID-19 Vaccine for individuals 12 years of age and older. The total quantity of mRNA contained in a booster dose of Moderna COVID-19 Vaccine, Bivalent for individuals 6 through 11 years is half the total quantity of mRNA contained in a booster dose for individuals 12 years of age and older.

In a clinical study, the adverse reactions in participants 18 years of age and older following administration of a booster dose of bivalent vaccine (Original and Omicron BA.1) included pain at the injection site (77.3%), fatigue (54.9%), headache (43.9%), myalgia (39.6%), arthralgia (31.1%), chills (23.8%), axillary swelling/tenderness (17.4%), nausea/vomiting (10.3%), erythema at the injection site (6.9%), swelling at the injection site (6.9%), and fever (4.4%).

Anaphylaxis and other severe allergic reactions, myocarditis, pericarditis, and syncope have been reported following administration of Moderna COVID-19 Vaccine outside of clinical trials.


3
Moderna COVID-19 Vaccine is a monovalent vaccine that encodes the spike protein of only the Original SARS-CoV-2.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

In five clinical trials (NCT04283461, NCT04405076, NCT04470427, NCT04649151, NCT04796896), approximately 40,000 participants aged 6 months and older received at least one dose of Moderna COVID-19 Vaccine. In one clinical trial (NCT04927065), approximately 400 participants 18 years of age and older received one dose of bivalent vaccine (Original and Omicron BA.1).

Study 1 (NCT04470427) is a Phase 3 randomized, placebo-controlled, observer-blind clinical trial conducted in the United States involving 30,346 participants 18 years of age and older who received at least one dose of Moderna COVID-19 Vaccine 4 (n=15,184) or placebo (n=15,162). Study 2 (NCT04405076) is a Phase 2, randomized, observer-blind, placebo-controlled, dose-confirmation study, which included an open-label phase involving 171 participants 18 years of age and older who received a booster dose of Moderna COVID-19 Vaccine 6 months (range of 5.8 to 8.5 months) after receiving the second dose of the primary series. Study 3 (NCT04649151) is a Phase 2/3 clinical trial with multiple parts. The first portion of the trial was a randomized, placebo-controlled, observer-blind trial conducted in the United States involving 3,726 participants 12 years through 17 years of age who received at least one dose of Moderna COVID-19 Vaccine (n=2,486) or placebo (n=1,240). The trial transitioned to an open-label study in which 1,364 participants 12 years through 17 years of age received a booster dose of Moderna COVID-19 Vaccine at least 5 months after the second dose of the primary series. Study 4 (NCT04796896) is a Phase 2/3 clinical trial with multiple parts. The study includes a randomized, placebo-controlled, observer-blind clinical trial component conducted in the United States and Canada involving 10,390 participants 6 months through 11 years of age who received at least one dose of Moderna COVID-19 Vaccine (n=7,799) or placebo (n=2,591). The trial protocol was amended to include an open-label booster dose phase which included 1,294 participants 6 years through 11 years of age who received a booster dose of Moderna COVID-19 Vaccine at least 6 months after the second dose of the primary series. Study 5 (NCT04927065) is Phase 2/3 open-label study in which 437 participants 18 years of age and older, who had received a two dose primary series and one booster dose of Moderna COVID-19 Vaccine, received a second booster dose with the bivalent vaccine (Original and Omicron BA.1) at least 3 months after the first booster dose.

Bivalent Vaccine (Original and Omicron BA.1) Administered as a Second Booster Dose

Study 5 (NCT04927065), a Phase 2/3 open-label study conducted in the United States, evaluated the immunogenicity, safety, and reactogenicity of a booster dose of the bivalent vaccine (Original and Omicron BA.1) compared to a booster dose of Moderna COVID-19 Vaccine when administered as a second booster dose to participants 18 years of age and older who had previously received a primary series and a first booster dose with Moderna COVID-19 Vaccine at least 3 months prior. The safety analysis set included 437 participants in the bivalent vaccine (Original and Omicron BA.1) booster dose group and 377 participants in the Moderna COVID-19 Vaccine booster dose group.

The median age of the population was 60 years (range 20-96); 490 (60.2%) participants were 18 through 64 years of age and 324 (39.8%) were 65 years and older. Overall, 44.8% were male, 55.2% were female, 10.2% were Hispanic or Latino, 86.4% were White, 7.4% were African American, 3.7% were Asian, 0.1% were American Indian or Alaska Native, 0.1% were Native Hawaiian or Pacific Islander, 0.6% were other races, and 1.1% were Multiracial. Demographic characteristics were similar among participants who received the bivalent vaccine (Original and Omicron BA.1) and those who received Moderna COVID-19 Vaccine. Following the booster dose through the cutoff date of April 27, 2022, the median follow-up time was 43 days among bivalent vaccine (Original and Omicron BA.1) recipients and 57 days among Moderna COVID-19 Vaccine recipients.

Solicited Adverse Reactions

Local and systemic adverse reactions and use of antipyretic medication were solicited in an electronic diary for 7 days following each injection (i.e., day of vaccination and the next 6 days) among participants receiving bivalent vaccine (Original and Omicron BA.1) and participants receiving Moderna COVID-19 Vaccine. Events that persisted for more than 7 days were followed until resolution.

Table 1 and Table 2 present the frequency and severity of reported solicited local and systemic adverse reactions within 7 days following a second booster dose with bivalent vaccine (Original and Omicron BA.1) booster dose compared to Moderna COVID-19 Vaccine in participants 18 to <65 years of age and ≥65 years of age.

Table 1: Number and Percentage of Participants 18 Years Through 64 Years of Age With Solicited Local and Systemic Adverse Reactions Starting Within 7 Days After a Second Booster Dose with Bivalent Vaccine (Original and BA.1) Compared to a Second Booster Dose with Moderna COVID-19 Vaccine (Solicited Safety Set)*

Bivalent Vaccine

(Original and Omicron BA.1)

Booster Dose

(N=263)

n (%)

Moderna COVID-19 Vaccine

Booster Dose

(N=211)

n (%)

Local Adverse Reactions

Pain

231 (87.8)

175 (82.9)

Pain, Grade 3a

2 (0.8)

4 (1.9)

Axillary swelling/tenderness

56 (21.3)

39 (18.5)

Axillary swelling/tenderness, Grade 3a

0 (0)

4 (1.9)

Swelling (hardness) ≥25 mm

22 (8.4)

15 (7.1)

Swelling (hardness), Grade 3b

4 (1.5)

2 (0.9)

Erythema (redness) ≥25 mm

20 (7.6)

10 (4.7)

Erythema (redness), Grade 3b

7 (2.7)

1 (0.5)

Systemic Adverse Reactions

Fatigue

154 (58.6)

115 (54.5)

Fatigue, Grade 3c

10 (3.8)

7 (3.3)

Headache

129 (49.0)

100 (47.4)

Headache, Grade 3d

4 (1.5)

1 (0.5)

Myalgia

113 (43.0)

90 (42.7)

Myalgia, Grade 3c

9 (3.4)

8 (3.8)

Arthralgia

87 (33.1)

69 (32.7)

Arthralgia, Grade 3c

3 (1.1)

2 (0.9)

Chills

64 (24.3)

54 (25.6)

Chills, Grade 3e

1 (0.4)

0 (0)

Nausea/vomiting

35 (13.3)

27 (12.8)

Fever

10 (3.8)

10 (4.7)

Fever, Grade 3f

1 (0.4)

0 (0)

Use of antipyretic or pain medication

104 (39.5)

67 (31.8)

* 7 days included day of vaccination and the subsequent 6 days. Events and use of antipyretic or pain medication were collected in the electronic diary (e-diary). Solicited Safety Set consisted of participants who received a booster dose and contributed solicited adverse reaction data. Absence of rows for Grade 3 or Grade 4 adverse reactions indicates no events were reported.

a Grade 3 pain and axillary swelling/tenderness: Defined as any use of prescription pain reliever; prevents daily activity.

b Grade 3 swelling and erythema: Defined as >100 mm / >10 cm.

c Grade 3 fatigue, myalgia, arthralgia: Defined as significant; prevents daily activity.

d Grade 3 headache: Defined as significant; any use of prescription pain reliever or prevents daily activity.

e Grade 3 chills: Defined as prevents daily activity and requires medical intervention.

f Grade 3 fever: Defined as ≥39.0° – ≤40.0°C / ≥102.1° – ≤104.0°F.

Table 2: Number and Percentage of Participants ≥65 Years of Age With Solicited Local and Systemic Adverse Reactions Starting Within 7 Days After a Second Booster Dose with Bivalent Vaccine (Original and Omicron BA.1) Compared to a Second Booster Dose with Moderna COVID-19 Vaccine (Solicited Safety Set)*

Bivalent Vaccine

(Original and Omicron BA.1)

Booster Dose

(N=174)

n (%)

Moderna COVID-19 Vaccine

Booster Dose

(N=140)

n (%)

Local Adverse Reactions

Pain

107 (61.5)

94 (67.1)

Pain, Grade 3a

2 (1.1)

0 (0)

Axillary swelling/tenderness

20 (11.5)

15 (10.7)

Axillary swelling/tenderness, Grade 3a

1 (0.6)

0 (0)

Swelling (hardness) ≥25 mm

8 (4.6)

8 (5.7)

Swelling (hardness), Grade 3b

1 (0.6)

3 (2.1)

Erythema (redness) ≥25 mm

10 (5.7)

3 (2.1)

Erythema (redness), Grade 3b

2 (1.1)

1 (0.7)

Systemic Adverse Reactions

Fatigue

86 (49.4)

65 (46.8)

Fatigue, Grade 3c

5 (2.9)

4 (2.9)

Myalgia

60 (34.5)

45 (32.4)

Myalgia, Grade 3c

1 (0.6)

5 (3.6)

Headache

63 (36.2)

44 (31.7)

Headache, Grade 3d

1 (0.6)

1 (0.7)

Arthralgia

49 (28.2)

42 (30.2)

Arthralgia, Grade 3c

1 (0.6)

1 (0.7)

Chills

40 (23.0)

20 (14.4)

Chills, Grade 3e

0 (0)

1 (0.7)

Nausea/vomiting

10 (5.7)

8 (5.8)

Nausea/vomiting, Grade 3f

1 (0.6)

0 (0)

Fever

9 (5.2)

2 (1.4)

Use of antipyretic or pain medication

46 (26.4)

40 (28.6)

* 7 days included day of vaccination and the subsequent 6 days. Events and use of antipyretic or pain medication were collected in the electronic diary (e-diary). Solicited Safety Set consisted of participants who received a booster dose and contributed solicited adverse reaction data. Absence of rows for Grade 3 or Grade 4 adverse reactions indicates no events were reported.

a Grade 3 pain and axillary swelling/tenderness: Defined as any use of prescription pain reliever; prevents daily activity.

b Grade 3 swelling and erythema: Defined as >100 mm / >10 cm.

c Grade 3 fatigue, myalgia, arthralgia: Defined as significant; prevents daily activity.

d Grade 3 headache: Defined as significant; any use of prescription pain reliever or prevents daily activity.

e Grade 3 chills: Defined as prevents daily activity and requires medical intervention.

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

The median duration of solicited local and systemic adverse reactions was 2 days in participants who received either vaccine booster dose.

Unsolicited Adverse Events

Participants were monitored for unsolicited adverse events for up to 28 days following the booster dose. Serious adverse events and medically attended adverse events will be recorded for the entire study duration. As of April 27, 2022, among participants who had received a booster dose (bivalent vaccine [Original and Omicron BA.1]=437, Moderna COVID-19 Vaccine=377), unsolicited adverse events that occurred within 28 days following vaccination were reported by 18.5% of participants (n=81) who received bivalent vaccine (Original and Omicron BA.1) and 20.7% of participants (n=78) who received Moderna COVID-19 Vaccine. In these analyses, 99.9% of study participants had at least 28 days of follow-up after the booster dose. The incidence of unsolicited adverse events was similar between the vaccine groups and no new safety concerns were identified.

Serious Adverse Events

As of April 27, 2022, the median duration of follow-up was 43 days among bivalent vaccine (Original and Omicron BA.1) recipients and 57 days among Moderna COVID-19 Vaccine recipients. Serious adverse events were reported by 0.7% (n=3) of participants who received bivalent vaccine (Original and Omicron BA.1) and 0.3% (n=1) of participants who received Moderna COVID-19 Vaccine. None of the events in the bivalent vaccine (Original and Omicron BA.1) group or Moderna COVID-19 Vaccine group were considered related to vaccine.

Moderna COVID-19 Vaccine Administered as a Two-Dose Primary Series

Participants 18 Years and Older

The safety of Moderna COVID-19 Vaccine was evaluated in an ongoing Phase 3 randomized, placebo-controlled, observer-blind clinical trial conducted in the United States involving 30,346 participants 18 years of age and older who received at least one dose of Moderna COVID-19 Vaccine (n=15,184) or placebo (n=15,162) (Study 1, NCT04470427). Upon issuance of the Emergency Use Authorization (December 18, 2020) for Moderna COVID-19 Vaccine, participants were unblinded in a phased manner over a period of months to offer placebo participants Moderna COVID-19 Vaccine. The median duration of follow up for safety after the second injection during the blinded phase was 4 months. The median duration of follow up for safety after the second injection including both the blinded phase and the open-label phase was 6 months.

In Study 1, the median age of the population was 52 years (range 18-95); 22,826 (75.2%) participants were 18 to 64 years of age and 7,520 (24.8%) participants were 65 years of age and older. Overall, 52.6% of the participants were male, 47.4% were female, 20.5% were Hispanic or Latino, 79.2% were White, 10.2% were African American, 4.6% were Asian, 0.8% were American Indian or Alaska Native, 0.2% were Native Hawaiian or Pacific Islander, 2.0% were other races, and 2.1% were Multiracial. Demographic characteristics were similar between participants who received Moderna COVID-19 Vaccine and those who received placebo.

Unsolicited Adverse Events

Participants were monitored for unsolicited adverse events for 28 days following each dose. Serious adverse events and medically attended adverse events will be recorded for the entire study duration (2 years). Among the 30,346 participants who had received at least 1 dose of vaccine (N=15,184) or placebo (N=15,162), unsolicited adverse events that occurred within 28 days following any vaccination were reported by 31.3% of participants (n=4,752) who received Moderna COVID-19 Vaccine and 28.6% of participants (n=4,338) who received placebo.

During the 28-day follow-up period following any dose, lymphadenopathy-related events were reported by 1.7% of vaccine recipients and 0.8% of placebo recipients. These events included lymphadenopathy, lymphadenitis, lymph node pain, vaccination-site lymphadenopathy, injection-site lymphadenopathy, and axillary mass.

During the 7-day follow-up period of any vaccination, hypersensitivity events of injection site rash or injection site urticaria, likely related to vaccination, were reported by 6 participants in the Moderna COVID-19 Vaccine group and none in the placebo group. Delayed injection site reactions that began >7 days after vaccination were reported in 1.4% of vaccine recipients and 0.7% of placebo recipients. Delayed injection site reactions included pain, erythema, and swelling and are likely related to vaccination.

In the blinded portion of the study, there were 8 reports of facial paralysis (including Bell’s palsy) in the Moderna COVID-19 Vaccine group, and 3 in the placebo group. In the 28-day follow-up period there were two cases of facial paralysis in the Moderna COVID-19 Vaccine group, which occurred on 8 and 22 days, respectively, after vaccination, and one in the placebo group, which occurred 17 days after vaccination. Currently available information on facial paralysis is insufficient to determine a causal relationship with the vaccine.

In the blinded portion of the study, there were 50 reports of herpes zoster in the Moderna COVID-19 Vaccine group, and 23 in the placebo group. In the 28-day period after any vaccination, there were 22 cases of herpes zoster in the Moderna COVID-19 Vaccine group, and 15 in the placebo group. Currently available information on herpes zoster infection 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 adverse events (including other neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to Moderna COVID-19 Vaccine.

Serious Adverse Events

During the blinded phase of the study, serious adverse events were reported by 1.8% (n=268) of participants who received Moderna COVID-19 Vaccine and 1.9% (n=292) of participants who received placebo.

There were three serious adverse events of angioedema/facial swelling in the vaccine group in recipients with a history of injection of dermatological fillers. The onset of swelling was reported 1-2 days after the second dose and was likely related to vaccination.

There were no other notable patterns or imbalances between treatment groups for specific categories of serious adverse events (including neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to Moderna COVID-19 Vaccine.

Adolescents 12 Years Through 17 Years of Age

Safety data for Moderna COVID-19 Vaccine in adolescents were collected in an ongoing Phase 2/3 clinical trial with multiple parts. The first portion of the trial was a randomized, placebo-controlled, observer-blind, clinical trial conducted in the United States involving 3,726 participants 12 years through 17 years of age who received at least one dose of Moderna COVID-19 Vaccine (n=2,486) or placebo (n=1,240) (Study 3, NCT04649151). Overall, 51.4% were male, 48.6% were female, 11.6% were Hispanic or Latino, 83.9% were White, 3.4% were African American, 5.9% were Asian, 0.5% were American Indian or Alaska Native, <0.1% were Native Hawaiian or Pacific Islander, 1.0% were other races, and 4.5% were Multiracial. Demographic characteristics were similar among participants who received Moderna COVID-19 Vaccine and those who received placebo.

Unsolicited Adverse Events

Participants were monitored for unsolicited adverse events for up to 28 days following each dose. Serious adverse events and medically attended adverse events will be recorded for the entire study duration. As of May 8, 2021, among participants who had received at least 1 dose of vaccine or placebo (vaccine=2,486, placebo=1,240), unsolicited adverse events that occurred within 28 days following each vaccination were reported by 20.5% of participants (n=510) who received Moderna COVID-19 Vaccine and 15.9% of participants (n=197) who received placebo. In these analyses, 97.3% of study participants had at least 28 days of follow-up after Dose 2.

A 14-year-old male experienced probable myocarditis with onset of symptoms 1 day after Dose 2 of Moderna COVID-19 Vaccine. Symptoms resolved after 8 days and no sequelae were observed at 5 months. There were no cases of myocarditis among placebo recipients.

During the 28-day follow-up period following any dose, lymphadenopathy-related events that were not necessarily captured in the 7-day e-diary were reported by 5.0% of vaccine recipients and 0.5% of placebo recipients. These events included lymphadenopathy, vaccination-site lymphadenopathy and injection-site lymphadenopathy which were plausibly related to vaccination.

During the 28-day follow-up period following any dose, hypersensitivity adverse events were reported in 1.8% of vaccine recipients and 0.6% of placebo recipients. Hypersensitivity events in the vaccine group included injection site rash and injection site urticaria, which are likely related to vaccination. Delayed injection site reactions that began >7 days after vaccination were reported in 0.9% of vaccine recipients and in no placebo recipients. Delayed injection site reactions included pain, erythema, and swelling and are likely related to vaccination.

There were no other notable patterns or numerical imbalances between treatment groups for specific categories of adverse events that would suggest a causal relationship to Moderna COVID-19 Vaccine.

Serious Adverse Events

As of May 8, 2021, serious adverse events were reported by 0.2% (n=6) of participants who received Moderna COVID-19 Vaccine and 0.2% (n=2) of participants who received placebo. In these analyses, 97.3% of study participants had at least 28 days of follow-up after Dose 2, and the median follow-up time for all participants was 53 days after Dose 2.

There were no notable patterns or imbalances between treatment groups for specific categories of serious adverse events that would suggest a causal relationship to Moderna COVID-19 Vaccine.

Additional Safety Analyses

Study 3 participants started to enter an open-label, observational phase after May 10, 2021. A long-term safety analysis was conducted in participants from Study 3 who received Moderna COVID-19 Vaccine (n=2,486) with a cut-off date of January 31, 2022. In these analyses, the median duration of follow-up including both the blinded and open-label phases was 312 days after Dose 2 and 95.6% of study participants have had at least 6 months of follow-up after Dose 2. Through the cut-off date, there were no serious adverse events causally related to the vaccine.

Individuals 6 Years Through 11 Years of Age

Safety data for Moderna COVID-19 Vaccine from the blinded portion of Study 4 included data in 4,002 participants 6 years through 11 years of age who received at least one dose of Moderna COVID-19 Vaccine (n=3,007) or placebo (n=995). As of the data cutoff date of November 10, 2021, the median duration of blinded follow-up for safety was 51 days after Dose 2, and 1,284 participants had been followed for at least 2 months after Dose 2 (vaccine=1,006, placebo=218).

Demographic characteristics in Study 4 were similar among participants who received Moderna COVID-19 Vaccine and those who received placebo. Overall, 50.8% were male, 49.2% were female, 18.5% were Hispanic or Latino, 65.6% were White, 10.0% were African American, 9.9% were Asian, 0.4% were American Indian or Alaska Native, <0.1% were Native Hawaiian or Pacific Islander, 2.1% were other races, and 10.6% were Multiracial.

Unsolicited Adverse Events

Participants were monitored for unsolicited adverse events for up to 28 days following each dose. Serious adverse events and medically attended adverse events will be recorded for the entire study duration. As of November 10, 2021, among participants who had received at least 1 dose of vaccine or placebo (vaccine=3,007, placebo=995), unsolicited adverse events that occurred within 28 days following each vaccination were reported by 29.6% of participants (n=891) who received Moderna COVID-19 Vaccine and 25.1% of participants (n=250) who received placebo. In these analyses, 98.6% of study participants had at least 28 days of follow-up after Dose 2.

During the 28-day follow-up period following any dose, lymphadenopathy-related events were reported by 1.8% of vaccine recipients and 0.6% of placebo recipients. These events included lymphadenopathy, lymph node pain, injection-site lymphadenopathy, and vaccination-site lymphadenopathy which were plausibly related to vaccination.

During the 28-day follow-up period following any dose, hypersensitivity adverse events were reported in 4.3% of vaccine recipients and 2.1% of placebo recipients. Hypersensitivity events in the vaccine group included injection site rash and injection site urticaria, which are likely related to vaccination. Delayed injection site reactions that began >7 days after vaccination were reported in 2.7% of vaccine recipients and in 0.2% of placebo recipients. Delayed injection site reactions included pain, erythema, and swelling and are likely related to vaccination.

During the 28-day follow-up period following any dose, events of abdominal pain (including abdominal pain, abdominal pain upper, and abdominal pain lower) were reported by 1.1% of vaccine recipients and 0.6% of placebo recipients. 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 adverse events that would suggest a causal relationship to Moderna COVID-19 Vaccine.

Serious Adverse Events

As of November 10, 2021, serious adverse events were reported by 0.2% (n=6) of participants who received Moderna COVID-19 Vaccine and 0.2% (n=2) participants who received placebo. None of the events in the Moderna COVID-19 Vaccine group were considered related to vaccine. In these analyses, 98.6% of study participants had at least 28 days of follow-up after Dose 2, and the median follow-up time for all participants was 51 days after Dose 2.

There were no notable patterns or imbalances between treatment groups for specific categories of serious adverse events that would suggest a causal relationship to Moderna COVID-19 Vaccine.

Additional Safety Analyses

Participants 6 years through 11 years in Study 4 started to enter an open-label, observational phase after November 1, 2021. A long-term safety analysis was conducted in participants 6 years through 11 years from Study 4 who received Moderna COVID-19 Vaccine (n=3,007) with a cut-off date of February 21, 2022. In these analyses, the median duration of follow-up including both the blinded and open-label phases was 158 days after Dose 2. Through the cut-off date, there were no serious adverse events causally related to the vaccine.

Individuals 6 Months Through 5 Years of Age

Safety data for Moderna COVID-19 Vaccine from the blinded portion of Study 4 included data in 6,388 participants 6 months through 5 years of age who received at least one dose of Moderna COVID-19 Vaccine (n=4,792) or placebo (n=1,596). As of the data cutoff date of February 21, 2022, the median duration of blinded follow-up for safety for participants 6 months through 23 months was 68 days after Dose 2. For participants 2 years to 5 years, the median duration of blinded follow-up for safety was 71 days after Dose 2.

For participants 6 months through 23 months, 51.1% were male, 48.9% were female, 13.2% were Hispanic or Latino, 79.0% were White, 3.1% were African American, 4.9% were Asian, 0.2% were American Indian or Alaska Native, 0.0% were Native Hawaiian or Pacific Islander, 1.5% were other races, and 10.6% were Multiracial. For participants 2 years through 5 years, 50.8% were male, 49.2% were female, 14.2% were Hispanic or Latino, 76.5% were White, 4.5% were African American, 6.0% were Asian, 0.4% were American Indian or Alaska Native, 0.3% were Native Hawaiian or Pacific Islander, 1.5% were other races, and 10.4% were Multiracial. Demographic characteristics were similar among participants who received Moderna COVID-19 Vaccine and those who received placebo.

Unsolicited Adverse Events

Participants were monitored for unsolicited adverse events for up to 28 days following each dose and follow-up is ongoing. Serious adverse events and medically attended adverse events will be recorded for the entire study duration.

As of February 21, 2022, among participants 6 months through 23 months of age who had received at least 1 dose of vaccine or placebo (vaccine=1,761, placebo=589), unsolicited adverse events that occurred within 28 days following each vaccination were reported by 49.3% of participants (n=869) who received Moderna COVID-19 Vaccine and 48.2% of participants (n=284) who received placebo. In these analyses, 83.1% of study participants 6 months through 23 months of age had at least 28 days of follow-up after Dose 2. Among participants 2 years through 5 years of age who had received at least 1 dose of vaccine or placebo (vaccine=3,031, placebo=1,007), unsolicited adverse events that occurred within 28 days following each vaccination were reported by 40.0% of participants (n=1,212) who received Moderna COVID-19 Vaccine and 37.5% of participants (n=378) who received placebo. In these analyses, 89.3% of study participants 2 years through 5 years of age had at least 28 days of follow-up after Dose 2.

During the 28-day follow-up period following any dose, lymphadenopathy-related events were reported by 1.5% of vaccine recipients and 0.2% of placebo recipients who were 6 months through 23 months of age and 0.9% of vaccine recipients and <0.1% of placebo recipients who were 2 years through 5 years of age. These events included lymphadenopathy, injection-site lymphadenopathy, and vaccination-site lymphadenopathy which were plausibly related to vaccination.

During the 28-day follow-up period following any dose, hypersensitivity adverse events were reported in 3.9% of vaccine recipients and 5.3% of placebo recipients who were 6 months through 23 months of age and 3.5% of vaccine recipients and 2.5% of placebo recipients who were 2 years through 5 years of age. Hypersensitivity events in the vaccine group included injection site rash and injection site urticaria, which are likely related to vaccination. Delayed injection site reactions that began >7 days after vaccination were reported in 1.2% of vaccine recipients and no placebo recipients who were 6 months through 23 months of age and 1.4% of vaccine recipients and <0.1% of placebo recipients who were 2 years through 5 years of age. Delayed injection site reactions included pain, erythema, and swelling and are likely related to vaccination.

During the 28-day follow-up period following any dose, events of abdominal pain (including abdominal pain, abdominal pain upper, and abdominal discomfort) were reported by 0.7% of vaccine recipients and 0.4% of placebo recipients who were 2 years through 5 years of age. 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 adverse events that would suggest a causal relationship to Moderna COVID-19 Vaccine.

Serious Adverse Events

As of February 21, 2022, serious adverse events were reported by 0.9% (n=15) of participants who received vaccine and 0.2% (n=1) of participants who received placebo who were 6 months through 23 months of age and 0.3% (n=9) of participants who received Moderna COVID-19 Vaccine and 0.2% (n=2) of participants who received placebo who were 2 years through 5 years of age. In these analyses, 83.1% of study participants 6 months through 23 months of age had at least 28 days of follow-up after Dose 2, and the median follow-up time for all participants was 68 days after Dose 2. In these analyses, 89.3% of study participants 2 years through 5 years of age had at least 28 days of follow-up after Dose 2, and the median follow-up time for all participants was 71 days after Dose 2.

In participants 6 months through 23 months of age who received the vaccine, a 1-year-old female experienced serious adverse events of a Grade 3 fever 6 hours after Dose 1 and a febrile convulsion 1 day after Dose 1. These events were considered related to vaccination. In participants 2 years through 5 years of age who received Moderna COVID-19 Vaccine, none of the events were considered related to vaccine.

Moderna COVID-19 Vaccine Administered as a First Booster Dose Following a Primary Series of Moderna COVID-19 Vaccine

Participants 18 Years and Older

Study 2 is a Phase 2, randomized, observer-blind, placebo-controlled, dose-confirmation study to evaluate the safety, reactogenicity, and immunogenicity of Moderna COVID-19 Vaccine in participants 18 years of age and older (NCT04405076). In this study, 198 participants received two doses (0.5 mL 1 month apart) of Moderna COVID-19 Vaccine primary series. In an open label-phase, 171 of those participants received a single booster dose (0.25 mL) at least 6 months (range of 5.8 to 8.5 months) after receiving the second dose of the primary series.

Among the 171 booster dose recipients, the median age was 55 years (range 18-87), 39.2% were male and 60.8% were female, 95.9% were White, 5.8% were Hispanic or Latino, 2.9% were Black or African American, 0.6% were Asian, and 0.6% were American Indian or Alaska Native. Following the booster dose, the median follow-up time was 5.7 months (range of 3.1 to 6.4 months).

Solicited Adverse Reactions

Table 3 presents the frequency and severity of reported solicited local and systemic adverse reactions among Study 2 Moderna COVID-19 Vaccine booster dose recipients 18 to <65 years of age and ≥65 years of age within 7 days of a booster vaccination.

Table 3: Number and Percentage of Participants 18 Years of Age and Older With Solicited Local and Systemic Adverse Reactions Starting Within 7 Days* After the Moderna COVID-19 Vaccine Booster Dose (Solicited Safety Set)

Participants

18 Years Through64 Years

(N=129)

n (%)

Participants

≥65 Years

(N=38)

n (%)

Local Adverse Reactions

Pain

111 (86.0)

29 (76.3)

Pain, Grade 3a

4 (3.1)

2 (5.3)

Axillary swelling/tenderness

32 (24.8)

2 (5.3)

Axillary swelling/tenderness, Grade 3a

1 (0.8)

0 (0)

Swelling (hardness) ≥25 mm

8 (6.2)

1 (2.6)

Swelling (hardness), Grade 3b

0 (0)

1 (2.6)

Erythema (redness) ≥25 mm

7 (5.4)

1 (2.6)

Erythema (redness), Grade 3b

1 (0.8)

0 (0.0)

Systemic Adverse Reactions

Fatigue

80 (62.0)

18 (47.4)

Fatigue, Grade 3c

4 (3.1)

3 (7.9)

Headache

76 (58.9)

16 (42.1)

Headache, Grade 3d

1 (0.8)

1 (2.6)

Myalgia

64 (49.6)

18 (47.4)

Myalgia, Grade 3c

4 (3.1)

1 (2.6)

Arthralgia

54 (41.9)

15 (39.5)

Arthralgia, Grade 3c

4 (3.1)

1 (2.6)

Chills

52 (40.3)

7 (18.4)

Nausea/vomiting

16 (12.4)

3 (7.9)

Fever

9 (7.0)

2 (5.4)

Fever, Grade 3e

2 (1.6)

0 (0.0)

Rash

3 (2.3)

0 (0)

Use of antipyretic or pain medication

64 (49.6)

11 (28.9)

* 7 days included day of vaccination and the subsequent 6 days. Events and use of antipyretic or pain medication were collected in the electronic diary (e-diary).

† Absence of rows for Grade 3 or Grade 4 adverse reactions indicates no events were reported.

a Grade 3 pain and axillary swelling/tenderness: Defined as any use of prescription pain reliever; prevents daily activity.

b Grade 3 swelling and erythema: Defined as >100 mm / >10 cm.

c Grade 3 fatigue, myalgia, arthralgia: Defined as significant; prevents daily activity.

d Grade 3 headache: Defined as significant; any use of prescription pain reliever or prevents daily activity.

e Grade 3 fever: Defined as ≥39.0° – ≤40.0°C / ≥102.1° – ≤104.0°F.

In participants who received a booster dose, the median duration of solicited local and systemic adverse reactions was 2 to 3 days.

Unsolicited Adverse Events

Overall, the 171 participants who received a booster dose had a median follow-up time of 5.7 months after the booster dose to the cut-off date (August 16, 2021). Through the cut-off date, there were no unsolicited adverse events not already captured as solicited local and systemic reactions that were considered causally related to Moderna COVID-19 Vaccine.

Serious Adverse Events

Of the 171 participants who received a booster dose of Moderna COVID-19 Vaccine, there were no serious adverse events reported from the booster dose through 28 days after the booster dose. Through the cut-off date of August 16, 2021, there were no serious adverse events following the booster dose considered causally related to Moderna COVID-19 Vaccine.

Adolescents 12 Years Through 17 Years of Age

Safety data for a booster dose of Moderna COVID-19 Vaccine in adolescents were collected in an ongoing Phase 2/3 clinical trial with multiple parts. The open-label booster portion of the study involved 1,364 participants 12 years through 17 years of age who received a booster dose of Moderna COVID-19 Vaccine at least 5 months after the second dose of the primary series (Study 3, NCT04649151). Overall, 51.2% were male, 48.8% were female, 13.1% were Hispanic or Latino, 84.9% were White, 3.2% were African American, 4.8% were Asian, 0.5% were American Indian or Alaska Native, <0.1% were Native Hawaiian or Pacific Islander, 0.7% were other races, and 5.2% were Multiracial. As of the data cutoff date of May 16, 2022, the median duration of follow-up for safety was 116 days after the booster dose.

Solicited Adverse Reactions

Local and systemic adverse reactions and use of antipyretic medication were solicited in an electronic diary for 7 days following the injection (i.e., day of vaccination and the next 6 days) among participants receiving Moderna COVID-19 Vaccine as a booster dose. Events that persisted for more than 7 days were followed until resolution.

Table 4 presents the frequency and severity of reported solicited local and systemic adverse reactions among Study 3 Moderna COVID-19 Vaccine booster dose recipients 12 years through 17 years of age within 7 days of a booster vaccination.

Table 4: Number and Percentage of Adolescents 12 Years Through 17 Years of Age With Solicited Local and Systemic Adverse Reactions Starting Within 7 Days* After the Moderna COVID-19 Vaccine Booster Dose (Solicited Safety Set)

Moderna COVID-19 Vaccine Booster Dose (N=1,312)n (%)

Local Adverse Reactions

Pain

1,196 (91.2)

Pain, Grade 3a

39 (3.0)

Axillary swelling/tenderness

367 (28.0)

Axillary swelling/tenderness, Grade 3a

4 (0.3)

Swelling (hardness) ≥25 mm

176 (13.4)

Swelling (hardness), Grade 3b

9 (0.7)

Erythema (redness) ≥25 mm

120 (9.2)

Erythema (redness), Grade 3b

9 (0.7)

Systemic Adverse Reactions

Fatigue

769 (58.7)

Fatigue, Grade 3c

53 (4.0)

Headache

748 (57.1)

Headache, Grade 3d

28 (2.1)

Myalgia

529 (40.4)

Myalgia, Grade 3c

47 (3.6)

Arthralgia

316 (24.1)

Arthralgia, Grade 3c

17 (1.3)

Chills

399 (30.4)

Chills, Grade 3e

7 (0.5)

Nausea/vomiting

234 (17.8)

Nausea/vomiting, Grade 3f

2 (0.2)

Fever

79 (6.1)

Fever, Grade 3g

8 (0.6)

Use of antipyretic or pain medication

515 (39.3)

* 7 days included day of vaccination and the subsequent 6 days. Events and use of antipyretic or pain medication were collected in the electronic diary (e-diary).

† Absence of rows for Grade 4 adverse reactions indicates no events were reported.

a Grade 3 pain and axillary swelling/tenderness: Defined as any use of prescription pain reliever; prevents daily activity.

b Grade 3 swelling and erythema: Defined as >100 mm / >10 cm.

c Grade 3 fatigue, myalgia, arthralgia: Defined as significant; prevents daily activity.

d Grade 3 headache: Defined as significant; any use of prescription pain reliever or prevents daily activity.

e Grade 3 chills: Defined as prevents daily activity and requires medical intervention.

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

g Grade 3 fever: Defined as ≥39.0° – <40.0°C / ≥102.1° – < 104.0°F.

In participants who received a booster dose, the median duration of solicited local and systemic adverse reactions was 3 days.

Unsolicited Adverse Events

Participants were monitored for unsolicited adverse events for up to 28 days following the booster dose. Serious adverse events and medically attended adverse events will be recorded for the entire study duration. As of May 16, 2022, among the 1,364 participants who had received a booster dose, unsolicited adverse events that occurred within 28 days following vaccination were reported by 14.2% of participants (n=194). In these analyses, 97.4% of study participants had at least 28 days of follow-up after the booster dose. No new safety concerns were identified.

Serious Adverse Events

Through the cut-off date of May 16, 2022, with a median follow-up duration of 116 days after booster, no serious adverse events following the booster dose were reported.

Individuals 6 Years Through 11 Years of Age

Safety data for a booster dose of Moderna COVID-19 Vaccine in individuals 6 years through 11 years of age were collected in an ongoing Phase 2/3 clinical trial with multiple parts. The open-label booster portion of the study involved 1,294 participants 6 years through 11 years of age who received a booster dose of Moderna COVID-19 Vaccine at least 6 months after the second dose of the primary series (Study 4, NCT04796896). Overall, 51.9%% were male, 48.1% were female, 15.6% were Hispanic or Latino, 65.7% were White, 11.0% were African American, 7.8% were Asian, 0.5% were American Indian or Alaska Native, <0.1% were Native Hawaiian or Pacific Islander, 1.9% were other races, and 11.8% were Multiracial. As of the data cutoff date of May 23, 2022, the median duration of follow-up for safety was 29 days after the booster dose.

Solicited Adverse Reactions

Local and systemic adverse reactions and use of antipyretic medication were solicited in an electronic diary for 7 days following the injection (i.e., day of vaccination and the next 6 days) among participants receiving Moderna COVID-19 Vaccine. Events that persisted for more than 7 days were followed until resolution.

Table 5 presents the frequency and severity of reported solicited local and systemic adverse reactions among Study 4 Moderna COVID-19 Vaccine booster dose recipients 6 years through 11 years of age within 7 days of a booster vaccination.

Table 5: Number and Percentage of Participants 6 Years Through 11 Years of Age With Solicited Local and Systemic Adverse Reactions Starting Within 7 Days* After the Moderna COVID-19 Vaccine Booster Dose (Solicited Safety Set)

Moderna COVID-19 Vaccine Booster Dose (N=1,280)n (%)

Local Adverse Reactions

Pain

1,152 (90.1)

Pain, Grade 3a

24 (1.9)

Axillary swelling/tenderness

355 (27.8)

Axillary swelling/tenderness, Grade 3a

4 (0.3)

Swelling (hardness) ≥25 mm

139 (10.9)

Swelling (hardness), Grade 3: >100 mm

4 (0.3)

Erythema (redness) ≥25 mm

137 (10.7)

Erythema (redness), Grade 3: >100 mm

4 (0.3)

Systemic Adverse Reactions

Fatigue

625 (48.9)

Fatigue, Grade 3b

47 (3.7)

Headache

489 (38.2)

Headache, Grade 3b

22 (1.7)

Myalgia

269 (21.0)

Myalgia, Grade 3b

19 (1.5)

Arthralgia

160 (12.5)

Arthralgia, Grade 3b

12 (0.9)

Chills

179 (14.0)

Chills, Grade 3c

4 (0.3)

Nausea/vomiting

168 (13.1)

Nausea/vomiting, Grade 3a

6 (0.5)

Fever ≥38.0°C / >100.4°F

108 (8.5)

Fever, Grade 3: 39.0° — 40.0°C / 102.1° — 104.0°F

16 (1.3)

Fever, Grade 4: > 40° C / 104.0°F

1 (<0.1)

Use of antipyretic or pain medication

462 (36.1)

* 7 days included day of vaccination and the subsequent 6 days. Events and use of antipyretic or pain medication were collected in the electronic diary (e-diary).

† Absence of rows for Grade 4 adverse reactions indicates no events were reported.

a Grade 3 pain, axillary swelling/tenderness, nausea/vomiting: Defined as prevents daily activity.

b Grade 3 fatigue, headache, myalgia, arthralgia: Defined as significant; prevents daily activity.

c Grade 3 chills: Defined as prevents daily activity and requires medical intervention.

In participants who received a booster dose, the median duration of solicited local and systemic adverse reactions was 3 days.

Unsolicited Adverse Events

Participants were monitored for unsolicited adverse events for up to 28 days following the booster dose. Serious adverse events and medically attended adverse events will be recorded for the entire study duration. As of May 23, 2022, among the 1,294 participants who had received a booster dose, unsolicited adverse events that occurred within 28 days following vaccination were reported by 13.1% of participants (n=169). In these analyses, 55.4% of study participants had at least 28 days of follow-up after the booster dose. Serum sickness-like reaction with onset 10 days following administration of a booster dose was reported in an 8-year-old participant. This event was assessed as related to vaccination. After initiation of treatment with antihistamines and steroids, symptoms resolved within 15 days with the exception of intermittent urticaria that was ongoing 31 days after the onset of the reaction.

Serious Adverse Events

As of May 23, 2022, with a median follow-up duration of 29 days after booster, there was one serious adverse event of abdominal pain reported 16 days following booster dose by a 7-year-old participant. Currently available information is insufficient to determine a causal relationship with the vaccine.

Moderna COVID-19 Vaccine Administered as a First Booster Dose Following Primary Vaccination with Another Authorized or Approved COVID-19 Vaccine

The safety of a Moderna COVID-19 Vaccine booster dose in individuals who completed primary vaccination with another authorized or approved COVID-19 vaccine (heterologous booster dose) is inferred from the safety of a Moderna COVID-19 Vaccine booster dose administered following completion of a Moderna COVID-19 Vaccine primary series (homologous booster dose) and from data from an independent Phase 1/2 open-label clinical trial (NCT04889209) conducted in the United States that evaluated a booster dose of Moderna COVID-19 Vaccine. The booster dose that study participants received contained twice the amount of mRNA compared to the authorized booster dose of Moderna COVID-19 Vaccine. In this study, adults who had completed primary vaccination with a Moderna COVID-19 Vaccine 2-dose series (N=151), a Janssen COVID-19 Vaccine single dose (N=156), or a Pfizer-BioNTech COVID-19 Vaccine 2-dose series (N=151) at least 12 weeks (range 12 to 20 weeks) prior to enrollment and who reported no history of SARS-CoV-2 infection were randomized 1:1:1 to receive a booster dose of one of three vaccines: Moderna COVID-19 Vaccine, Janssen COVID-19 Vaccine, or Pfizer-BioNTech COVID-19 Vaccine. Adverse events were assessed through 28 days after the booster dose. An overall review of adverse reactions reported following the Moderna COVID-19 Vaccine heterologous booster dose did not identify any new safety concerns, as compared with adverse reactions reported following Moderna COVID-19 Vaccine primary series doses or homologous booster dose.

Moderna COVID-19 Vaccine Administered as a Second Booster Dose Following Primary and Booster Vaccination with Another Authorized or Approved COVID-19 Vaccine

In an independently conducted study (Gili Regev‑Yochay, Tal Gonen, Mayan Gilboa, et al. 2022 DOI: 10.1056/NEJMc2202542), Moderna COVID-19 Vaccine was administered as a second booster dose to 120 participants 18 years of age and older who had received a 2-dose primary series and a first booster dose of Pfizer-BioNTech COVID-19 Vaccine at least 4 months prior. No new safety concerns were reported during up to three weeks of follow-up after the second booster dose.

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