ParticipantsC4591031 Substudy B (Participants 12–30 Years Old)

The study was conducted at sites in Germany, South Africa, and the United States from December 20, 2021, to November 29, 2022. Participant disposition is summarized in Fig. 1A; 1485 participants received study intervention and comprised the safety population (Sequence 1 [BNT162b2 → placebo], n = 753; Sequence 2 [placebo → BNT162b2], n = 732).

Fig. 1

Disposition of participants in a C4591031 Substudy B (12–30 years of age), b in Study C4591007 (5– < 12 years of age), and c in Study C4591007 (12–15 years of age). aTwo participants (0.1%) were randomized to Sequence 2 (placebo → BNT162b2) in error and were withdrawn from the study before receiving the study vaccine. bOne participant randomized to Sequence 1 (BNT162b2 → placebo) received BNT162b2 instead of placebo for their second vaccination. cOne participant received BNT162b2 10 µg as dose 1 because of a dosing error, and BNT162b2 30 µg was received for dose 2 and dose 3. In C4591031 Substudy B, participants received BNT162b2 at the 30-µg dose level. In Study C4591007, the decrease in the number of participants who received placebo as dose 2 and with no participants receiving placebo as dose 3 is a result of the emergency use authorization. In Study C4591007, 149 participants were unblinded after the first vaccination, 110 were unblinded after the second vaccination, and one participant was not unblinded but lost to follow-up after the first vaccination

Demographic characteristics in the two vaccine sequence groups were balanced (Table 1). Overall, 40.7% of participants were male, 66.3% White, 21.1% Black, and 78.9% non-Hispanic/non-Latino. Median time between the last prior dose of BNT162b2 (received before the study) and the first study vaccination was 8.9 months; 22.4% of participants were obese (≥ 16 years old, 24.5%; 12–15 years old, 13.5%). Medical history included myocardial infarction in one participant, occurring before study enrollment; two participants with a history of obesity had a medical history of fatty liver disease.

Table 1 Participant demographic and clinical characteristicsStudy C4591007 (Participants 5–15 Years Old)

This portion of the study was conducted at sites in Mexico, Spain, and the United States from October 2021 to December 2023. Disposition of 5- to  < 12-year-old participants is summarized in Fig. 1B. The safety population of 5- to < 12-year-old participants included 778 (BNT162b2 10 µg, n = 518; placebo, n = 260) of the 784 randomized participants; six randomized participants did not receive study vaccination and were excluded from the safety population. In accordance with protocol allowance and because of the two-dose primary series EUA for BNT162b2 10 μg for 5- to < 12-year-olds, participants who originally received placebo were unblinded and offered the opportunity to receive BNT162b2. Therefore, percentages of participants who received placebo declined from the first to second dose (99.6–42.1%), with no participants receiving placebo as dose 3. Eleven participants in the BNT162b2 group were ≥ 12 years old at the time of dose 3 administration and therefore received the age-appropriate 30-µg dose level. Disposition of 12- to 15-year-old participants who received open-label BNT162b2 30 µg is summarized in Fig. 1C. The safety population of 12- to 15-year-old participants included 487 of the 507 assigned participants; one participant did not receive study vaccination and 19 participants’ parent/guardian did not provide compliant informed consent; these participants were therefore excluded from the safety population.

Demographic characteristics of 5- to < 12-year-old participants are shown in Table 1 and were balanced across the BNT162b2 and placebo groups. Overall, 52.2% of 5- to < 12-year-old participants were male, 82.8% White, 88.9% non-Hispanic/non-Latino, 14.7% SARS-CoV-2 positive at baseline, and 10.2% obese. Demographic characteristics of 12- to 15-year-old participants are also shown in Table 1. Overall, 55.6% of 12- to 15-year-old participants were male, 46.8% White, 86.7% Hispanic/Latino, and 21.4% obese. In contrast to 5- to  < 12-year-old participants, most participants in this age group were SARS-CoV-2positive at baseline (88.7 vs. 14.7%), reflecting the longer duration of enrollment for 12- to 15-year-old participants encompassing the period when Omicron sublineages were predominant.

Troponin I LevelsC4591031 Substudy B (Participants 12–30 Years Old)

The data after BNT162b2 or placebo administration were summarized by combining data from participants in Sequence 1 (BNT162b2 → placebo) and Sequence 2 (placebo → BNT162b2), thereby providing the overall number of elevated troponin I results in each group (results by vaccine sequence are provided in Table S1). Before receipt of BNT162b2 or placebo, seven (0.5%) and 11 (0.8%) participants, respectively, had elevated troponin I results (Fig. 2A). At 4 days after receipt of BNT162b2 or placebo, nine (0.7%) and 14 (1.0%) participants, respectively, had elevated troponin I results, and the difference in the percentage of participants with elevated troponin I results between the BNT162b2 and placebo groups was −0.5% (95% CI −1.1%, 0.2%). One month after receipt of BNT162b2 or placebo, nine (0.7%) and seven (0.5%) participants, respectively, had elevated troponin I results; the difference in the percentage of participants with elevated troponin I results between the BNT162b2 and placebo groups was 0.2% (95% CI −0.3%, 0.7%).

Fig. 2

Participants a 12–30 years of age in C4591031 Substudy B and b 5–15 years of age in Study C4591007 with elevated troponin I levels. Elevated troponin I levels were defined as > 35 ng/l in male participants and > 17 ng/l in female participants

Percentages of elevated troponin I results after receipt of BNT162b2 and after receipt of placebo were similar across age groups and by sex at all time points (Fig. 3). After receipt of BNT162b2 or placebo, percentages of elevated troponin I results were generally higher in younger compared with older age groups and in males compared with females. Additionally, there were similar percentages of participants with elevated troponin I results before and after receipt of BNT162b2 or placebo (Table S2). Results by troponin value range are summarized in Fig. S2.

Fig. 3

Participants in C4591031 Substudy B (12–30 years of age) with elevated troponin I levels by a age group and b sex. The exact two-sided 95% confidence interval (CI) was based on the Clopper–Pearson method. Data by troponin I level are summarized in Fig. S2

Study C4591007 (Participants 5–15 Years Old)

Four 5- to   < 12-year-old participants had elevated troponin I levels at any measured time point, all of whom received BNT162b2. One female participant (0.2%; 95% CI 0.0, 1.1) who received BNT162b2 10 µg had an elevated troponin value range of > 17–35 ng/ml at baseline (Fig. 2B). This participant did not have subsequent elevated troponin I levels after dose 2 or 3. At 4 days after dose 2 of BNT162b2 10 µg, two participants (0.4%; 95% CI 0.0, 1.4) had elevated levels (1 male, troponin value range of > 200 ng/ml; 1 female, troponin value range of > 17–35 ng/ml); neither had elevated levels at baseline nor reported symptoms of potential myocarditis or pericarditis, and additional troponin I levels are not available for these participants because neither received dose 3 (1 withdrew from study and 1 lost to follow-up). At 4 days after dose 3 of BNT162b2 10 µg, one male participant (0.2%; 95% CI 0.0, 1.3) had an elevated troponin I level (troponin value range > 50–100 ng/ml); this participant did not have elevated levels at the other time points. No participant in the placebo group had an elevated troponin I result.

Seven 12 to 15-year-old participants who received open-label BNT162b2 30 µg had elevated troponin I results and none reported symptoms of potential myocarditis or pericarditis. Two male participants (0.4%; 95% CI 0.0, 1.5) had an elevated troponin I value range of > 50–100 ng/ml at baseline, with no further elevated levels at the other time points (Fig. 2B). At 4 days after dose 2, two participants (0.4%; 95% CI 0.1, 1.5) had elevated levels (1 male, troponin value range > 35–50 ng/ml; 1 female, troponin value range > 17–35 ng/ml); neither had elevated levels at the other time points. At 4 days after dose 3, three participants (0.7%; 95% CI 0.1, 2.1) had elevated levels (1 male, troponin value range > 35–50 ng/ml; 1 male, troponin value range > 50–100 ng/ml; 1 female, troponin value range > 35–50 ng/ml); none had elevated levels at the other time points. Results by sex and troponin value range are provided in Table S3.

Adverse EventsC4591031 Substudy B (Participants 12–30 Years Old)

No clinical cases of myocarditis or pericarditis were reported. AESIs reported in participants after receiving BNT162b2 30 µg included COVID-19 (8 [0.6%]), dyspnea (2 [0.1%]), chest pain (2 [0.1%]), tachycardia (1 [< 0.1%]), and chest discomfort (1 [< 0.1%]; Table S4). AESIs reported in participants after receiving placebo included COVID-19 (2 [0.1%]) and chest discomfort (1 [< 0.1%]).

Seven participants (4 after receipt of BNT162b2; 3 after receipt of placebo) underwent evaluation for potential myocarditis or pericarditis based on protocol-defined symptoms (i.e., acute chest pain, shortness of breath, palpitations, or any other symptoms potentially indicative of myocarditis or pericarditis) in the 4 weeks after vaccination. Following investigations including troponin (I and T) levels, ECG, echocardiogram, and cardiac MRI, none were determined to be myocarditis or pericarditis. Of these seven participants, four (1 after receipt of BNT162b2 30 µg; 3 after receipt of placebo) had normal troponin results that were assessed by a local laboratory. Troponin results for the other three participants were not reported.

One participant experienced chest discomfort and dyspnea on the same day of BNT162b2 vaccination that were assessed by the investigator as related to study vaccination, with an abnormal ECG (heart rate 109 bpm; ST elevation) the next day. The echocardiogram and cardiac MRI were normal. Both events were reported as resolved after 2 days. The protocol-specified day 4 troponin level made available at the end of the study was 53.2 ng/l (prevaccination level was < 3.5 ng/l).

Frequencies of local reactions and systemic events were consistent with that reported in other clinical trials assessing additional BNT162b2 doses. No new safety or tolerability signals were identified.

Study C4591007 (Participants 5–15 Years Old)

No 5- to < 12-year-old or 12- to 15-year-old participants in the troponin group with elevated troponin I levels at baseline or after vaccination reported symptoms of potential myocarditis or pericarditis. Six participants (2 male; 4 female) reported symptoms within 4 weeks after a dose of vaccine that prompted evaluation for potential myocarditis or pericarditis. These participants reported chest pain (n = 5), shortness of breath (n = 3), and palpitations (n = 3); symptoms resolved in all participants. Three of the six participants had troponin evaluations and four of the six participants had ECG performed; all results were normal. One of the six participants had cardiac MRI performed with abnormal results (i.e., peribronchial parahilar linear interstitial opacities suggestive of reactive airway disease/viral infection) but no cardiac abnormalities reported. No confirmed myocarditis or pericarditis cases were observed in either age group.