The Long-Term Tolerability of BNT162b2 in Children and Adolescents (the CoVacU18 Study)

Background: The available safety data on the use of the messenger RNA–based COVID-19 vaccine BNT162b2 in persons under age 18 are limited to observation periods of up to six months.

Methods: In a retrospective, cross-sectional study, we evaluated self-reported vaccine tolerability (SRVT) in eleven symptom categories among persons who were under 18 years old when they received at least one dose of the BNT162b2 vaccine in Germany on or after 1 October 2021. Data were collected online from the parents or legal guardians of the vaccinated persons. Individual participation codes enabled authenticated and pseudonymous participation in the survey. In a subgroup, the SRVT of BNT162b2 was compared with that of vaccines against other illnesses than SARS-CoV-2 (e.g., influenza).

Results: Tolerability data were obtained from 3228 persons with a median age of 5.7 years; 49.6% were male. The median period of observation was 524 days. The more commonly reported undesired effects of the vaccine, mainly in older subjects, were local reactions—pain (49.7%), redness (23%)—with less common systemic symptoms including fatigue (20.1%), fever (11.4%), general feeling of illness (8.0%), and headache (6.5%). Compared to vaccines against other illnesses, BNT162b2 was more commonly associated with local and systemic symptoms (gastrointestinal, musculoskeletal, dermatological, neurological, psychological). 41 (1.3%) of the subjects reported that their SRVT persisted for ≥90 days after vaccination with BNT162b2: these symptoms were mainly psychological (15 subjects), neurological (9 subjects), and dermatological (8 subjects). There were 45 serious adverse events; these were associated with female sex (OR = 4.70, 95% confidence interval [2.17; 10.20]) and with long-term medication use (OR = 4.06 [1.53; 10.79]).

Conclusion: Vaccination with BNT162b2 was reportedly well tolerated by more than 98% of the children and adolescents who received it, although symptoms were more common than after vaccination against other illnesses than SARS-CoV-2. The participants in our study may have had a more positive attitude toward vaccination. On the other hand, a selection bias might exist for participants who experienced vaccination side effects.

Cite this as: Grieshaber V, Strumann C, Holzwarth S, Toepfner N, von Meissner WCG, Konstantopoulos N, von Poblotzki M, Hensel KO, Moor MB, Chao CM: The long-term tolerability of BNT162b2 in children and adolescents (The CoVacU18 Study). Dtsch Arztebl Int 2025; 122: 257–63. DOI: 10.3238/arztebl.m2025.0032

Table 3

Most frequent self reported vaccination reactions with a duration of ≥ 90 days

The messenger-RNA(mRNA)-based COVID-19 vaccine BNT162b2 was licensed only in October 2022 because of insufficient study data for children aged 6 months or older. We reported on the tolerability of the COVID-19 vaccinations in children younger than 5 years, which were carried out off-label until that date, in the CoVacU5 Study (1). Through 8 April 2023, 22.4% of children aged 5–11 years and only 0.1% of those younger than 4 years received at least one COVID-19 vaccination. By comparison, >69% of 12–17 year olds received the basic immunization (2). Basic immunization with BTN162b2 consists of a 3-dose vaccination schedule for children aged up to 4 years (3 μg/dose) and a 2-dose schedule for children from the age of 5 years (5–11 years: 10 μg/dose; from age 12 years: 30 μg/dose) (status: January 2024) (3). Retrospectively, COVID-19 associated hospital admissions in childhood were reduced by 44.2–98.7% as a result of vaccination (4, 5, 6, 7). In the approval studies the vaccine was found to be safe in all age groups. Safety signals were, however, detected—among others—for the occurrence of myocarditis in adolescents (8, 9, 10, 11). In the earlier CoVacU5 study, long-lasting postvaccination symptoms occurred for >90 days in individual cases (0.5%) (1). On this background, long-term data on the tolerability of BNT162b2 that exceed the observation periods of six months used to date, are relevant (4, 5, 8, 9, 10, 12). We present the results on the self-reported long-term tolerability of BNT162b2 in 0–17 year olds from the perspective of parents or legal guardians. Information gained from this may contribute to the characterization of the long-term tolerability profile of BNT162b2.

Methods

To evaluate the self-reported vaccine tolerability (SRVT) of BNT162b2 in persons younger than 18 years we undertook a non-commercial retrospective cross sectional study. We used the platform REDCap (Research Electronic Data Capture) to collect the data by means of an online survey, addressed to parents or legal guardians of children and adolescents vaccinated against COVID-19. Participants were recruited in free-of-charge cooperation with the initiative BildungAberSicher (a social media grassroots initiative concerned with improving protection from infection in schools and nurseries, https://bildungabersicher.net/) and 10 outpatient doctors’ practices nationwide that had registered in their databases the email addresses of parents or legal guardians of children vaccinated against COVID-19 in order to receive a vaccination certificate or be re-contacted (eMethods section). Invitations to participate in the study were sent by email three times by collaborators to all registered parents or legal guardians during the study period (25 May 2023 through 11 July 2023). The concrete content of the survey was not named for reasons of data protection. Allocation of an individual authentication code to parents or legal guardians enabled eligible, one-time, and pseudonymized participation in the study. The data collection included demographic data (age, sex, height, weight) as well as underlying diseases, long-term medication, number, date, and batch numbers (documented in the vaccination passport) of past COVID-19 vaccinations as well as the number and timings of confirmed infections with SARS-CoV-2. SRVT was collected in the following 11 symptom categories with closed questions for concrete symptoms: local (for example, pain), general (for example, chills, fatigue), fever, musculoskeletal (for example, myalgia), gastrointestinal (for example, abdominal pain), ear-nose-throat/ENT (for example, swelling of the lip), pulmonary (for example, cough), cardiovascular (for example, syncope), neurological (for example, headache), psychological (for example, disrupted sleep/impaired concentration), dermatological including lymph nodes (for example, petechiae, swollen lymph nodes). For additional symptoms, free-text fields were available. Temporal characteristics (symptom onset and duration in days) and symptoms related measures (for example, medication intake) were asked for all self-reported vaccination reactions (SRVR). The personal assessment of the medical risk/threat was captured by using an end point-named scale from 0 (not threatening) to 10 (very threatening). For children who in the 3 months preceding the COVID-19 vaccination had been vaccinated against a pathogen other than SARS-CoV-2 (Table 1), tolerability information was obtained on the basis of the same symptom categories so as to contrast vaccine tolerability in an internal comparison analysis. Retrospectively, study participation entailed 30 minutes/participant if symptoms were reported. The REDCap database was closed on 11 July 2023; completed questionnaires were extracted in an anonymized form and submitted for statistical analysis. The data were backed up by the Coordinating Centre for Clinical Trials Dresden. All children and adolescents were included who had received ≥1 dose of BNT162b2 from 1 October 2021 and before completing their 18th year of life. Exclusion criteria for questionnaires were multiple datasets with identical values for the variables age, sex, height, weight, and authentication code without any indication that they were one of several siblings (multiple pregnancies): missing/invalid authentication code; vaccination only with vaccines other than BNT162b2. Follow-up vaccinations after the 18th year of life were excluded from our analysis. Free-text responses were filtered by the terms “myocarditis”/”pericarditis”. Consistent with Good Clinical Practice (GCP), hospital admissions and deaths were categorized as serious adverse events (SAE). Furthermore, we categorized symptom duration ≥90 days as an SAE (in accordance with a long-term health impairment in the GCP definition of SAEs) (13). Ethics approval for the study was granted by the ethics committee of Witten/Herdecke University (vote No. S-61/2023). Participation necessitated written consent from the parents or legal guardians to voluntary study participation and data processing. We followed the STROBE guidelines for reporting study results.

Table 1

Number of reported vaccinations using BNT162b2- and non-SARS-CoV-2 vaccinations, considered in the internal comparison analysis

Outcome measures

The primary outcome measures were the frequency and duration of SRVRs after application of BNT162b2, subdivided into 11 symptom categories, as well as symptom related measures, stratified by age groups (0–23 months, 2–4 years, 5–11 years, 12–17 years), sex, and vaccine dose. The secondary outcome was the comparison of the frequency and duration of SRVRs compared with vaccinations for diseases other than SARS-CoV-2.

Statistical analyses

We used the software package IBM SPSS Statistics, version 29.0.0.0 (241) for all our statistical calculations. We defined the significance level at p<0.05. Odds ratios (OR) for the occurrence of SRVRs were determined in binary logistic regression models. We selected as predictors age groups, sex, comorbidities, and long-term medication. The models were controlled for height, weight, and dose [µg]. The tolerance values of the predictors were determined a priori in order to rule out multicollinearity. We selected as the independent variable “at least one SRVR”, one of the 11 symptom categories, or the occurrence of an SAE. In a subgroup of children who received BNT162b2 as well as a vaccine against a pathogen other than SARS-CoV-2, we undertook an internal comparison analysis to contrast rates/frequencies of SRVRs. In these regression models, BNT162b2 in comparison to non-SARS-CoV-2 vaccines was selected as the variable of greatest interest.

We used the Bonferroni correction for multiple testing to adjust calculated p values and confidence intervals of the binary logistic regression models. To assess the risk of bias we used the Chi square [X²] test to carry out sensitivity analyses for the occurrence of ≥1 SRVR in dependence of the vaccination period (deadline 1 October 2021) and the validity of reported batch numbers.

Results

We contacted persons at 15 423 email addresses and received 5842 completed questionnaires (response rate=37.9%). Figure 1 shows the total number and reasons for exclusion. We included 3228 children/adolescents (median age=5.7 years; interquartile range [IQR]=3.4–9.5) who had received ≥1 dose of BNT162b2 aged < 18 years in Germany. eSupplement Table 1 shows differences between included and excluded participants. The median observation period was 524 days (IQR=500–553 days). 3119 children (96.6%) received the basic immunization (≥doses of BNT162b2), 49.6% were male, 12.3% reported chronic underlying diseases, and 7.6% reported taking long-term medication (eSupplement Table 2). The greatest numbers of reports were for existing pulmonary (n=120 [3.7%]) and cardiovascular diseases (n=53 [1.6%]) and chromosomal aberrations (n=37 [1.1%]). We used using the drug information system of the German Federal Institute for Drugs and Medical Devices to check batch numbers for authenticity while considering the vaccination date (14). Where required, information on the vaccine variant was corrected (monovalent/bivalent) for 74.1% of all reported vaccinations, a valid batch number had been reported; this information was missing for 24.8%. eSupplement Table 3 shows the nationwide distribution of included study participants.

Figure 1

Overview of inclusions and exclusions of received study participation notices

Table 2

Internal comparison analysis SRVR after BNT162b2 and non-SARS-CoV-2 vaccinations, stratified by age groups

Tolerability data

We analyzed SRVRs chronologically by 11 symptom categories and stratified them by age groups. Local reactions at the injection site (pain: 49.7%, erythema: 23%), fatigue (20.1%), fever (11.4%), general malaise (8.0%), and headache (6.5%) were reported most often. Figure 2 shows age-group specific rates of adverse events. Compared with the 1st vaccination, rates of SRVRs fell after every subsequent vaccination. In this cohort, no significant association existed between SRVRs and the vaccine dose. Older children more often reported adverse effects. 6.2% of all children received medication for post-vaccination symptoms. 0.5% of all children presented to a doctor as outpatients. Parents or legal guardians reported significantly more adverse effects for girls after the 1^st and 2^nd dose (1st dose: OR=1.31 [1.07; 1.61], p=0.003; 2nd dose: OR=1.26 [1.03; 1.55], p=0.016) and for people with chronic diseases after the 2nd dose (OR=1.47 [1.01; 2.15], p=0.039) (eSupplement Table 4). 98.6% assessed SRVRs as constituting medically no risk/threat or only a mild one (range 0–3) (eSupplement Table 5). eSupplement Table 6 shows frequency rates for all symptoms asked.

Figure 2

Evaluations of reports regarding self reported vaccine tolerability (SRVT) in 3228 children vaccinated against COVID-19

Internal comparison analysis

In a subgroup of 1021 children the SRVT of BNT162b2 was compared with vaccines for diseases other than SARS-CoV-2 that had been administered a maximum of 3 months before BNT162b2, based on the rates/frequency of SRVRs. The minimum observation period for both vaccines was five months. In total, 3226 vaccinations using BNT162b2 and 1504 vaccinations for diseases other than SARS-CoV-2 were included in the analysis (Table 1). In the mean, SRVRs after non-SARS-CoV-2 vaccinations started on the day the vaccination was given and lasted two days. Table 2 shows the age-group specific results of the logistic regression models.

Severe adverse events

48 SAE were reported for 45 children (1.39%). 69% of those affected were 5 years or older. In 41 children (1.3%), SRVRs lasted ≥90 days (median onset=1.5 days; median duration=126.5 days) and were persistent in 22 children at the time of the data collections (eSupplement Table 7). Most reports were of headache, depressive moods, and impaired concentration (Table 3). 63% (n=26) of those affected reported a positive history of SARS-CoV-2 (positive antigen or PCR test). In 58% (n=15), the initial infection started ≥60 days after the latest vaccination.

Seven (n=6) inpatient stays were reported (median age=11.7 years; female, n=5 [83.3%]; comorbidities, 0 [0%]; median duration of stay=6 days). Hospital admission was prompted according to reports by neurological, gastrointestinal, and/or psychological SRVRs within 0–42 days after the vaccination (eSupplement Table 8). No cases of thromboembolism, myocarditis, facial palsy, intensive medical treatment were reported, and neither were any deaths. The group comparison of all those affected by SAE (n=45) with those not affected by SAE (n=3183) did not show any significant association between the administered vaccine dose relative to the dosage recommendation (overdosed/underdosed) and the occurrence of an SAE (15). Reports of an SAE were associated with female sex (OR=4.70 [2.17; 10.20], p<0.001 and long-term medication (OR=4.06 [1.53; 10.79]; p=0.005).

Sensitivity analysis

Including or excluding participation without batch number reference did not have any relevant effect on data stability. The vaccination period (deadline 1 October 2021) did not have any relevant effect on the frequency of SRVRs either.

Discussion

The present retrospective study is the first to show results for self-reported long-term tolerability (SRVT) (median: 524 days correspond to about 1.5 years) of the mRNA-based COVID-19 vaccine BNT162b2 in a pediatric cohort (0–17 year olds). 96% of vaccinations in under-5-year olds reported here were given off-label and represent important additional data for this age group (1, 8, 9, 10, 16). Observation periods of other BNT162b2 studies in childhood covered ≤6 months after the second vaccination or included people primarily affected with specific disorders/treatments (4, 5, 12, 16, 17, 18, 19, 20, 21, 22, 23). In >98% the parents or legal guardians surveyed here reported good vaccine tolerability. The most common SRVRs were localized reactions, fatigue, and headache, as several other prospective studies had already reported (8, 9, 10, 21). By comparison, some symptoms were rarer in our cohort, especially in the group of 12–17 year olds (headache: 11% vs 55%, fatigue: 27% vs 60%) (10). In our study and in approval studies, systemic reactions to the vaccine (fatigue, myalgia, headache) were more common in adolescents than in young children. It is possible that the age and development related perception, localization, and communication ability of the vaccinated child has a role here.

Discrepancies of the rates of adverse effects from randomized controlled trials can be due to the retrospective design (asking for the vaccination date), but they also appear in prospective, survey based studies and spontaneous reporting systems (21, 23, 24, 25). Reporting bias as a result of an attitude of positive expectation of vaccine tolerability may be assumed especially for off-label vaccinations, of which 78% were carried out in the age group of children aged 0–4 years; comparable studies are scarce (1, 9, 16, 26, 27). Overall, however, comparability is good, with reported rates of adverse effects from meta-analyses, randomized controlled trials, and evaluations of age-group specific spontaneously reporting data from the US Centers for Disease Control and Prevention (CDC) (V-safe, VEARS) ab (4, 5, 16, 19, 23, 25).

1.3% of survey participants reported in the long-term follow-up sustained SRVRs ≥90 days, predominantly psychological symptoms (33.3%). Persistent symptoms >1 month have been described in single studies (incidence: 0.2–1.4%), but in these studies, >30% of included adults reported underlying diseases (28, 29). In our cohort, significant associations exist between reported SAEs and sex (80.5% female) and intake of medications. Because of the small number of affected persons taking long-term medication (n=8) we were not able to study whether certain drug categories (for example, immunosuppressants) correlated particularly strongly with SAEs. The higher sex specific burden of events (81.2% of affected persons were female) is consistent with statements from earlier studies about the sex-specific differences in the tolerability of the mRNA-based BNT162b2 vaccine, which we also confirmed in separate analyses (12, 17, 21, 25, 26, 30, 31). Several aspects should be considered when trying to find an explanation: in the context of the somatic post-COVID-19 vaccination syndrome (PCVS), similar symptoms have been described (chronic fatigue, pain, vasomotor symptoms, cardiovascular or cognitive impairments, and headache) and thus overlap with our data (32, 33, 34, 35, 36). The study design did not allow for measuring serological biomarkers (angiotensin-II-type-1 receptor antibodies, alpha-2B-adrenergic antibodies, IL-6) to prove a somatic process in PCVS (36). Distinguishing post-COVID-19 vaccination syndrome from post-COVID-19 syndrome or other pandemic related psychosocial burdens is difficult in routine clinical practice. Most of the participants in this study who were affected by SAE reported an earlier infection with SARS-CoV-2, but this occurred mostly ≥ 60 days after the latest vaccination, which makes a temporal association with the onset of symptoms questionable.

The rate of SAEs of 1.4% reported here is within a broad range of published SAE rates (0–4%) after BNT162b2 and does not represent an outlier (1, 8, 9, 10, 16, 37, 38, 39). Self-reported hospital admissions occurred in our study up to 42 days after the vaccinations and therefore lie within the regular SAE duration of 6 months observed in safety studies (8, 9, 10). The pandemic events themselves may constitute a strong confounder for the high rates of long-term psychological symptoms. No events of thromboembolism, facial palsy, or myocarditis/pericarditis were reported. The incidence of myocarditis after mRNA vaccinations is low (age/sex dependent: 1.3–93/1 000 000) and is therefore statistically not to be expected in our sample (n=3228) (4, 12, 25, 40).

Limitations

The study design is subject to various limitations. The data are not based on real-time documentation. A risk of recall bias exists, as the reported vaccinations took place several months before the survey. Sensitivity analyses did not show any relevant association between reported rates of adverse effects and the time of the vaccination. A predefined time window between BNT162b2 and non-SARS-CoV-2 vaccinations was intended to reduce the risk for biases in the internal comparison analysis. Reporting was done on a voluntary basis, which may mean a great willingness of participants depending on experienced post-vaccination symptoms (negative effect regarding tolerability) or by advocating the vaccination (positive effects regarding tolerability). Methodologically, selection bias may occur as a result of recruitment via vaccination sites with an off-label vaccination service. 12–17 year olds have the highest vaccination rate in childhood/adolescence nationwide but are underrepresented in this study.

The response rate of 37.9% is acceptable, but the survey scope was limited as a result of the following factors: In accordance with data protection stipulations, no concrete survey subject was mentioned in the email; emails may have disappeared unnoticed into spam folders; the public interest in mRNA-based COVID-19 vaccines has waned after the official end of the pandemic. In the past, mRNA-based vaccines have led to controversial discussions, which means that a potential risk of manipulation existed for our study. We minimized this by collaborating with official vaccination centers, allocating individual authentication codes, checking batch numbers, and excluding duplicate entries. We assessed lacking batch numbers in some included datasets as being caused by layperson-inherent problems in understanding how to handle medical documents. We deemed the inclusion of such participants as justifiable since the sensitivity analysis did not throw up any effect on data stability. At the time of our survey, the pandemic had been declared over by the World Health Organization and Germany’s health ministry, so the risk of sociopolitical conflicts was notably reduced. We estimate that the manipulation risk was lower than in the study period of the CoVacU5 Study. Any causality between reported SAEs and the vaccine can neither be ruled out nor confirmed on the basis of these data.

Relevance

98.6% of survey participants reported good vaccine tolerability for BNT162b2 in the long-term follow-up and after repeated immunization in 0–17 year olds. 1.3% of parents or legal guardians, however, reported long-term post-vaccination symptoms lasting 90 days or longer, whose causal relation to the vaccine in uncertain.

Acknowledgment

The authors thank all participating vaccination centers and survey participants. For their charitable support in recruiting participants we thank the initiative BildungAberSicher and Dr Anke Böhnke (gynecology practice, Berlin), Dr Joachim Moersdorf (primary care practice Moersdorf and Herschel, Pretzfeld), Dr Johannes Püschel (primary care center Greven, Greven), and Prof. Dr Rainer Blasczyk (Hannover Medical School, Hannover). We thank Witten/Herdecke University for financial funding for this study.

Study registration

This study is registered in the German Clinical Trials Register (ID: DRKS00031994).

Conflict of interest statement
NT is deputy chair of the German Society for Pediatric Infectious Diseases (DGPI) and treasurer in the network Junge Infektionsmedizin JUNTE [https://www.netzwerk-infektionsmedizin.de/—a professional network connecting young doctors in infection medicine to each other].

The remaining authors declare that no conflict of interest exists.

Manuscript received on 18 August 2024, revised version accepted on 11 February 2025

Translated from the original German by Birte Twisselmann, PhD.

Corresponding author
PD Dr. med. Cho-Ming Chao, PhD MBA

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