In December 2021, Spain began its COVID-19 vaccination campaign for children aged 5–11 years with Comirnaty. The speed with which this vaccine was developed and tested, as well as its novel mechanism of action (via messenger RNA), generated some mistrust and uncertainty in the general population regarding the potential deleterious effects it could have on individuals. These concerns were even more pronounced in relation to children, as they are particularly vulnerable to the effects of drugs, coupled with the fact that, to date, no major consequences of COVID-19 infection had been reported in the pediatric population.1 This led to significant hesitancy and refusal from parents when it came to vaccinating their children, prompting scientific societies to make statements in support of vaccination,2 chiefly based on the important role of the pediatric population in the epidemiological control of this infection.

The reported incidence of SARS-CoV-2 infection in children when vaccination began in 2021 was in the range of 0.8%–2.1%,3 values that were unrealistic given the known fact that most cases presented with mild symptoms or were even asymptomatic and were therefore not diagnosed. At the time, the global mortality was 0.08%, with substantial variation between countries4: less than 0.0094% in children aged less than 14 years in Spain.5 However, the disease was not free of potentially serious consequences,6 such as, for example, multisystem inflammatory syndrome in children (MIS-C). Today, we know that following exposure to the virus and active infection, the pediatric population is particularly vulnerable to MIS-C, a clinically heterogeneous syndrome that in some cases (up to 65%) requires advanced life support and that, according to some studies, could be prevented with vaccination.7,8

In the phase II and III trials of Comirnaty9 in the pediatric population (which included 2268 children aged 5–11 years, of who 1517 received the vaccine), the vaccine exhibited a favorable safety profile, as most reactions were mild to moderate, with an incidence of adverse reactions that was similar in vaccinated vs placebo-controlled participants. However, to date, few safety data have been published following mass vaccination of the pediatric population in the real world.

Currently, the need for epidemiological control has decreased; however, vaccination is still recommended for children in risk groups.10

Therefore, it seems relevant to obtain objective data regarding the safety of the vaccine under real-world conditions, especially if, aside from the data included in the summary of product characteristics,11 there are few postmarketing surveillance studies estimating the incidence of adverse drug reactions (ADRs) following the administration of this vaccine in the pediatric population.

This information could guide decision-making regarding vaccination in this population, both for the prevention of disease and for epidemiological control.

Between December 19, 2021, and March 2, 2022, a total of 3677 patients were vaccinated, and all of them were included in the hospital's pediatric vaccination registry. This registry is the database that contains the information on ADRs that occur at the point of care within 15 min of vaccination (which would be considered immediate ADRs); we identified 42 patients that experienced a combined total of 59 immediate ADRs.

The registry only contained contact details for 2914 of the total of vaccinated patients, and 480 did not answer the calls. A total of 308 parents refused to consent to participation, so the final sample for the prospective follow-up included 2126 children; all patients who experienced immediate ADRs consented to participation in the prospective follow-up. All of them received Comirnaty 10 micrograms.

Participants were aged 5–11 years, with a mean (SD) age of 109.5 (25.9) months (9.1 years), and 142 months (11.8 years) was the most frequent age; 52.2% of the patients were male (Table 1).

Of the total sample, 16.9% (n = 359) patients had a relevant medical history prior to recruitment, 11.6% (n = 246) had a history of allergy and 18.3% (n = 388) were infected by SARS-CoV-2 (before or during the study). Only 6.2% (n = 132) received chronic medication and 9.2% (n = 195) took some medication (chronic or otherwise) the same day that they received a dose of vaccine.

Of the total sample, 757 patients had at least one ADR (35.6%; 95% CI, 25.7 %–44.4 %). A total of 1437 ADRs were identified, with an approximate average of two per patient (mean, 1.88; 95% CI, 1.81–1.96; SD, 1.04), and the frequency of ADRs was similar after both doses (46.8% after the first dose, 53.2% after the second) (Fig. 1).

Figure 1.

Frequency distribution of patients by number of identified adverse reactions.

In terms of severity, based on the Venulet criteria, most ADRs were classified as mild (99.5%), with few classified as moderate (0.4%) and only one as severe (0.1%); 99.4% could be managed at the outpatient level, and 0.6% required hospital admission.

The adverse reaction classified as serious was a generalized tonic-clonic seizure following the first dose of vaccine in a patient with no previous history of seizures. It resolved without treatment, but the specialist recommended that the second dose of vaccine not be administered. The patient has not experienced any similar episodes since.

In the classification of ADRs by the involved system organ class, the most frequent reactions were those categorized as “general disorders and administration site conditions”, followed (in order of decreasing frequency) by nervous system disorders, musculoskeletal disorders, gastrointestinal disorders and blood and lymphatic system disorders. The frequency distribution was similar after administration of each of the doses, except for blood and lymphatic system disorders and general disorders and administration site conditions, whose frequency increased markedly following administration of the second dose. Table 2 presents the frequency distribution of the observed adverse reactions by system organ class.

The most frequent ADR was pain at the site of injection (820 [57.1%]), followed by fever/low-grade fever (both categorized as “general disorders and administration site conditions”), observed in 11.1% of children with ADRs (n = 159), and headache (82 [5.7%]). Fatigue (60 [4.2%]), local inflammation or swelling (58 [4%]) and asthenia (55 [3.8%]) were the next most frequently observed ADRs. Table 3 provides a detailed description of the suspected ADRs detected in more than five patients.

In terms of the temporal relationship, most reactions (55.3%) were acute, with 43.1% of subacute to delayed reactions, and no documentation of the temporal relationship for the rest.

With regard to the management of the ADR, most did not require treatment (54.1%); in two cases (0.1%), administration of the second dose was discouraged.

The vast majority of ADRs (99%) had resolved by the end of follow-up. The reactions that had not resolved or were improving over time were lymphadenopathies (n = 3), headaches (n = 2), skin lesions, abdominal pain, hyperthyrotropinemia under treatment with thyroid-stimulating hormone, changes in taste and nocturnal cough (n = 1 for each).

The relationship between the suspected ADRs and the administered vaccine was categorized according to the Karch-Lasagna criteria as “related” in 37.8% of cases (n = 543), “probable” in 27.1% (n = 389), “possible” in 18.5% (n = 266) and “conditional” in 15.3% (n = 220), with the remaining events considered “unrelated” (1.3% [n = 19]).

The population vaccinated at our hospital was similar to the populations included in the clinical trials and post-authorization surveillance studies conducted by the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA).9,16,17 The mean age of patients vaccinated in clinical trials of the vaccine before its authorization9 was 8.2 years (9.1 years in our patients), and the mean age of patients with notified ADRs in post-authorization surveillance studies16,17 was 8 years, with similar characteristics in terms of the sex distribution and previous medical history.

The main reason why some patients were not included in the study was the difficulty in reaching them by telephone. This factor was unrelated to their clinical characteristics, motivations, or any other variable that could affect the study findings. Therefore, we consider that the inability to contact them did not introduce bias into the results, as their exclusion was based solely on logistical limitations and not on criteria that could affect the validity or representativeness of the sample.

When comparing the frequency of the ADRs observed in our cohort with the reported frequency in the summary of product characteristics,11 we found agreement for some ADRs, such as pain at the site of injection, lymphadenopathy, hypersensitivity reactions, insomnia, nausea and vomiting.

However, there were other reactions for which the reported incidence was higher in the summary of product characteristics11 compared to the observed frequency in our cohort. Among the reactions labeled as very common in the summary of product characteristics, we found a lower frequency in some ADRs, including irritability, somnolence, headache, diarrhea, arthralgia, myalgia, fatigue, chills, fever and swelling at the site of injection. The absence of detected episodes of irritability is particularly salient, as the reported frequency of reaction in controlled trials exceeded 10%.

ADRs with an incidence of less than 0.1% (facial paralysis, pericarditis, myocarditis) may not have been identified in the cohort due to the sample size (too low to detect ADRs with an incidence of less than 1/1000).

The incidence of dizziness, pain in the extremity of administration and asthenia (all of them mild reactions that resolve spontaneously) was higher in the study cohort compared to the incidence reported in the summary of product characteristics.11Table 4 presents a detailed comparison of the incidence of ADRs.

In addition to ADRs whose frequency in the cohort we were unable to compare with the incidence reported in the summary of product characteristics11 (anaphylaxis, paresthesia/hypoesthesia, erythema multiforme and menstrual bleeding, swelling of the vaccinated extremity), there were ADRs identified in our patients that were not reported in the summary of product characteristics, out of which we ought to highlight dyspnea, cold symptoms and abdominal pain, with an estimated incidence in our cohort of 1/1000 to 1/100, that were categorized as “uncommon”.

Apart from the data included in the summary of product characteristics, there is little post-authorization data on the incidence of ADRs following administration of this vaccine.18

In the preauthorization pediatric clinical trials controlled with placebo,9 the most frequent local ADR was pain at the site of injection (71% after the second dose and 74% after the first dose), and fatigue and headache were the most common general disorders (0.9% and 0.3%). The incidence of severe adverse events was 0.1%, the same incidence observed in our cohort.

These studies detected a higher incidence of systemic ADRs (general disorders) after administration of the second dose compared to the first. However, in our cohort, there was no evidence of an increased risk of adverse reactions with the second dose. Nevertheless, the existing evidence suggests that when patients experience ADRs, they usually develop more than one, rather than an isolated event. This also differs from the evidence in the adult population, where greater reactogenicity for systemic reactions has been observed after the second dose compared to the first.

Considering the number and characteristics of the adverse reactions reported, our study shows that the Comirnaty vaccine maintains a favorable safety profile in real-world clinical practice, with a low frequency of adverse reactions that, in addition, are mild and self-limiting in most cases.

Although our findings were generally consistent with the previous literature, we identified some peculiarities in the pediatric cohort under study, and we did not observe an increase in reactogenicity after the second dose.

This study did not receive external funding.