mRNA vaccines

Though the focus of this review is severe adverse events, it is important to first consider side effects and adverse events of paediatric COVID-19 vaccination. Side effects tend to be routine, mild, temporary, and similar to those observed as a consequence of any routine vaccination (tetanus, Measles Mumps Rubella, etc.). Unsolicited adverse events tend to have an unclear connection to vaccine immunology and include symptoms of vertigo, arthralgias, skin or eye irritation, musculoskeletal pain, and more. ^{Reference Alwafi, Naser and Aldhahir23} In a cohort of 6-month to 3-year-old children, the most common side effects are pain at vaccination site, swelling of lymph nodes, irritability/crying, sleepiness, and loss of appetite. ²⁴ Pain at vaccination site is expected, as the vaccines are intramuscular, and other side effects such as lymph node swelling and loss of appetite are indicative of vaccine immunogenicity. Several studies report that amongst immunocompromised patients such as oncology patients, vaccine immunogenicity and thus routine side effect incidence rates are low. ^{Reference Tran, Truong and Narendran25,Reference Monin, Laing and Muñoz-Ruiz26}

The KidCOVE trial conducted across 79 centres in the USA and Canada revealed valuable data on the safety and immunogenicity of mRNA-1273 COVID-19 vaccine in children aged 6 months to 5 years. The study found that solicited local and systemic vaccine side effects presented at a low grade and appeared an average of 2 days after injection, persisting for an average of 2–3 additional days. Side effects were most common after the second vaccination and occurred at a higher rate in the experimental compared with the placebo group. Researchers also found that unsolicited adverse events reported an average of 28 days post-vaccination occurred at similar rates between experimental and placebo groups. Severe adverse events were also similar amongst the two study groups, with only eight severe adverse events reported in infants aged 6–23 months and 0 in children aged 2–5 years. Of the eight children experiencing severe adverse events, one experienced a fever and febrile seizure with concurrent maculopapular rash developing 2 days after the first dose administration, suggesting an incidental concomitant viral infection. Symptoms eventually resolved, and the second dose was administered with no complications. Post-vaccine COVID-19 antibody titres were similar to figures reported in similar studies of older children, adolescents, and adults. ^{Reference Anderson, Creech and Berthaud27} Another study cited the incidence of maculopapular rash in 43 participants across three observational studies, 49% of whom received the BNT162b2 vaccine and 51% of whom received the mRNA-1273 vaccine. ^{Reference Sun, Fathy, McMahon and Freeman28} All but one resolved within 2–3 days, with one persisting for 1 month. Several other studies reported similar results amongst this age group. ^{Reference Muñoz, Sher and Sabharwal29} Limited information is available on adverse events of other vaccine modalities, owing to their limited of use in young cohorts.

Results are similar in older paediatric age groups. A study by Kasif et al. found that amongst the 3,732 adolescents that were randomised in a 2:1 ratio into experimental and placebo groups, only mild, non-remarkable local or systemic adverse events occurred in both groups. No incidence of death, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were observed. Researchers also noted that the incidence of unsolicited adverse events was similar in participants 12–15 years of age and 16–17 years of age, indicating homogeneous findings. ^{Reference Ali, Berman and Zhou30} In an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy trial of 44.165 participants aged 16 and above, the incidence of life-threatening adverse events was 0.1% in both placebo and experimental groups, and the incidence of severe adverse events was also the same (0.3%) amongst both study groups. ^{Reference Thomas, Moreira and Kitchin31} A visual summary of the most common side effects and severe adverse events of these vaccine modalities can be found in Figure 1.

Figure 1. A visual summary of side effects and severe adverse events observed post-paediatric COVID-19 vaccination.²⁴ ***This figure was developed using Biorender software.

Interestingly, a recent systematic review found that the frequency of events/manifestations following vaccination decreased with subsequent dosing in attenuated, viral vector and protein subunit vaccines. Adverse events (43.7% of which were cutaneous manifestations) decreased in frequency from 52 post-first dose to two after the booster dose. Additionally, almost 90% of cutaneous manifestations were of known etiology, treatable, and resolved in less than 10 days, suggesting that even in the case of adverse events safety is not significantly compromised. ^{Reference Sadat Larijani, Doroud, Banifazl, Karami, Bavand and Ashrafian32}

Other vaccines

A double-blind phase 1/2 clinical trial conducted in China revealed that amongst children aged 3–17 years old, the Sinovac vaccine showed a 26% rate of side effects (injection site pain, fever, fatigue) for one dose and 63% for a double dose. Pneumonia was the only severe adverse event recorded and affected one participant, with researchers considering it unrelated to vaccination. ^{Reference Han, Song and Li33} Pneumonia is more correlated with exaggerated COVID-19 infection rather than COVID-19 vaccination. ^{Reference Zheng, Wang and Feng34} Humoral responses were high in both single- and double-dose cohorts with seroconversion being 100% in both cohorts with 95% confidence intervals of 87.2–100% and 86.8–100%, respectively. ^{Reference Han, Song and Li33}

Further data on Sinovac are comparative, as the vaccine has not yet been authorised for use in paediatric cohorts. ³⁵ Thus, reports of severe adverse events for this vaccine are limited. A study of 39 children and adults with inborn errors of immunity revealed no severe adverse event with both mRNA and Sinovac vaccines, though results suggested that three doses of each vaccine must be given to reach optimal immunogenicity comparable with that observed in non-immunocompromised persons. ^{Reference Leung, Mu and Duque36}

Limited data is available on the AZD122 vaccine. A study including more than 300 participants between the ages of 6 and 17 revealed a safety profile comparable with that observed in all other vaccine modalities. Notably, fewer adverse events (severe, unsolicited and otherwise) were observed after the second rather than the first dose of the vaccine, irrespective of the timing between the doses. ^{Reference Li, Cappuccini and Marchevsky37}

An experimental recombinant adenovirus type-5 (Ad5)–vectored COVID-19 vaccine developed in China was also assessed for adverse events in participants more than 6 years old. Results indicate the same adverse events noted for routine vaccination and other COVID-19 vaccines summarised above, with no severe or life-threatening reactions. Two other experimental vaccines (WIBP-CorV and BBV-152) are also in development with very similar safety profiles. ^{Reference Xia, Duan and Zhang38,Reference Ella, Reddy and Jogdand39} Interestingly, fewer adverse events were reported following boost vaccination than following primary vaccination. ^{Reference Zhu, Jin and Zhu CanSino40} Another experimental vaccine in development is the ZyCoV-D vaccine being researched in India. Khobragade et al. found that much like all other vaccines, mild side effects were observed at higher rates in experimental compared with control groups of participants aged 12 and older. However, researchers also noted that two deaths were observed in the experimental group, though causes of death were not attributed to vaccine side effects. Two doses of ZyCoV-D were also found to be 100% efficacious at preventing severe cases of COVID-19. ^{Reference Khobragade, Bhate and Ramaiah41} Two doses of the tetanus toxoid COVID-19 vaccine FINLAY-FR-2 followed by one dose of FINLAY-FR-1A in children revealed extremely promising results. No severe adverse events were noted, and the vaccines mounted a humeral response similar to that of natural infection. Adverse events that were observed were unremarkable and solicited. ^{Reference Puga-Gómez, Ricardo-Delgado and Rojas-Iriarte42}

Vaccine combinations have also been under study. Viral vector (AstraZeneca) and attenuated (Sinopharm) vaccines were tested in combination with Postovac protein subunits by Larjiani et al. Results show that combined vaccination carries a 4.2% increased risk of adverse events compared with isolated Postovac vaccination during an 18-month follow-up period. However, results show a low number of adverse events after the 18-month period in all experimental and control groups, suggesting favourable safety profiles. ^{Reference Sadat Larijani, Sorouri and Eybpoosh43}

Severe adverse event 1: Anaphylaxis

As is the case with other novel vaccines and drugs, the risk of anaphylaxis is of interest. A nationwide observational study in the adult population found that there were 66 incidences of anaphylaxis out of 61,414,803 administered doses of various COVID-19 vaccines, corresponding to an incidence of 1.07 per 1,000,000, with most (86%) being female. ^{Reference Toledo-Salinas, Scheffler-Mendoza and Castano-Jaramillo44} One prospective cohort study conducted in 2021 suggested a higher incidence, with nine patients out of 403 (2.2%) experiencing severe anaphylactic reactions after the administration of either the Pfizer or AstraZeneca vaccines. Having a prior history of anaphylaxis did not appear to be a risk factor, as 1.5% of enrolled patients with a prior history of anaphylactic reactions experienced a reaction with a COVID vaccine, while 3% of enrolled patients with no prior history experienced a reaction. ^{Reference Wentrys and Stopyra45} This contrasts with the findings of a case series in which 15 out of 22 (68%) patients who were enrolled after suffering an anaphylactic reaction to a COVID-19 vaccine were found to have a prior history of such reactions. The basophil activation test was positive to PEG in the 11 patients who agreed to further testing, though PEG IgE was negative, suggesting a non-IgE-mediated aetiology. ^{Reference Warren, Snow and Lee46} A review published in the Italian Journal of Pediatrics points out that though the risk of post-COVID-19 vaccine anaphylaxis in children is low, high-risk children, including those with prior history of anaphylaxis or reactions to other vaccines, should consult with their paediatrician before receiving a dose. ^{Reference Novembre, Tosca and Caffarelli47}

Severe adverse event 2: multisystem inflammatory syndrome in children

Multisystem inflammatory syndrome in children is a rare side effect of COVID-19 exposure, including vaccination. A 2022 study used the Vaccine Adverse Event Reporting System to determine the incidence of post-vaccination multisystem inflammatory syndrome in children in patients aged 12–20 years. It was found that 21 individuals out 21,335,331 were diagnosed with multisystem inflammatory syndrome in children, corresponding to a reporting rate of 1 in 1,000,000. ^{Reference Yousaf, Kunkel and Abrams48} There have also been two published case reports discussing the hospital course of three paediatric patients who developed multisystem inflammatory syndrome in children shortly after vaccination, all of whom made uneventful recoveries. ^{Reference Yalçinkaya, Öz and Polat49} The evidence in the current literature suggests that though multisystem inflammatory syndrome in children can occur post-vaccination, such events are much more common following organic COVID-19 infection, with vaccination even having a protective effect in some cases. ^{Reference Zambrano, Newhams and Olson50}

Other severe adverse events

There are a few reports of autoimmune and/or neurological disease following COVID-19 vaccination in paediatric patients, including cases of Guillain–Barre syndrome and thrombotic thrombocytopenic purpura. A case report published in the British Journal of Clinical Pharmacology details the case of a 13-year-old female that presented with bilateral weakness and was subsequently diagnosed with Guillain–Barre syndrome. The patient had received the COVID-19 vaccine 3 days ago. ^{Reference Rohilla, Kakkar, Divyashree, Mohindra and Suri51} Another case report discussed similar findings in a 14-year-old male 1 month after COVID-19 vaccination. Both cases were treated with multiple sessions of Intravenous immunoglobulins (IVIG) followed by gradual complete resolution. ^{Reference Malamud, Otallah, Caress and Lapid52} As is the case with multisystem inflammatory syndrome in children, it appears that Guillain–Barre syndrome is much more common after COVID-19 infection than after vaccination. ^{Reference Aladawi, Elfil and Abu-Esheh53} As for thrombotic thrombocytopenic purpura, there are two published papers that discussed cases in paediatric patients following COVID-19 vaccination. The first describes the cases of two females, 15 and 19 years old, who developed thrombotic thrombocytopenic purpura following Pfizer COVID-19 vaccination. ^{Reference Vorster, Kirk, Muscal, Despotovic, Cohen and Sartain54} The second paper discussed the case of a 14-year-old female who also developed thrombotic thrombocytopenic purpura after the first dose of COVID-19 vaccination. ^{Reference Kirpalani, Garabon and Amos55} All patients were treated with plasma exchange, methyl prednisone, and immunosuppressants and subsequently improved. ^{Reference Kirpalani, Garabon and Amos56}

Cardiac severe adverse events

Several peer-reviewed articles report incidence of myocarditis following mRNA COVID-19 vaccination in a paediatric cohort. ^{Reference Konno, Osada, Watanabe, Sakurai and Aso57–Reference Minocha, Better, Singh and Hoque62} In the case of Snapiri et al, ^{Reference Snapiri, Rosenberg Danziger and Shirman63} myocarditis was transient, and there was no data on prior COVID-19 infection or receival of a second dose of the BNT162b2 vaccine. ^{Reference Tano, San Martin, Girgis, Martinez-Fernandez and Sanchez Vegas64} The majority of reported cases of myocarditis post mRNA vaccination have been reported in adolescents and young adults between the ages of 12 and 24 after receiving a second dose of the vaccine. Conditions have been reported to be mild and transient in most cases, with only minimal treatment required and complete recovery within a few days. ^{Reference Kwan, Chua and Chow65} A typical presentation for a case is a 17-year-old previously healthy male presenting with chest pain and having fulfilled multisystem inflammatory syndrome in children criteria post-BNT162b2 vaccination. ^{Reference Das, Kohli and Ramachandran66,Reference Castagnola, Mariani and Sticchi67} Diagnosis is myocarditis with a reduced ejection fraction up to 20%. Many patients do not satisfy the multisystem inflammatory syndrome in children criteria and present with myocarditis or myopericarditis nonetheless. ^{Reference Marshall, Ferguson and Lewis68} Treatment entails admission to the ICU for around 6 days for high-flow oxygen therapy, norepinephrine infusion, steroids, intravenous immunoglobulins, and antibiotics. Several cases are self-resolving or require a simple course of nonsteroidal anti-inflammatory drugs. ^{Reference Tano, San Martin, Girgis, Martinez-Fernandez and Sanchez Vegas69} Discharge is typically 10 days post-admission with a normalization of ejection fraction on MRI at 62%. Follow-up 8 days post-discharge typically reveals an asymptomatic patient with residual fatigue of no obvious clinical consequence. ^{Reference Chai, Nygaard, Schmidt, Zaremba, Møller and Thorvig70}

Furthermore, a study published in Nature found that 1,615 (0.004%) of 38,615,491 patients presented with myocarditis after receiving a COVID-19 vaccine shot. Of these patients, 359 (22.2%) tested positive for COVID-19, 287 (80%) of whom tested positive for COVID-19 prior to vaccination. Authors further report an association between 1–7 and 1–238 days post-COVID-19 vaccination and the incidence of myocarditis, particularly following the second dose. ^{Reference Patone, Mei and Handunnetthi71} It is worth mentioning that this is true for a sample population aged 12 and over and is therefore not necessarily characteristic of vaccinated paediatric patients. Further studies are needed to properly characterise myocarditis post-COVID-19 vaccination in paediatric patients.

A study published in the Pediatric Infectious Diseases Journal describes a time association between adolescents aged 16–18 receiving the COVID-19 BNT162b2 vaccine and the incidence of peri-myocarditis. In six of the seven patients, symptoms proceeded the second dose, while the seventh patient showed symptoms following the first dose. The sample case displays several cardiac and laboratory findings indicating myocarditis and pericarditis, the hallmark of which is more than a 22-fold increase in troponin levels. Upon treatment with ibuprofen (dose not mentioned) and hospitalisation in the paediatric ICU, the patient recovered in 6 days and left the paediatric ICU with normal troponin levels. ^{Reference Snapiri, Rosenberg Danziger and Shirman63} Interestingly, patients presenting with concurrent GI symptoms were subjected to more intensive care but also recovered well. ^{Reference Woo, Kim and Yon72}

The exact mechanism through which COVID-19 vaccines may trigger myocarditis and troponinemia are unknown. Suspected mechanisms include molecular mimicry between SARS-Cov-2 and self-antigens and dysregulated activation of the immune system. Several earlier studies found that myocarditis is amongst the main cardiovascular manifestations of paediatric COVID-19 infection, triggered primarily by an overwhelming immune response manifested by an elevation in the level of inflammatory markers such as IL6, C-reactive protein, and pro-calcitonin. Authors of the paper mentioned previously suggested potential inoculation with COVID-19 during the study period to explain the incidence of myocarditis, though this is not confirmed. ^{Reference Bozkurt, Kamat and Hotez73}

It is postulated that free-floating spike protein from vaccination may interact with ACE-2 receptors resulting in degradation and consequently hypertension. Thus, COVID-19 vaccination may lead to cardiac discomfort that does not manifest as myocarditis. This is especially true in young adult (aged 18–26) and adult populations compared with teenage populations (aged 12–17). Myocarditis is known to have a slight increased propensity to occur in teenagers. Likewise, myocarditis following COVID-19 vaccination is observed in paediatric populations more so than adult ones, though the incidence of cardiac symptoms post-vaccination does not follow this trend. ^{Reference Chaichuum, Tseng and Chang74}

Paediatric patients with significant comorbidities such as CHD may be at greater risk of severe adverse events with COVID-19 and possibly even following vaccination. There is very limited data on the incidence of severe adverse events following COVID-19 vaccination in paediatric patients with CHD, though some studies on adults exist. A 2022 report described the case of a 63-year-old woman with a ventricular septal defect who suffered a transient episode of ventricular tachycardia following administration of an adenoviral COVID-19 vaccine. ^{Reference Bassareo, Mihali and Walsh75} Another study, conducted in an Italian tertiary care centre, found that 0 out of 208 adult CHD patients suffered major adverse events from the vaccine, and the number of minor adverse events was no different from the control group. ^{Reference Fusco, Scognamiglio and Merola76} There is no available evidence to suggest that COVID-19 vaccination is more dangerous in CHD patients than others. In fact, the risk of complication following organic COVID-19 infection far outweighs the risks of vaccination in these patients. A retrospective review using the Vizient Clinical Database found that children with CHD had a 4.75 times higher risk of mortality from COVID-19. ^{Reference Hamedi, Loftus, Traylor, Goodwin and Arce77} Another study described the hospital course of 9 children with CHD that were admitted for COVID-19. Two of the patients, both of whom had hypoplastic left heart syndrome and aortic stenosis, died. ^{Reference Haji Esmaeil Memar, Pourakbari and Gorgi78} Other studies are more ambivalent as to whether COVID-19 infection is more dangerous in CHD patients, with the consensus being that patients in poor physiologic states may indeed have worse outcomes. ^{Reference Sabatino, Di Salvo and Calcaterra79–Reference Raj, Vyas and Yeruva82} This points to the importance of vaccination to protect from COVID-19 in these vulnerable patients.