Safety outcomes following COVID-19 vaccination and infection in 5.1 million children in England

The safety and efficacy of COVID-19 vaccines in children remain a topic of ongoing research and public health concern. While vaccine uptake in adults was high in the UK, it was considerably lower in children. This disparity highlights the need for robust evidence regarding the safety profile of COVID-19 vaccines in pediatric populations. The UK's Joint Committee on Vaccination and Immunisation (JCVI) made recommendations for vaccine use in children, predominantly using the Pfizer-BioNTech (BNT162b2) vaccine for older children and a lower dose for younger children. However, concerns around potential adverse events, particularly myocarditis, have fueled debate around the overall risk-benefit analysis for vaccinating children. This study aimed to address these concerns by conducting a large-scale analysis of safety outcomes in a diverse cohort of English children who received COVID-19 vaccination and/or experienced natural infection. Understanding the relative risks of adverse events associated with vaccination versus natural infection is critical for informing public health policy and guiding parental decisions. This study aimed to provide a comprehensive assessment of vaccine safety in children and adolescents, comparing the risk of adverse events following vaccination to the risk associated with natural SARS-CoV-2 infection. The findings have important implications for vaccination strategies and for guiding public health decisions regarding the use of COVID-19 vaccines in children.

The literature surrounding the safety of COVID-19 vaccines in children is extensive and somewhat conflicting. Several studies have reported an increased risk of myocarditis, particularly in adolescent males, following mRNA vaccination. Other studies have shown increased risks of other adverse events, though the evidence is less consistent. Conversely, data on the risks associated with SARS-CoV-2 infection in children, including the potential for severe complications like multisystem inflammatory syndrome in children (MIS-C), demonstrates a clear need to weigh the benefits of vaccination against the risks of infection. This study builds on existing research by employing a large population-based dataset to provide a more comprehensive assessment of vaccine safety, taking into account various vaccine types, age groups, and the risk of natural infection. This comprehensive approach allows for a more nuanced and accurate evaluation of the risk-benefit profile.

This study employed a self-controlled case series (SCCS) design using linked data from the NHS in England. The cohort included 5.1 million children aged 5-17 years. Data sources included NHS vaccination records, hospital admission data (Hospital Episode Statistics), and SARS-CoV-2 positive test results. The study investigated the association between three COVID-19 vaccine types (BNT162b2, mRNA-1273, and ChAdOx1) and 12 pre-specified adverse events resulting in hospitalization. The SCCS design is well-suited to assessing rare adverse events following vaccination, as it controls for individual-level confounding factors. The analysis compared the risk of pre-specified outcomes within a defined time window following vaccination (1-42 days) to a baseline risk period. Separate analyses were conducted for each outcome, accounting for vaccination type, dose, age group (5-11 years and 12-17 years), sex, and seasonality. Additionally, the study compared the risk of adverse events following SARS-CoV-2 infection in both vaccinated and unvaccinated children. The analysis used conditional Poisson regression models to estimate incidence rate ratios (IRRs) and the number of excess events per million exposures. Sensitivity analyses, including a matched cohort analysis, were conducted to assess the robustness of the findings. The study incorporated several methods to address potential biases. For example, to control for potential confounding due to individuals with recent hospitalizations being less likely to get vaccinated, a pre-risk period of 1-28 days before vaccination was excluded from the baseline period. The study period was further divided into weekly blocks to account for temporal confounding. Furthermore, a positive control outcome (anaphylaxis) was used to ensure the validity of the study methods.

The key findings of the study are as follows: 1. **Children aged 5-11 years:** No increased risk of any of the 12 pre-specified adverse events following COVID-19 vaccination was observed. 2. **Adolescents aged 12-17 years:** A small increased risk of myocarditis (3-5 excess cases per million doses) and epilepsy (12 excess cases per million second doses) was observed following BNT162b2 vaccination. A sex-stratified analysis revealed a greater risk of myocarditis in males and epilepsy in females. 3. **SARS-CoV-2 infection:** SARS-CoV-2 infection was associated with increased risks of hospitalization for several adverse outcomes (e.g., MIS-C, myocarditis), but these risks were significantly reduced or absent in those who were vaccinated prior to infection. 4. **Vaccine type:** The study found no evidence of a significantly increased risk of myocarditis following mRNA-1273 vaccination in adolescents, but the sample size for this vaccine was relatively small. A substantially increased risk of appendicitis was observed in adolescents following a second dose of ChAdOx1, but the small sample size and lack of confirmation in the matched cohort analysis suggest that the evidence for a causal association was weak. A similar finding was seen for epilepsy following a first dose of ChAdOx1, particularly in females. The study also highlighted that while there was an increased risk of hospitalization with epilepsy following SARS-CoV-2 infection in unvaccinated adolescents, this risk was substantially reduced in those who were vaccinated prior to infection. The increased risk of myocarditis was mostly seen in males, and epilepsy in females.

This large-scale study provides valuable evidence on the safety profile of COVID-19 vaccines in children and adolescents. The findings support the overall favorable safety profile of mRNA vaccines in this population. The observed small increased risks of myocarditis and epilepsy associated with BNT162b2 vaccination should be considered in the context of the significantly higher risk of severe adverse events associated with SARS-CoV-2 infection. The reduction in risk of these severe outcomes among vaccinated children further underscores the importance of vaccination. The lack of significant safety signals in younger children supports current vaccination recommendations for this age group. The observed increase in appendicitis and epilepsy after receiving the ChAdOx1 vaccine warrants further investigation, but caution is needed due to limited sample sizes and inconsistencies between analyses. While the study provides valuable evidence, further research is needed to explore the long-term effects of vaccination and infection, particularly regarding the neurological consequences.

This large-scale study provides reassuring evidence about the safety of COVID-19 mRNA vaccines in children and adolescents, especially when weighed against the risks of SARS-CoV-2 infection. The small increased risks of myocarditis and epilepsy observed in adolescents with the BNT162b2 vaccine should be viewed in the context of the much greater risk of serious adverse events associated with COVID-19 infection. Future research should investigate long-term effects and explore potential risk factors for specific adverse events. This study informs public health decision-making, underscoring the benefits of vaccination in protecting against severe COVID-19 outcomes in young people.

Despite its large sample size, this study has limitations. The relatively low vaccination rates among 5-11-year-olds may have limited the ability to detect small risks in this age group. The study relied on hospitalization codes, which may have missed mild cases not requiring hospitalization. The data on SARS-CoV-2 infections were limited to RT-PCR confirmed cases and therefore underrepresent the true extent of infections. The study could not analyze the impact of different SARS-CoV-2 variants, which may influence adverse event risk. Finally, the study did not assess the influence of deprivation levels, which should be considered in future research.