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Real-world effectiveness and causal mediation study of BNT162b2 on long COVID risks in children and adolescents
Qiong Wu1,2,3, Bingyu Zhang3,4, Jiayi Tong2,3,5
1Department of Biostatistics and Health Data Science, University of Pittsburgh, Pittsburgh, PA, USA.
Insights
The BNT162b2 vaccine significantly reduces the risk of long COVID in children and adolescents. Its effectiveness stems mainly from preventing SARS-CoV-2 infection, not from a direct effect on long COVID development.
Area of Science:
- Pediatric infectious diseases
- Vaccinology
- Epidemiology
Background:
- The impact of pre-infection vaccination on long COVID risk in pediatric populations is not well understood.
- Assessing the effectiveness of the BNT162b2 vaccine against SARS-CoV-2 variants and its potential to mitigate long COVID is crucial.
Purpose of the Study:
- To evaluate the effectiveness of the BNT162b2 vaccine in preventing long COVID in children and adolescents.
- To determine if BNT162b2 vaccination reduces long COVID risk beyond its protective effect against SARS-CoV-2 infection.
Main Methods:
- Comparative effectiveness study using real-world electronic health record data from twenty health systems.
- Three cohorts analyzed: adolescents (Delta variant), and children and adolescents (Omicron variant).
- Causal mediation analysis to distinguish direct vaccine effects from indirect effects via infection prevention.
Main Results:
- BNT162b2 vaccine showed high effectiveness against long COVID: 95.4% in adolescents (Delta), 60.2% in children (Omicron), and 75.1% in adolescents (Omicron).
- Direct vaccine effects on long COVID risk were not statistically significant across all cohorts.
- Indirect effects, mediated by preventing SARS-CoV-2 infection, were significant, indicating the primary mechanism of protection.
Conclusions:
- BNT162b2 vaccination is effective in reducing long COVID risk in pediatric populations during Delta and Omicron waves.
- The primary benefit of BNT162b2 in preventing long COVID is through its efficacy in preventing SARS-CoV-2 infection.
Background:
The impact of pre-infection vaccination on the risk of long COVID remains unclear in the pediatric population. We aim to assess the effectiveness of BNT162b2 on long COVID risks with various strains of the SARS-CoV-2 virus in children and adolescents, using comparative effectiveness methods. We further explore if such pre-infection vaccination can mitigate the risk of long COVID beyond its established protective benefits against SARS-CoV-2 infection using causal mediation analysis.
Methods:
We conducted real-world vaccine effectiveness study and mediation analysis using data from twenty health systems in the RECOVER PCORnet electronic health record (EHR) Program. Three independent cohorts were constructed including adolescents (12-20 years) during the Delta phase (July 1-November 30, 2021), children (5-11 years) and adolescents (12-20 years) during the Omicron phase (January 1-November 30, 2022). The intervention is first dose of the BNT162b2 vaccine in comparison with no receipt of COVID-19 vaccine. The outcomes of interest include conclusive or probable diagnosis of long COVID following a documented SARS-CoV-2 infection, and body-system-specific condition clusters of post-acute sequelae of SARS-CoV-2 infection (PASC), such as cardiac, gastrointestinal, musculoskeletal, respiratory, and syndromic categories. The effectiveness was reported as (1-relative risk)∗100 and mediating effects were reported as relative risks.
Findings:
112,590 adolescents (88,811 vaccinated) were included in the cohort for the analysis against Delta variant, and 188,894 children (101,277 vaccinated), and 84,735 adolescents (37,724 vaccinated) were included for the analysis against Omicron variant. During the Delta period, the estimated effectiveness of the BNT162b2 vaccine against long COVID among adolescents was 95.4% (95% CI: 90.9%-97.7%). During the Omicron phase, the estimated effectiveness against long COVID among children was 60.2% (95% CI: 40.3%-73.5%) and 75.1% (95% CI: 50.4%-87.5%) among adolescents. The direct effect of vaccination, defined as the effect beyond their impact on SARS-CoV-2 infections, was found to be statistically non-significant in all three study cohorts, with estimated relative risk of 1.08 (95% CI: 0.75-1.55) in the Delta study among adolescents, 1.24 (95% CI: 0.92-1.66) among children and 0.91 (95% CI: 0.69-1.19) among adolescents in the Omicron studies. Meanwhile, the estimated indirect effects, which are effects through protecting SARS-CoV-2 infections, were estimated as 0.04 (95% CI: 0.03-0.05) among adolescents during Delta phase, 0.31 (95% CI: 0.23-0.42) among children and 0.21 (95% CI: 0.16-0.27) among adolescents during the Omicron period.
Interpretation:
Our study suggests that BNT162b2 was effective in reducing risk of long COVID outcomes in children and adolescents during the Delta and Omicron periods. The mediation analysis indicates the vaccine's effectiveness is primarily derived from its role in reducing the risk of SARS-CoV-2 infection.
Funding:
National Institutes of Health.
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