Real-world Effectiveness and Causal Mediation Study of BNT162b2 on Long COVID Risks in Children and Adolescents
Authors: Wu Qiong , Zhang Bingyu , Tong Jiayi , Bailey L. Charles , Bunnell H. Timothy , Chen Jiajie , Chrischilles Elizabeth A. , Christakis Dimitri A. , Downs Stephen M. , Hirabayashi Kathryn , Jhaveri Ravi , Mishkin Aaron D. , Mosa Abu S.M. , Pajor Nathan M. , Rao Suchitra , Razzaghi Hanieh , Schwenk Hayden T. , Sills Marion R. , Wang Huiyuan , Wang Linbo , Wang Yudong , Zhang Dazheng , Zhou Ting , Tchetgen Tchetgen Eric J. , Morris Jeffrey S. , Forrest Christopher B. , Chen Yong 
Published: December 2024

Background

The impact of pre-infection vaccination on the risk of long COVID remains unclear in the pediatric population. Further, it is unknown if such pre-infection vaccination can mitigate the risk of long COVID beyond its established protective benefits against SARS-CoV-2 infection.

Objective

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. To disentangle the overall effectiveness of the vaccine on long COVID outcomes into its independent impact and indirect impact via prevention of SARS-CoV-2 infections, using causal mediation analysis.

Design

Real-world vaccine effectiveness study and mediation analysis in three independent cohorts: adolescents (12 to 20 years) during the Delta phase, children (5 to 11 years) and adolescents (12 to 20 years) during the Omicron phase.

Setting

Twenty health systems in the RECOVER PCORnet electronic health record (EHR) Program.

Participants

112,590 adolescents (88,811 vaccinated) in the Delta period, 188,894 children (101,277 vaccinated), and 84,735 adolescents (37,724 vaccinated) in the Omicron period.

Exposures

First dose of the BNT162b2 vaccine vs. no receipt of COVID-19 vaccine.

Measurements

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.

Results

During the Delta period, the estimated effectiveness of the BNT162b2 vaccine against long COVID among adolescents was 95.4% (95% CI: 90.9% to 97.7%). During the Omicron phase, the estimated effectiveness against long COVID among children was 60.2% (95% CI: 40.3% to 73.5%) and 75.1% (95% CI: 50.4% to 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 estimates of 1.08 (95% CI: 0.75 to 1.55) in the Delta study among adolescents, 1.24 (95% CI: 0.92 to 1.66) among children and 0.91 (95% CI: 0.69 to 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 to 0.05) among adolescents during Delta phase, 0.31 (95% CI: 0.23 to 0.42) among children and 0.21 (95% CI: 0.16 to 0.27) among adolescents during the Omicron period.

Limitations

Observational study design and potentially undocumented infection.

Conclusions

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.

Primary Funding Source

National Institutes of Health.