Real-world Effectiveness and Causal Mediation Study of BNT162b2 on Long COVID Risks in Children and Adolescents (preprint)

BackgroundThe 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. ObjectiveTo 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. DesignReal-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. SettingTwenty health systems in the RECOVER PCORnet electronic health record (EHR) Program. Participants112,590 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. ExposuresFirst dose of the BNT162b2 vaccine vs. no receipt of COVID-19 vaccine. MeasurementsOutcomes 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. ResultsDuring 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. LimitationsObservational study design and potentially undocumented infection. ConclusionsOur 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 vaccines effectiveness is primarily derived from its role in reducing the risk of SARS-CoV-2 infection. Primary Funding SourceNational Institutes of Health.

Vaccine Effectiveness Against Long COVID in Children: A Report from the RECOVER EHR Cohort (preprint)

Objective Vaccination reduces the risk of acute COVID-19 in children, but it is less clear whether it protects against long COVID. We estimated vaccine effectiveness (VE) against long COVID in children aged 5 to 17 years. Methods This retrospective cohort study used data from 17 health systems in the RECOVER PCORnet electronic health record (EHR) Program for visits between vaccine availability, and October 29, 2022. Conditional logistic regression was used to estimate VE against long COVID with matching on age group (5 to 11, 12 to 17) and time period and adjustment for sex, ethnicity, health system, comorbidity burden, and pre-exposure health care utilization. We examined both probable (symptom-based) and diagnosed long COVID in the year following vaccination. Results The vaccination rate was 56% in the cohort of 1,037,936 children. The incidence of probably long COVID was 4.5% among patients with COVID-19, while diagnosed long COVID was 0.7%. Adjusted vaccine effectiveness within 12 months was 35.4% (95 CI 24.5 - 44.5) against probable long COVID and 41.7% (15.0- 60.0) against diagnosed long COVID. VE was higher for adolescents 50.3% [36.3 - 61.0]) than children aged 5-11 (23.8% [4.9 -39.0]). VE was higher at 6 months (61.4% [51.0 - 69.6]), but decreased to 10.6% (-26.8 - 37.0%) at 18 months. Discussion This large retrospective study shows a moderate protective effect of SARS-CoV-2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Understanding VE mechanism against long COVID requires more study, including EHR sources and prospective data. Discussion This large retrospective study shows a moderate protective effect of SARS-CoV-2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Understanding VE mechanism against long COVID requires more study, including EHR sources and prospective data.

THE IMPACT of COVID-19 TREATMENTS on PATIENT OUTCOMES: A PROBABILISTIC VIEW

Background: The World Health Organization (WHO) ordinal scale (OS) is used to evaluate participant outcomes in clinical trials. We modified the WHO OS to enable assessment of patient outcomes associated with various treatment agents using the National COVID Cohort Collaborative (N3C), a national database containing electronic Health Record (EHR) data from > 2.7 million persons with a COVID-19 diagnosis from > 55 U.S. sites. Methods: Modified OS severity scores (Table 1) were assigned in the first through fourth weeks following COVID-19 diagnosis for a sample of patients in N3C. To adjust for disease severity at patient hospitalization, we developed separate models to examine OS levels of 3, 5, 7, and 9. Elastic net penalized multinomial logistic regression was used to simultaneously identify risk factors and predict the probability of each level of the ordinal scale at week 4. We studied groups of anticoagulants (AC), steroids, antibiotics, antiviral agents (AA), monoclonal antibodies (MA), and a miscellaneous group that included all other treatments. Other factors considered were presence of comorbid conditions using the Charlson Comorbidity Index (CCI), ethnicity, age, gender, and time of diagnosis (by quarter). Results: We included 1,489,191 COVID-19 (161,385 outpatients were excluded) patients. Patient characteristics and treatment approaches applied to each OS level were analyzed (Table 1). For hospitalized patients with a Week 1 OS score of 3,5,7, or 9, we found that increased CCI values are associated with higher probabilities of a worsened OS score at Week 4. Given that MAs are a standard treatment for patients at OS levels 3 and 5, and that steroids are typically used at OS 7 and 9, we studied treatment combinations related to MA and steroids given during Week 1. Improved outcomes by Week 4 were demonstrated with AA+MA for OS 3 and for AC+MA for OS 5 (Table 1). Patients at OS 7 in Week 1 had improved Week 4 outcomes with steroids alone while OS 7 patients with CCI>10 had better outcomes with steroids+AC. OS 9 patients treated with steroids+MA had better outcomes compared with those not given that combination. Conclusion: Our analyses identify relationships between COVID-19 serverity, specific treatments and outcomes at 4 weeks after diagnosis. Use of MA at lower levels of severity, and steroids at higher severity levels were associated with survival to hospital discharge.