Real-world effectiveness and causal mediation study of BNT162b2 on long COVID risks in children and adolescents, 2025, Wu

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(24)00541-8/fulltext

Real-world effectiveness and causal mediation study of BNT162b2 on long COVID risks in children and adolescents
Qiong Wu Bingyu Zhang Jiayi Tong L. Charles Bailey H. Timothy Bunnell Jiajie Chen b,c ∙ et al.


Summary

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.

 

Research in context

Evidence before this study

We conducted a search in PubMed from the database’s inception to August 12, 2023, for studies published in English using the following terms: (“children” OR “adolescent” OR “pediatric” OR “paediatric”) AND (“long COVID” OR “long-haul COVID” OR “post-acute sequelae of SARS-CoV-2” OR “PASC” OR “MIS”) AND (“vaccine” OR “vaccination”) AND (“effectiveness” OR “efficacy”). Among the 36 identified records, only one study quantitatively reported vaccine effectiveness against multisystem inflammatory syndrome in children (MIS-C). No studies focused on the vaccine effectiveness against long COVID or post-COVID-19 condition in children. Furthermore, although studies on vaccine effectiveness against long COVID in adults are available, their findings are inconsistent. Most existing studies in the adult population compare the long COVID following breakthrough infections in vaccinated individuals to infections in unvaccinated individuals, which only reveal the vaccine’s effectiveness within the infected population. This approach does not accurately represent the true impact of vaccination on long COVID given the risk of infection is substantially reduced in the vaccinated group and introduces selection bias.

Added value of this study

Using data from the largest pediatric electronic health record (EHR) clinical research network in the U.S., our study is among the first studies to assess the real-world effectiveness of the BNT162b2 vaccines at the population level while quantifying the vaccine’s influence on long COVID outcomes, either beyond or through the prevention of SARS-CoV-2 infections, using causal mediation analysis. Our study found a high overall protective effect of BNT162b2 against long COVID during Delta period, and moderate protective effects during the Omicron period. The estimated direct and indirect effects indicated that the vaccine’s primary advantage in protecting against long COVID outcomes stems from its ability to reduce the risk of SARS-CoV-2 infection in both Delta and Omicron period.

Implications of all the available evidence

Our findings demonstrate the effectiveness of BNT162b2 vaccines on long COVID in U.S. pediatric population. The causal mediation analysis suggested a comparable risk of long COVID for documented infections after vaccination to those occurring without prior vaccination. Given that the causal pathways for developing long COVID are still not fully understood, our findings underscore the importance of continually prioritizing the prevention of SARS-CoV-2 infections and using vaccination as a key focus of public health policy to mitigate the risk of long COVID.

 

https://www.eurekalert.org/news-releases/1081173

News Release 21-Apr-2025
COVID vaccine protected kids from long COVID
Peer-Reviewed Publication

University of Pennsylvania School of Medicine

Unvaccinated children and adolescents were up to 20 times more likely to develop long COVID than their vaccinated peers, according to new research led by a team from the Perelman School of Medicine at the University of Pennsylvania. However, the analysis they performed also indicated that protection afforded by the vaccine primarily comes from preventing infection in the first place, rather than offering special protection against long COVID itself.

“In other words, vaccination has been key to preventing COVID-19 infection, which is important to reducing the risk of long COVID as well,” said Yong Chen, PhD, a professor of Biostatistics and senior author of the study publish in Lancet eClinicalMedicine.

Long COVID’s impact

One of enduring mysteries of the COVID-19 pandemic is the cause of “long COVID,” a collection of symptoms that can appear or persist weeks and months after a person’s initial infection has subsided. While the underlying mechanisms of this syndrome remain unclear, scientists know that viral infections often give rise to post-viral syndromes featuring fatigue, “brain fog,” and other non-specific symptoms.

COVID-19 infections, caused by the emergent coronavirus SARS-CoV-2, are no exception: Long COVID, known more formally as post-acute sequelae of SARS-CoV-2 infection (PASC), became remarkably common during the pandemic.

Even in June 2022, after the worst phases of the pandemic had passed, a survey conducted by the US Centers for Disease Control & Prevention (CDC) suggested that about 7.5 percent of Americans, including more than 9 percent of American women, were still suffering from long COVID symptoms.

Since the causes of long COVID remain unclear and no common treatments are currently available, some prior studies have examined whether vaccination prior to infection offers any protection against developing long COVID. However, their findings have been inconsistent. New research now suggests that vaccines may offer greater protection against long COVID than previously thought.

“Prior studies that simply compare vaccinated and unvaccinated individuals may not fully capture the true impact of vaccination on long COVID, as they often overlook the fact that vaccination substantially reduces the risk of infection in the first place.” said co-author Jeffrey Morris, PhD, director of Biostatistics.

Most research on vaccine effectiveness against long COVID has primarily focused on adults.

"Our study targets children and adolescents because their immune responses to vaccines and the development of long COVID symptoms might differ significantly from those seen in adults," Morris explained.

Protection against long COVID or infection?

As part of an NIH-sponsored research initiative known as RECOVER—which gathers and analyzes electronic health records from health systems nationwide to better understand long COVID—the research team conducted an observational study with de-identified electronic health records from nearly 400,000 children and adolescents across the United States. The study pulled data from the major COVID-19 waves of 2021 and 2022.

With these records, the researchers constructed three separate groups or “cohorts” of vaccinated and unvaccinated young people: 112,590 adolescents (12-to-20-year-olds) whose records from July through Nov 2021—when Delta variants of SARS-CoV-2 dominated—were analyzed, and 188,894 children (5–to-11-year-olds) and 84,735 adolescents from records dating to January through November 2022—when Omicron was dominant.

The analysis suggested that the vaccine was about 95 percent effective in preventing long COVID in adolescents during the Delta wave of 2021—meaning vaccinated adolescents were only about 5 percent as likely to get long COVID compared to their unvaccinated peers. In this cohort, the researchers found 0.11 cases of long COVID in the vaccinated group per 10,000 person-weeks (a statistical measure that accounts for the number of participants and how long they participated), compared to 3.54 cases in the unvaccinated group—a 32-fold difference.

In 2022, against Omicron variants, vaccination was about 60 percent effective in preventing long COVID in the 5-to-11-year-old group and 75 percent effective in the 12-to-20-year-old group. In the children’s group, the long COVID incidence rates were 0.33 in vaccinated children and 1.07 among the unvaccinated (the rate tripled in unvaccinated children). Among adolescents in omicron, the incidence rates were 0.24 in the vaccinated and 1.43 among the unvaccinated (almost a six-fold difference).

“Using mediation analysis, we were able to disentangle how much of the vaccine’s protection was due to preventing initial infection versus a direct benefit on long COVID after infection,” said first author Qiong Wu, PhD, who conducted the research as a postdoctoral fellow at Penn Medicine and is now an assistant professor at the University of Pittsburgh.

The mediation analysis suggested that, once infected, vaccinated children and adolescents were just as likely to develop long COVID as their unvaccinated peers. This seemed to indicate no additional, special protective effect once infection occurred.

“Preventing COVID-19 infections in the first place, including through vaccination, appears to be the best way to avoid long COVID,” Chen said.

Christopher Forrest, MD, PhD, a professor of Pediatrics at Children's Hospital of Philadelphia, was a co-senior author on this study.

The research was supported by various National Institutes of Health grants (OT2HL161847-01, 1R01LM012607, 1R01AI130460, 1R01AG073435, 1R56AG074604, 1R01LM013519, 1R01LM014344, 1R56AG069880, 1R01AG077820, 1U01TR003709, 1R21AI167418, 1R21EY034179) and by Project Program Awards (ME-2019C3-18315 and ME-2018C3-14899) from the Patient-Centered Outcomes Research Institute.

Journal
EClinicalMedicine

DOI
10.1016/j.eclinm.2024.102962

Method of Research
Data/statistical analysis

Subject of Research
People

Article Title
Real-world effectiveness and causal mediation study of BNT162b2 on long COVID risks in children and adolescents