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.”

Jeffrey Morris, PhD, co-author, 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.