STUDY: "Long Covid" symptoms may be from Covid Vaccine

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COVID-19 vaccines have been instrumental in reducing the impact of the pandemic, preventing severe illness and death, and they appear to protect against long COVID. However, some individuals have reported chronic symptoms that developed soon after receiving a COVID-19 vaccine. This little-understood, persistent condition, referred to as post-vaccination syndrome (PVS), remains unrecognized by medical authorities, and little is known about its biological underpinnings.

In a new study, Yale researchers have taken initial steps to characterize this condition, uncovering potential immunological patterns that differentiate those with PVS from others. The findings are early and require further confirmation but may eventually guide strategies to help affected individuals.

“This work is still in its early stages, and we need to validate these findings,” said Akiko Iwasaki, Sterling Professor of Immunobiology at Yale School of Medicine (YSM) and co-senior author of the study published Feb. 19 as a preprint on MedRxiv. “But this is giving us some hope that there may be something that we can use for diagnosis and treatment of PVS down the road.”

Some of the most common chronic symptoms of PVS include exercise intolerance, excessive fatigue, brain fog, insomnia, and dizziness. They develop shortly after vaccination, within a day or two, can become more severe in the days that follow, and persist over time. More studies are needed to understand the prevalence of PVS.

“It’s clear that some individuals are experiencing significant challenges after vaccination. Our responsibility as scientists and clinicians is to listen to their experiences, rigorously investigate the underlying causes, and seek ways to help,” said Harlan Krumholz, the Harold H. Hines, Jr. Professor of Medicine (Cardiology) at YSM and co-senior author of the study.

Data for the study came from Yale’s Listen to Immune, Symptom, and Treatment Experiences Now (LISTEN) Study, through which researchers aim to better understand long COVID and PVS. For the new study, researchers included data from 42 LISTEN participants who reported symptoms of PVS and 22 individuals who did not report any PVS symptoms after receiving a COVID-19 vaccination.

From participants’ blood samples, the researchers looked for immune features that were different between the two groups. They found several differences in immune cell populations; those with PVS had lower levels of effector CD4+ T cells and higher levels of TNF-alpha+ CD8 T cells — both are types of white blood cells — among other differences.

There were also differences in the levels of antibodies that the body uses to target SARS-CoV-2. Participants with PVS who had never contracted COVID-19 had lower levels of antibodies against the SARS-CoV-2 spike protein than control participants, likely because they tended to have fewer vaccine doses than individuals without PVS. Fewer vaccine doses and no viral infection means the body’s immune system has had little opportunity to develop a defense to the virus, said the researchers.

When the researchers measured levels of SARS-CoV-2 spike protein — the part of the virus that enables it to penetrate and infect host cells and what COVID-19 vaccines use to trigger immune responses against the virus — they found that some individuals with PVS, even those without evidence for infection, had higher levels of spike protein than controls. Typically spike protein can be detected for a few days after vaccination, but some participants with PVS had detectable levels more than 700 days after their last vaccination. Persistent spike protein has been associated with long COVID as well.

“That was surprising, to find spike protein in circulation at such a late time point,” said Iwasaki. “We don’t know if the level of spike protein is causing the chronic symptoms, because there were other participants with PVS who didn’t have any measurable spike protein. But it could be one mechanism underlying this syndrome.”

Krumholz explained that PVS might be similar to how different infections can cause chronic symptoms through distinct biological pathways. “One person might develop chronic symptoms due to immune dysregulation, while another experiences lingering effects from viral reactivation,” he said. “We need to map these different pathways carefully to understand what is happening in each case. This work is just beginning, and further studies are essential to guide diagnosis and treatment.”

Going forward, the researchers want to further validate these findings in a larger group of people “This is far from a final answer on PVS,” said Iwasaki.

They’re also investigating several possible drivers of PVS. Along with spike protein persistence, the researchers are assessing the contributions of autoimmunity, tissue damage, and Epstein-Barr Virus (EBV) reactivation. In the study, individuals with PVS were more likely than those without the syndrome to have evidence of reactivated EBV, which is the most common cause of infectious mononucleosis, also known as “mono.”

A deeper understanding of PVS and its drivers could lead to better vaccines that have fewer side effects, effective methods for diagnosing the syndrome, and targets for treatment, said the researchers.

“For instance, if we can determine why spike protein is persisting for as long as it is in some people, maybe we can remove it — with monoclonal antibodies, for example — and maybe that could help reduce PVS symptoms,” said Iwasaki.

Iwasaki is also a professor of dermatology and of molecular, cellular, and developmental biology in Yale’s Faculty of Arts and Sciences, a professor of epidemiology at Yale School of Public Health, and an investigator of the Howard Hughes Medical Institute.

“We’re only just starting to make headway in understanding PVS,” said Krumholz. “Every medical intervention carries some risk, and it’s important to acknowledge that adverse events can occur with vaccines. Our focus must remain on understanding what these people are experiencing through rigorous science and addressing the needs of those affected with compassion and an open mind.”

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