Post-Vaccination Syndrome: Researchers Identify Potential Immunological Patterns

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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.

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. 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. The researchers also found that individuals with PVS were more likely to have evidence of reactivated Epstein-Barr Virus (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. The study is limited by its small sample size and the fact that post-vaccination syndrome is "a very, very heterogeneous" disorder. Despite these limitations, the researchers found interesting data that need further study, particularly in the arena of hyper-innate immune system activation and its consequences, persistent S1 protein circulating, and immune cell subset perturbations. Much larger studies of very carefully defined and phenotyped individuals are needed to be sure of the findings, but these investigators are approaching it correctly and pointing the way.

The immune findings came from an analysis of 42 people with post-vaccination syndrome and 22 controls who did not have post-vaccination syndrome after receiving a COVID vaccine from the LISTEN study. All blood samples were collected between December 2022 and November 2023. The median age of participants was 42.5 years. The most frequent symptoms reported by those with post-vaccination syndrome were excessive fatigue, tingling and numbness, exercise intolerance, brain fog, difficulty concentrating or focusing, trouble falling or staying asleep, neuropathy, muscle aches, anxiety, tinnitus, and burning sensations. The study was funded in part by the Howard Hughes Medical Institute Collaborative COVID-19 Initiative. The researchers reported relationships with government agencies and industry, and the study’s findings have been published as a preprint on medRxiv. The next steps are to reverse-engineer vaccines to prevent post-vaccination syndrome and to develop therapeutic approaches to reverse what has happened to these patients. The following are some key points from the study: * List of key findings: * Lower levels of effector CD4+ T cells in individuals with PVS * Higher levels of TNF-alpha+CD8 T cells in individuals with PVS * Lower levels of antibodies against the SARS-CoV-2 spike protein in individuals with PVS * Higher levels of circulating spike protein in some individuals with PVS * Evidence of reactivated Epstein-Barr Virus (EBV) in individuals with PVS * Timeline of events: * December 2022: Blood sample collection began * November 2023: Blood sample collection ended * February 2025: Study findings published as a preprint on medRxiv * Policy points: * Further research is needed to understand the prevalence and biological underpinnings of PVS * Development of effective methods for diagnosing and treating PVS is crucial * Reverse-engineering vaccines to prevent PVS and developing therapeutic approaches to reverse its effects are potential next steps * Statistical data: * 42 participants with PVS * 22 controls without PVS * Median age of participants: 42.5 years * Most frequent symptoms reported by those with PVS: excessive fatigue (85%), tingling and numbness (80%), exercise intolerance (80%), brain fog (77.5%), difficulty concentrating or focusing (72.5%)