Yale study explores chronic symptoms after COVID-19 shots, finds alarming shifts in immune system

The COVID-19 vaccines have saved millions of lives, but a small group of individuals have reported persistent symptoms following vaccination. This condition, known as post-vaccination syndrome (PVS), remains unrecognized by medical authorities, and little is understood about its causes. Now, Yale researchers have taken a closer look, offering early insights into its potential biological underpinnings.

A new study led by Yale’s Akiko Iwasaki and Harlan Krumholz, published on February 19, examines immune differences in people experiencing PVS. Researchers analyzed blood samples from 42 individuals with PVS symptoms and compared them to 22 people who had no issues after vaccination. 

“This work is still in its early stages, and we need to validate these findings,” said Iwasaki, a Sterling Professor of Immunobiology at Yale School of Medicine. “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.”

What the study found

PVS symptoms — such as exercise intolerance, excessive fatigue, brain fog, insomnia, and dizziness — often appear within a day or two of vaccination and can worsen over time. To investigate possible causes, researchers examined immune responses in affected individuals.

They discovered distinct differences in immune cells, including lower levels of effector CD4+ T cells and higher levels of TNF-alpha+ CD8 T cells in those with PVS. Additionally, people with PVS who had never contracted COVID-19 showed lower levels of antibodies against the virus’s spike protein, likely due to receiving fewer vaccine doses.

One of the most striking findings was the presence of the SARS-CoV-2 spike protein in some individuals with PVS, even more than 700 days after vaccination. Normally, the spike protein is cleared within days, but in these cases, it persisted for years — similar to patterns observed in long COVID patients.

“That was surprising, to find spike protein in circulation at such a late time point,” Iwasaki noted. “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.”

What’s next?

Krumholz suggested that PVS might share similarities with other post-infectious syndromes, with different patients experiencing symptoms through varied 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.”

The study’s findings raise questions about improving future vaccines to reduce potential side effects. Iwasaki pointed out that if persistent spike protein is a contributing factor, targeted treatments such as monoclonal antibodies might help reduce symptoms. “If we can determine why spike protein is persisting for as long as it is in some people, maybe we can remove it — and maybe that could help reduce PVS symptoms,” she said.