As Understanding of Long COVID Deepens, the Search for Therapies Continues

CHICAGO—About 400 million people are experiencing long COVID around the world, including, as of last year, about 5% of adults in the U.S., so the syndrome remains a serious clinical challenge, experts said in a session at ACR Convergence 2025.

Progress has been made in clarifying the clinical picture in an effort to make long COVID more easily identified, and in pinpointing the mechanisms underlying it. But so far no long-COVID-specific therapies have emerged, although steps continue in this direction.

Zhaoqi Yan, PhD, a scientist and researcher at the San Francisco-based Gladstone Institute for Neurological Disease, discussed the progress that has been made to understand the role of fibrin in long-COVID-induced inflammation and suggested that an antibody already being studied in other diseases could be useful in long COVID.

This therapeutic avenue would be a significant step, he said.

Complex Biological Mechanisms

“The biological mechanisms of long COVID are still very complex—there’s been a lot of study to find the mechanism,” Dr. Yan said. “There are multiple hypotheses, including acute infection, virus persistence, post-acute infection, autoimmunity thrombosis, latent virus reactivation, dysbiosis and gut microbes finding their way into other tissues.” But up until now, he said, “there’s not a lot of medications that can actually reverse the course of long COVID.”

In the lab of Katerina Akassoglou, PhD, where he works, he has focused on the role of fibrin, the key component of the body’s natural blood clotting process, because clotting has come to be recognized as a common feature of COVID-19, and fibrinogen, a protein closely related to fibrin, has been associated with cognitive deficits after infection with the SARS-CoV-2 virus.¹

Role of Fibrin

In a mouse model, Dr. Yan has found that fibrin is required for SARS-CoV-2 inflammation and suppresses the natural killer cells that have a role in viral clearance. Dr. Yan said that experiments in mice have found that the 5B8 antibody, which targets an inflammatory fibrin domain that is only expressed on pathogenic fibrin, is able to target the inflammatory function of fibrin without having adverse anticoagulant effects.

A humanized version of this antibody, known as THN391, is now in phase 1b studies in Alzheimer’s disease and diabetic macular edema.² Dr. Yan said it has been found to suppress brain inflammation in non-neuroinvasive and in neuroinvasive COVID-19.

“Our data shed new light on the enigmatic coagulopathy found in COVID-19, revealing a causal role for fibrinogen in thromboinflammation,” Dr. Yan said. “Fibrin-targeting immunotherapy may represent an approach to selectively suppress COVID-19 pathogenesis in the brain or other organs without adverse effects on normal hemostasis.”