Dompé farmaceutici in Milan, the National Institute on Drug Abuse (part of the U.S. National Institutes of Health), Johns Hopkins University, the Scripps Institute, Stanford School of Medicine, and the University of L'Aquila in Italy all teamed up to study why a minority of subjects receiving the SARS-CoV-2 vaccine have certain reactions (Science Advances, November 30, 2022).

It is well understood that the SARS-CoV-2 virus can cause severe vasculopathy, which may result in fatal thrombosis, and now the research team understands why. They used Dompé's supercomputing platform, Exscalate, to identify spike protein binding partners beyond the canonical ACE2 receptor. The team identified prominent interactions between two human estrogen receptors (ERα, ERβ) and the SARS-CoV-2 S protein.

After an unbiased primary screen to profile the binding of full-length S protein against more than 9,000 human proteins, the researchers found ERα consistently showed up. Also, high ERα levels were measured in the damaged lungs of infected hamsters, as well as in human postmortem lung samples. Given the role of ERα in the coagulation cascade, S protein could increase the pro-coagulation activity of endothelial cells, and thus an increased risk of thrombosis, they posited.

Deleting the appropriate point mutations in the spike sequence abolished the binding of ERα and its effects without compromising its immunogenicity and points toward a way to mitigate the rare side effects observed with available vaccines, the researchers said.

The generic drug raloxifene -- with known efficacy and tolerability as an estrogen modulator for treating osteoporosis -- can also prevent the pro-coagulation activity of endothelial cells, the scientists added.