Study: Antibodies in Blood Soon After COVID-19 Onset May Predict Severity

Stanford Medicine investigators were able to estimate who is most likely to land in the hospital.

Blood drawn from individuals shortly after they were infected with SARS-CoV-2 may indicate who is most likely to become hospitalized, results of a study from Stanford Medicine show.

“We’ve identified an early biomarker of risk for progression to severe symptoms,” Taia Wang, MD, PhD, assistant professor of infectious diseases and of microbiology and immunology at Stanford University, said in a statement.

“And we found that antibodies elicited by an mRNA vaccine, in this case, Pfizer’s, differ in important, beneficial ways from those in people infected with SARS-CoV-2 who later progress to severe symptoms.”

The findings, which were published in Science Translation Medicine, suggest that there could eventually be a test, given soon after a positive COVID-19 result, that would help clinicians focus attention on individuals likely to need it most, according to the statement.

Investigators collected blood samples from 178 individuals who had tested positive for COVID-19 upon visiting a Stanford Health Care clinic or hospital. At the time of testing, the symptoms were universally mild. However, as time passed 15 individuals developed symptoms severe enough to land them in the emergency department.

Investigators analyzed the antibodies in the blood samples taken from study participants on the day of their positive COVID-19 tests and then again 28 days later.

Antibodies are proteins produced by immune cells that secrete a response when the body senses a foreign presence, like microbial pathogens. They are shaped, approximately, like 2-branched trees, where the branches can assume multiple shapes. The resulting electrochemical and spatial diversity of the areas defined by antibodies’ branches and their intersection is so great that, in the aggregate, antibodies take on all foreign presences.

When an antibody’s shape and electrochemistry is complementary to a feature of a pathogen, it gloms on tightly. Antibodies that bind pathogens in just the right places, preventing infection, are called neutralizing antibodies.

The resulting adhesion generates what is called an immune complex, drawing immune cells to the site.

The investigators found that though many participants whose symptoms remained mild had healthy levels of neutralizing antibodies to SARS-CoV-2 from day 1, those who ended up hospitalized initially had minimal or undetectable levels of neutralizing antibodies, though their immune cells started pumping them out later during the infection’s course.

A second finding shows that the antibody “trunks” contain chains of various sugar molecules linked together. These sugar chains influence how inflammatory an immune complex will be.

Investigators found that individuals who progressed to severe COVID-19 had sugar chains on certain antibodies targeting SARS-CoV-2 and were deficient in a variety of sugar called fucose. The deficiency was evident on the day individuals first tested positive.

Furthermore, immune cells in these patients featured inordinately high levels of receptors for these fucose-lacking types of antibodies. Such receptors, called CD16a, are known to boost immune cells’ inflammatory activity.

“Some inflammation is absolutely necessary to an effective immune response,” Wang said. “But too much can cause trouble, as in the massive inflammation we see in the lungs of people whose immune systems have failed to block SARS-CoV-2 quickly upon getting infected.”

The investigators also studied the antibodies elicited in 29 individuals after they received the first and second doses of the Pfizer-BioNTech mRNA vaccine. They compared the antibodies with those of individuals who did not progress to severe disease about a month after being vaccinated or infected.

They also compared them with antibodies from individuals who were hospitalized with COVID-19.

The 2 vaccine doses lead to overall higher neutralizing-antibody levels, and antibody fucose content was high in the vaccinated and mildly symptomatic group but low among the hospitalized individuals.

The investigators tested their findings in mice who were bioengineered so that their immune cells featured human receptors for antibodies on the surface. They applied immune complexes, varying from individuals with high fucose-deficient antibodies, individuals with normal levels, or vaccinated adults, to the mice’s windpipes.

Investigators observed that, 4 hours later, the fucose-deficient immune-complex extracts generated a massive inflammatory reaction in the mice’s lungs. Neither normal-fucose extracts or extracts from vaccinated individuals had the same effect.

When the experiment was repeated in similar mice that had been bioengineered to lack CD16a, there was no such hyperinflammatory response in their lungs.

Immunological factors that investigators identified were each, on their own, modestly predictive of COVID-19 severity, Wang said.

The factors were a sluggish, neutralizing antibody response, deficient fucose levels on antibody-attached sugar chains, and hyperabundant receptors for fucose-deficient antibodies.

Altogether, investigators were able to guess the disease course with an accuracy of about 80%.

The abundance of CD16a on immune cells and the relative absence of fucose on antibodies’ sugar chains may not be entirely unrelated phenomena in some individuals, and while neither is alone enough to consistently induce severe inflammatory symptoms, the combination leads to an inflammatory overdrive, Wang said.

Reference

Stanford-led study: Antibodies in blood soon after COVID-19 onset may predict severity. EurekAlert. News release. January 18, 2022. Accessed January 20, 2022. https://www.eurekalert.org/news-releases/940354