Whether a person suffers from severe COVID-19, or has a milder infection, hinges in part on an inflammatory response that is implicated in disease pathogenesis. The mechanisms underlying the contributions of the inflammatory response, however, remain unclear. IgG antibodies are one area of investigation as they can form immune complexes (ICs) upon viral antigen binding that may impact inflammation. More specifically, IgG interactions with activating and inhibitory Fc gamma receptors (FcγRs) on myeloid cells.

In a new study, blood drawn from patients shortly after SARS-CoV-2 infection may yield insight into disease pathogenesis. Early non-neutralizing, afucosylated IgG antibodies, specific to SARS-CoV-2, were found to be associated with progression from mild to more severe COVID-19. In addition, the antibodies detected were distinct from those elicited by the mRNA vaccines.

The study’s findings are published in Science Translational Medicine in the paper, “Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity.

“Severe COVID-19 is largely a hyperinflammatory disease, particularly in the lungs,” said Taia Wang, MD, PhD, assistant professor of infectious diseases and of microbiology and immunology at Stanford University. “We wondered why a minority of people develop this excessive inflammatory response, when most people don’t.”

“We’ve identified an early biomarker of risk for progression to severe symptoms,” said Wang. “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.”

Blood samples were taken from 178 adults who tested positive for COVID-19 upon visiting a Stanford Health Care hospital or clinic. At the time of testing, their symptoms were mild. However, 15 participants developed symptoms and entered the emergency department. By analyzing the antibodies in blood samples from day 1, and 28 days later, the researchers identified differences between those who developed severe symptoms and those who didn’t.

Many participants with mild symptoms had higher levels of neutralizing antibodies to SARS-CoV-2 early on, when compared to participants who ended up hospitalized, who had minimal or undetectable levels of neutralizing antibodies early on.

More specifically, the authors noted that early, non-neutralizing, afucosylated IgG antibodies specific to SARS-CoV-2 were associated with progression from mild to more severe COVID-19.

In addition, the antibodies elicited by mRNA SARS-CoV-2 vaccines were “ highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG.”

In participants who progressed to severe COVID-19, sugar chains on certain antibodies targeting SARS-CoV2 were deficient in a variety of fucose. This deficiency was evident on the day these “progressors” first tested positive. So, it wasn’t a result of severe infection but preceded it.

Furthermore, immune cells in these patients featured inordinately high levels of receptors for the antibodies lacking fucose. 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”—for example, because their early immune response didn’t generate enough neutralizing antibodies to the virus.

The researchers developed an in vivo mouse model to study the biology of afucosylated IgG immune complexes. They applied immune complexes extracted from patients with high levels of fucose-deficient antibodies, patients with normal levels, or vaccinated adults, to the mice.

The fucose-deficient immune-complex extracts generated a massive inflammatory reaction in the mice’s lungs. By contrast, vaccine-elicited IgG did not promote an inflammatory lung response. When the experiment was repeated in mice that lacked CD16a, there was no hyperinflammatory response in their lungs.

Wang said the immunological factors the researchers have identified were each, on their own, modestly predictive of COVID-19 severity. But taken together, they allowed the scientists to guess the disease’s course with an accuracy of about 80%.

Wang speculates that 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 people, and that while neither alone is enough to consistently induce severe inflammatory symptoms following SARS-CoV-2 infection, the combination leads to a devastating inflammatory overdrive.