Covid severity determined by antibody ratio not volume, study reveals

Covid-19 antibodies attack the spike protein in mild cases of coronavirus and other parts of the virus in more serious infections, according to a study by researchers at Stanford Medicine.

Immune response is also not the sole factor in determining the severity of infection and a patient's recovery prospects, the scientists have found.

The findings raise concerns over whether people can be reinfected and the prospect of repeat vaccinations to maintain a protective immune response.

"This is one of the most comprehensive studies to date of the antibody immune response to SARS-CoV-2 in people across the entire spectrum of disease severity, from asymptomatic to fatal," said Scott Boyd, associate professor of pathology at Stanford.

"We assessed multiple time points and sample types, and also analysed levels of viral RNA in patient nasopharyngeal swabs and blood samples. It's one of the first big-picture looks at this illness."

The study found that people with severe infections have low proportions of antibodies targeting the spike protein used by the virus to enter human cells compared with the number of antibodies targeting proteins of the virus's inner shell.

The researchers studied 254 people with asymptomatic, mild or severe infections. Of the people with symptoms, 25 were treated as outpatients, 42 were hospitalised outside the intensive care unit and 37 were treated in the intensive care unit. Twenty-five people in the study died of the disease.

Covid-19 binds to human cells via a structure on its surface called the spike protein. This protein binds to a receptor on human cells called ACE2.

Antibodies that recognise and bind to the spike protein block its ability to bind to ACE2, preventing the virus from infecting the cells, whereas antibodies that recognise other viral components are unlikely to prevent viral spread.

Current vaccine candidates use portions of the spike protein to stimulate an immune response.

"Although previous studies have assessed the overall antibody response to infection, we compared the viral proteins targeted by these antibodies," Prof Boyd said.

"We found that the severity of the illness correlates with the ratio of antibodies recognising domains of the spike protein compared with other nonprotective viral targets.

"Those people with mild illness tended to have a higher proportion of anti-spike antibodies, and those who died from their disease had more antibodies that recognised other parts of the virus."

Immune response not the only factor

Prof Boyd cautioned that antibody responses are not likely to be the sole determinants of someone's outcome. A study in November posited that even if antibodies fade, T-cells may offer some residual immunity six months after infection.

"Among people with severe disease, some die and some recover," he said. "Some of these patients mount a vigorous immune response, and others have a more moderate response. So there are a lot of other things going on.

"There are also other branches of the immune system involved. It's important to note that our results identify correlations but don't prove causation."

As in other studies, the researchers found that people with asymptomatic and mild illness had lower levels of antibodies overall than did those with severe disease.

"This is quite consistent with what has been seen with other coronaviruses that regularly circulate in our communities to cause the common cold," Boyd said.

"It's not uncommon for someone to get reinfected within a year or sometimes sooner.

"It remains to be seen whether the immune response to SARS-CoV-2 vaccination is stronger, or persists longer, than that caused by natural infection. It's quite possible it could be better. But there are a lot of questions that still need to be answered."

Foremost amongst these is whether a person who has already been infected should get the vaccine and when, said Prof Boyd.

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