COVID-19 severity affected by proportion of antibodies to the crucial viral protein

COVID-19 antibodies preferentially target a different part of the virus in mild cases of COVID-19 than in severe cases and decrease significantly within several months after infection, according to a new study by researchers at Stanford Medicine.

The findings identify new links between the course of the disease and the patient’s immune response. They also raise questions about whether people can be reinfected, whether antibody tests to detect a previous infection may underestimate the extent of the pandemic and whether vaccinations may need to be repeated at regular intervals to maintain a protective immune response.

“This is one of the most comprehensive studies to date of the antibody’s immune response to SARS-CoV-2 in people across the spectrum of disease severity, from asymptomatic to fatal,” said Scott Boyd, MD, Ph.D., associate professor of pathology. “We evaluated various points in time and sample types, and we also analyzed viral RNA levels in nasopharyngeal swabs and blood samples from patients. It is one of the first large images of this disease.”

The study found that people with severe COVID-19 have low proportions of antibodies to the spike protein used by the virus to enter human cells, compared to the number of antibodies to proteins in the virus’s inner layer.

Boyd is a senior author on the study, which was published on December 7 in Scientific Immunology. Other senior authors are Benjamin Pinsky, MD, Ph.D., associate professor of pathology and Peter Kim, Ph.D., from Virginia and DK Ludwig Professor of Biochemistry. The main authors are research scientist Katharina Röltgen, Ph.D .; postdoctoral scholars Abigail Powell, Ph.D., and Oliver Wirz, Ph.D .; and clinical instructor Bryan Stevens, MD.

The virus binds to the ACE2 receptor

The researchers studied 254 people with asymptomatic, mild or severe COVID-19 who were identified through routine tests or occupational health screening at Stanford Health Care or who attended a Stanford Health Care clinic with symptoms of COVID-19. Of the people with symptoms, 25 were seen on an outpatient basis, 42 were hospitalized outside the intensive care unit and 37 were treated in the intensive care unit. Twenty-five people in the study died of the disease.

SARS-CoV-2 binds to human cells through a structure on its surface called the spike protein. This protein binds to a receptor in human cells called ACE2. The link allows the virus to enter and infect the cell. Once inside, the virus takes off its outer layer to reveal an inner layer surrounding its genetic material. Therefore, the virus co-opts the cell’s protein production mechanism to produce more viral particles, which are then released to infect other cells.

Antibodies that recognize and bind to the spike protein block its ability to bind to ACE2, preventing the virus from infecting cells, whereas antibodies that recognize other viral components are unlikely to prevent viral spread. Current vaccine candidates use portions of the spike protein to stimulate an immune response.

Boyd and his colleagues analyzed the levels of three types of antibodies – IgG, IgM and IgA – and the proportions that targeted the viral protein or the inner layer of the virus as the disease progressed and patients recovered or became ill. They also measured levels of viral genetic material in nasopharyngeal samples and in patients’ blood. Finally, they evaluated the effectiveness of the antibodies in preventing the spike protein from binding to ACE2 on a laboratory plate.

“Although previous studies have assessed the overall antibody response to infection, we have compared the viral proteins targeted by these antibodies,” said Boyd. “We found that the severity of the disease correlates with the proportion of antibodies that recognize the spike protein domains compared to other non-protective viral targets. These people with mild disease tend to have a higher proportion of anti-spike antibodies, and those who died of their disease had more antibodies that recognized other parts of the virus. “

Substantial variability in the immune response

The researchers caution, however, that although the study identified trends among a group of patients, there is still substantial variability in the immune response mounted by individual patients, particularly those with severe illness.

“Antibody responses are probably not the only determinant of someone’s outcome,” said Boyd. “Among people with severe illness, some die and some recover. Some of these patients have a strong immune response and others have a more moderate response. So there are many other things going on. There are also other branches of the immune system involved. It is important note that our results identify correlations, but do not prove the cause. “

As in other studies, the researchers found that people with asymptomatic and mild illnesses had lower levels of antibodies in general than those with severe illnesses. After recovery, IgM and IgA levels continually decreased to low or undetectable levels in most patients for a period of about one to four months after the onset of symptoms or estimated date of infection, and IgG levels dropped significantly.

“This is quite consistent with what has been seen with other coronaviruses that circulate regularly in our communities to cause the common cold,” said Boyd. “It is not uncommon for someone to be reinfected in a year or sometimes earlier. It remains to be seen whether the immune response to vaccination against SARS-CoV-2 is stronger or persists for longer than that caused by natural infection. It is quite possible, it could be better. But there are many questions that still need to be answered. “

Boyd is co-president of the National Cancer Institute’s SeroNet Serological Sciences Network, one of the country’s largest coordinated research efforts to study the immune response to COVID-19. He is the principal investigator at the SeroNet Center of Excellence at Stanford, which is addressing critical questions about the mechanisms and duration of immunity to SARS-CoV-2.

“For example, if someone has already been infected, should they get the vaccine? If so, how should it be prioritized?” Boyd said. “How can we adapt seroprevalence studies in vaccinated populations? How does immunity from vaccination differ from that caused by natural infection? And how long can a vaccine be protective? These are all very interesting and important issues ”.