COVID-19 severity affected by proportion of antibodies targeting critical viral protein – sciencedaily

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

“This is one of the most comprehensive studies to date on the immune response of antibodies to SARS-CoV-2 in people across the spectrum of disease severity, from asymptomatic to fatal,” said said Scott Boyd, MD, PhD, associate professor of pathology. “We evaluated several time points and sample types, and also analyzed viral RNA levels in nasopharyngeal swabs and blood samples from patients. This is one of the first great panoramas of this disease.

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

Boyd is one of the lead authors of the study, which was published on December 7 in Scientific immunology. The other principal authors are Benjamin Pinsky, MD, PhD, associate professor of pathology, and Peter Kim, PhD, professor of biochemistry Virginia and DK Ludwig. The lead authors are researcher Katharina Röltgen, PhD; postdoctoral fellows Abigail Powell, PhD, and Oliver Wirz, PhD; and clinical instructor Bryan Stevens, MD.

The virus binds to the ACE2 receptor

Researchers studied 254 people with asymptomatic, mild or severe COVID-19 who were identified through routine tests or occupational health tests at Stanford Health Care or who presented to a Stanford Health Care clinic with symptoms of COVID-19. Of the people with symptoms, 25 were treated 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 from the disease.

SARS-CoV-2 binds to human cells via a structure on its surface called a spike protein. This protein binds to a receptor on human cells called ACE2. Binding allows the virus to enter and infect the cell. Once inside, the virus sheds its outer layer to reveal an inner shell containing its genetic material. Soon, the virus cooperates with the cell’s protein-making machinery 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, while 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 spike protein or inner envelope of the virus as the disease progressed and patients recovered or recovered. were getting sicker. They also measured levels of viral genetic material in nasopharyngeal samples and patients’ blood. Finally, they evaluated the effectiveness of the antibodies to prevent the spike protein from binding to ACE2 in a lab dish.

“Although previous studies have assessed the overall response of antibodies to infection, we have compared the viral proteins targeted by these antibodies,” Boyd said. “We found that disease severity correlated with the ratio of antibodies recognizing spike protein domains to other non-protective viral targets. their disease had more antibodies that recognized other parts of the virus. “

Substantial variability in immune response

The researchers warn, 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, especially those with severe disease.

“Antibody responses aren’t likely to be the sole determinant of someone’s outcome,” Boyd said. “Among people with serious illnesses, some die and some get better. Some of these patients develop a vigorous immune response, and others have a more moderate response. So there are a lot of other things going on. other branches of the immune system involved. It is important to note that our results identify correlations but do not prove causation. “

As in other studies, researchers found that people with asymptomatic and mild disease had lower antibody levels overall than those with severe disease. After recovery, IgM and IgA levels declined steadily to low or undetectable levels in most patients over a period of approximately one to four months after the onset of symptoms or the estimated date of infection. , and IgG levels dropped significantly.

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

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

“For example, if a person has already been infected, should they be vaccinated? If so, how should they be prioritized?” Boyd said. “How can we adapt seroprevalence studies in vaccinated populations? How will immunity from vaccination be different from that caused by natural infection? And how long can a vaccine be protective? This are all very interesting and important questions. “

Other co-authors of the study at Stanford are visiting pathology instructor Catherine Hogan, MD; postdoctoral fellows Javaria Najeeb, PhD, and Ana Otrelo-Cardoso, PhD; resident physician Hannah Wang, MD; researcher Malaya Sahoo, PhD; research professional ChunHong Huang, PhD; researcher Fumiko Yamamoto; director of the Monali Manohar laboratory, PhD; senior clinical laboratory scientist Justin Manalac; Tho Pham, MD, clinical assistant professor of pathology; medical researcher Arjun Rustagi, MD, PhD; Angela Rogers, MD, assistant professor of medicine; Nigam Shah, PhD, professor of medicine; Catherine Blish, MD, PhD, associate professor of medicine; Jennifer Cochran, PhD, president and professor of bioengineering; Theodore Jardetzky, PhD, professor of structural biology; James Zehnder, MD, professor of pathology and medicine; Taia Wang, MD, PhD, assistant professor of medicine and microbiology and immunology; principal investigator Balasubramanian Narasimhan, PhD; professor of pathology Saurabh Gombar, MD, PhD; Robert Tibshirani, PhD, professor of biomedical data science and statistics; and Kari Nadeau, MD, PhD, professor of medicine and pediatrics.

The study was supported by the National Institutes of Health (grants RO1AI127877, RO1AI130398, 1U54CA260517, T32AI007502-23, U19AI111825 and UL1TR003142), the Crown Family Foundation, the Stanford Maternal and Child Health Research Institute, the Swiss National Science Foundation and a Coulter COVID-19 Rapid Response Award.

Boyd, Röltgen, Kim and Powell have filed provisional patent applications related to serological testing for anti-SARS-CoV-2 antibodies.