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 a few 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 a patient’s immune response. It also raises concerns about whether people can be re-infected, or antibody tests to detect the infection, underestimate the extent of the pandemic and whether vaccinations are regularly needed to maintain a protective immune response.
‘This is one of the most comprehensive studies to date of the antibody’s immune response against EARS-CoV-2 in people across the spectrum of disease severity, from asymptomatic to fatal, ”says Scott Boyd, MD, associate professor of pathology. ‘We assessed various time points and types of samples and also analyzed levels of viral RNA in nasopharyngeal swabs and blood samples in patients. This is one of the first big photos of this disease. ‘
The study found that people with severe COVID-19 have low ratios of antibodies that target the protein of the virus used to invade human cells, compared to the number of antibodies that target proteins in the inner shell of the virus is.
Boyd is a senior author of the study, published on December 7, 2020 in Scientific immunology. Other senior authors are Benjamin Pinsky, MD, PhD, Associate Professor of Pathology, and Peter Kim, PhD, the Virginia and DK Ludwig Professor of Biochemistry. The lead authors are research scientist Katharina Röltgen, PhD; postdoctoral fellow Abigail Powell, PhD, and Oliver Wirz, PhD; and clinical instructor Bryan Stevens, managing director.
Virus binds to ACE2 receptor
The researchers studied 254 people with asymptomatic, mild, or severe COVID-19 who were identified by routine testing or health examination at Stanford Health Care, or who came to a Stanford Health Care clinic with symptoms of COVID-19. Of the people with symptoms, 25 were treated as outpatients, 42 were admitted outside the intensive care unit and 37 in the intensive care unit. Twenty-five people in the study died of the disease.
SARS-CoV-2 binds to human cells via a structure on the surface called the vein protein. This protein binds to a receptor on human cells called ACE2. With binding, the virus can enter the cell and infect. Once inside, the virus sheds its outer layer to contain an inner shell that contains the genetic material. The virus will soon work with the cell’s protein-making machinery to spread more viral particles, which are then released to infect other cells.
Antibodies that recognize and bind the vein protein block its ability to bind to ACE2, which prevents the virus from infecting the cells, while antibodies that recognize other viral components are unlikely to prevent viral spread. Current vaccine candidates use portions of the ear protein to stimulate an immune response.
Boyd and his colleagues analyzed the levels of three types of antibodies – IgG, IgM and IgA – and the ratios that target the viral peak protein or the inner shell of the virus as the disease progresses and patients recover or become ill. They also measured the levels of viral genetic material in nasopharyngeal samples and patients’ blood. Finally, they evaluated the effectiveness of the antibodies to prevent the ear protein from binding to ACE2 in a laboratory dish.
“Although previous studies assessed the overall antibody response to infection, we compared the viral proteins targeted by these antibodies,” Boyd said. ‘We found that the severity of the disease correlated with the ratio of antibodies that recognize vein protein domains compared to other non-protective viral targets. Those with a mild disease tended to have a higher percentage of antispike antibodies, and those who died from their disease had more antibodies that recognized other parts of the virus. ‘
Significant fluctuation in immune response
However, the researchers warn that although the trends among a group of patients have been identified, there is still significant variability in the immune response that individual patients, especially those with serious illnesses, have.
“Antibody reactions are probably not the only determining factor in someone’s outcome,” Boyd said. “Among people with serious illnesses, some die and others recover. Some of these patients have a strong 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 are also involved. It is important to note that our results identify correlations, but that they are not cause. ‘
As in other studies, the researchers found that people with asymptomatic and mild illnesses had lower antibodies than those with serious illnesses. After recovery, the levels of IgM and IgA in most patients gradually decreased to low or undetectable levels for about one to four months after the onset of the symptom or the estimated date of infection, and the IgG levels dropped significantly.
“This is consistent with what has been seen with other coronaviruses that are spreading regularly in our communities to cause colds,” Boyd said. ‘It’s not uncommon for someone to become infected again within a year or sometimes earlier. It remains to be seen whether the immune response to SARS-CoV-2 vaccination is stronger or lasts longer than that caused by natural infection. It is quite possible that it could be better. But there are still many questions to be answered. ”
Boyd is a co-chair of the SeroNet Serological Sciences Network of the National Cancer Institute, one of the country’s largest coordinated research efforts to study the immune response to COVID-19. He is the principal investigator of the Center of Excellence at SeroNet in Stanford, which addresses critical questions about the mechanisms and duration of immunity to SARS-CoV-2.
‘For example, if someone is already infected, should they get the vaccine? If so, how should they be prioritized? Boyd said. ‘How can we adapt seroprevalence studies in vaccinated populations? How will vaccination immunity differ from the natural infection? And how long can a vaccine be protective? These are all very interesting, important questions. ”
Reference: “Defining the Characteristics and Duration of Antibody Responses to SARS-CoV-2 Infection Associated with Severity and Outcome of the Disease” by Katharina Röltgen, Abigail E. Powell, Oliver F. Wirz, Bryan A. Stevens, Catherine A. Hogan, Javaria Najeeb, Molly Hunter, Hannah Wang, Malaya K. Sahoo, ChunHong Huang, Fumiko Yamamoto, Monali Manohar, Justin Manalac, Ana R. Otrelo-Cardoso, Tho D. Pham, Arjun Rustagi, Angela J. Rogers, Nigam H. Shah, Catherine A. Blish, Jennifer R. Cochran, Theodore S. Jardetzky, James L. Zehnder, Taia T. Wang, Balasubramanian Narasimhan, Saurabh Gombar, Robert Tibshirani, Kari C. Nadeau, Peter S. Kim, Benjamin A. Pinsky and Scott D. Boyd, December 7, 2020, Scientific immunology.
DOI: 10.1126 / sciimmunol.abe0240
Other Stanford co-authors of the study visit pathology instructor Catherine Hogan, MD; postdoctoral fellow Javaria Najeeb, PhD, and Ana Otrelo-Cardoso, PhD; medical resident Hannah Wang, managing director; research scientist Malaya Sahoo, PhD; research professor ChunHong Huang, PhD; research scientist Fumiko Yamamoto; Laboratory Director Monali Manohar, PhD; senior clinical laboratory scientist Justin Manalac; Tho Pham, MD, Clinical Assistant Professor of Pathology; medical assistant 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, chair and professor of bio-engineering; 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; senior research scientist Balasubramanian Narasimhan, PhD; pathology instructor 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 Award for Quick Response.
Boyd, Röltgen, Kim, and Powell filed preliminary patent applications relating to serological tests for SARS-CoV-2 antibodies.