Antibodies to COVID-19 prefer to target a different part of the virus in milder cases of COVID-19 than in severe cases and have disappeared significantly within months of infection, according to a new study by Stanford Medicine researchers.
The findings reveal new links between the course of the disease and the patient’s immune response. They also raise concerns about whether people may become re-infected, whether antibody tests to detect previous infection may underestimate the breadth of the pandemic, and whether vaccination may need to be repeated at regular intervals to maintain a protective immune response.
“This is one of the most comprehensive studies to date on the immune response of antibodies to SARS-CoV-2 in humans across the full spectrum of disease severity, from asymptomatic to fatal,” said Dr. Sc. Scott Boyd, associate professor of pathology. “We evaluated multiple time points and sample types, and we also analyzed viral RNA levels in the patient’s nasopharyngeal swabs and blood samples. This is one of the first major examinations of this disease.”
The study found that people with severe COVID-19 have a low proportion of antibodies that target the spikelet protein that the virus uses to enter human cells compared to the number of antibodies that target proteins in the virus’s inner shell.
Boyd is the senior author of a study published Dec. 7 Scientific immunology. Other older authors are Benjamin Pinsky, Ph.D. Med., Associate Professor of Pathology, etc. Peter Kim, Ph.D. Virginia and DK Ludwig, professor of biochemistry. The leading authors are scientific researcher Dr. Katharina Röltgen; postdoctoral fellows Dr. Abigail Powell and Dr. Oliver Wirz; and clinical instructor dr. Bryan Stevens.
The virus binds to the ACE2 receptor
The researchers studied 254 people with asymptomatic, mild or severe COVID-19 who were identified by either routine testing or screening for occupational health at Stanford Health Care or who came to the 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 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 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 the inner shell, which contains its genetic material. Soon, the virus co-opts the protein-producing machinery in the cell to expel more virus 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 the virus from spreading. Current vaccine candidates use portions of the protein class to stimulate an immune response.
Boyd and his colleagues analyzed levels of three types of antibodies – IgG, IgM and IgA – and proportions that targeted the viral spike protein or inner shell of the virus as the disease progressed and patients recovered or became increasingly ill. They also measured levels of viral genetic material in nasopharyngeal and blood samples from patients. Finally, they evaluated the efficacy of the antibody in preventing protein binding to ACE2 in a laboratory vessel.
“Although previous studies have evaluated the overall antibody response to infection, we have compared viral proteins targeted by these antibodies,” Boyd said. “We found that disease severity correlated with the ratio of antibodies recognizing spike protein domains compared to other unprotected viral targets. Those people with mild disease tended to have a higher proportion of spike antibodies and those who died from their disease had more antibodies that have recognized other parts of the virus. “
Significant variability of the immune response
The researchers warn, however, that although the study has identified trends among a group of patients, there is still significant variability in the immune response carried out by individual patients, especially those with severe disease.
“Antibody responses are unlikely to be the only determinant of someone’s outcome,” Boyd said. “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 a lot of other things happen. There are other branches The immune system is involved. It is important to note that our results identify correlations but do not prove causality. “
As in other studies, the researchers found that people with asymptomatic and mild diseases had lower levels of antibodies overall than those with serious illness. After recovery, IgM and IgA levels decreased continuously to low or undetected 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 quite in line with what has been seen with other coronaviruses that regularly circulate in our communities to cause colds,” Boyd said. “It is not uncommon for someone to become re-infected 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 the response caused by a natural infection. It is quite possible that it could be better. But there are a lot of questions that still need to be answered. “
Boyd is co-chair of the Serological Sciences Network of the National Cancer Institute, one of the largest coordinated research efforts in the country in studying the immune response to COVID-19. He is the principal investigator of the Center of Excellence at SeroNet at Stanford, which deals with 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 given priority?” Boyd said. “How can we adjust seroprevalence studies in vaccinated populations? How will immunity from vaccination differ from immunity caused by a natural infection? And how long can a vaccine be protective? These are all very interesting, important questions.”
Other co-authors of the study from Stanford are visiting pathology instructor dr. Catherine Hogan; postdoctoral students Dr. Javaria Najeeb and Dr. Ana Otrelo-Cardoso; nurse Hannah Wang, MD; scientific researcher, dr. Malaya Sahoo; ChunHong Huang, researcher-researcher; research scientist Fumiko Yamamoto; laboratory director Dr. Monali Manohar; senior scientist from clinical laboratories Justin Manalac; Tho Pham, Ph.D. Med., Clinical Assistant Professor of Pathology; medical colleague, dr. med. Arjun Rustagi; Angela Rogers, MD, Assistant Professor of Medicine; Dr. Nigam Shah, Professor of Medicine; Catherine Blish, Ph.D. Med., Associate Professor of Medicine; Dr. Jennifer Cochran, Chair and Professor of Bioengineering; Dr. Theodore Jardetzky, Professor of Structural Biology; James Zehnder, Ph.D. Med., Professor of Pathology and Medicine; Dr. Taia Wang, Assistant Professor of Medicine and Microbiology and Immunology; senior researcher dr. Balasubramanian Narasimhan; pathology instructor, dr. Saurabh Gombar; Dr. Robert Tibshirani, Professor of Biomedical Sciences Data and Statistics; and Kari Nadeau, Ph.D. med., 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 Institute for Maternal and Child Health Research, Switzerland and the CID 19 National Research Council. .
Boyd, Röltgen, Kim, and Powell have filed interim patent applications regarding serological tests for SARS-CoV-2 antibodies.