Scientists discover key element of strong antibody response to COVID-19

A team led by scientists at Scripps Research discovered a common molecular characteristic found in many of the human antibodies that neutralize SARS-CoV-2, the coronavirus that causes COVID-19.

The scientists, whose study appears July 13 in ScienceThey reviewed data on nearly 300 anti-SARS-CoV-2 antibodies that their labs and others have found in convalescent COVID-19 patients in recent months. They noted that a subset of these antibodies is particularly powerful in neutralizing the virus, and these potent antibodies are encoded, in part, by the same antibody gene, IGHV3-53.

The scientists used a powerful tool known as X-ray crystallography to obtain images of two of these antibodies attached to their target site in SARS-CoV-2. The details of the atomic structure resulting from this interaction should be useful to vaccine designers, as well as to scientists hoping to develop site-directed antiviral drugs in SARS-CoV-2.

Previous research suggests that antibodies encoded by IGHV3-53 are generally present, at least in small amounts, in the blood of healthy people. Therefore, the results offer hope that the use of a vaccine to increase the levels of these ever-present antibodies will adequately protect against the virus.

“This type of antibody has been frequently isolated in studies of patients with COVID-19, and we can now understand the structural basis for its interaction with SARS-CoV-2,” says study lead author Ian Wilson, DPhil, professor Hansen’s structural. Biology and President of the Scripps Research Integrative Computational and Structural Biology Department.

“This study provides important inspiration for the effective design of the COVID-19 vaccine,” says co-author Dennis Burton, Ph.D., professor and co-chair of the Department of Immunology and Microbiology at Scripps Research.

The research was a collaboration that primarily involved the Wilson and Burton laboratories, and the IAVI Center for Neutralizing Antibodies based on IAVI, a leading nonprofit vaccine research organization.

SARS-CoV-2 has so far infected more than 12 million people worldwide and killed more than 500,000, in addition to causing widespread socio-economic damage and disruption. Developing an effective vaccine to stop the pandemic is currently the world’s top public health priority.

Although several potential vaccines are already in clinical trials, scientists still do not have a complete understanding of the molecular characteristics that would define a protective antibody response. In the new study, scientists took a big step toward that goal.

The team began by analyzing 294 different SARS-CoV-2 neutralizing antibodies isolated from the blood of COVID-19 patients in recent months. Antibodies are Y-shaped proteins produced in immune cells called B cells. Each B cell produces a specific type of antibody, or clone, that is encoded by a unique combination of antibody genes in the cell. The scientists discovered that an antibody gene called IGHV3-53 was the most common of the genes for the 294 antibodies, which encoded about 10 percent of them.

The scientists also noted that the antibodies encoded by IGHV3-53 in their study contain an unusually short variant of the CDR H3 loop, typically a key target-binding element. However, these antibodies are very powerful against SARS-CoV-2 compared to other antibodies not encoded by IGHV3-53.

A powerful response from the start

The IGHV3-53 antibodies had another property that suggested that increasing their numbers would be a good and achievable target for a SARS-CoV-2 vaccine: they appeared to have mutated only minimally from the original versions that would be circulating, initially in small amounts. , in the blood of healthy people.

Normally, when activated by an encounter with a virus to which they conform, B cells will begin to proliferate and also mutate parts of their antibody genes, to generate new B cells whose antibodies are even better suited to the viral target. The more mutations it takes for this “affinity maturation” process to generate virus neutralizing antibodies, the more difficult it can be to induce this same process with a vaccine.

Fortunately, the IGHV3-53 antibodies found in the study appeared to have had little or no affinity maturation, and yet were already very potent in neutralizing the virus, suggesting that a vaccine may induce a protective response from these potent neutralizers with relative ease. .

“Coronaviruses have been around for hundreds or thousands of years, and one can imagine that our immune system has evolved in such a way that we carry antibodies like these that can give a powerful response from the start, so to speak,” says Wilson.

Map for vaccine manufacturers, indicator for clinical trials

Wilson’s team used high-resolution x-ray crystallography to image two different IGHV3-53 antibodies attached to their target in SARS-CoV-2. This target, known as the receptor binding site, is a crucial structure in the viral “spike” protein that normally connects to a receptor in human cells to begin the process of cellular infection. Many of the antibodies that neutralize SARS-CoV-2 appear to do so by blocking this virus receptor connection.

“We were able to reveal unique structural features of these IGHV3-53 encoded antibodies, features that facilitate their high binding affinity and specificity for the SARS-CoV-2 receptor binding site,” says first co-author Meng Yuan, Ph. D ., associate postdoctoral researcher at the Wilson Laboratory.

Detailed structural data at the atomic scale should be of interest to vaccine designers and drug developers. Furthermore, the researchers say, identifying antibodies encoded by IGHV3-53 as key elements of the immune response to COVID-19 suggests that levels of these antibodies could be useful as an indirect marker of success in ongoing and future vaccine trials. .