CALIFORNIA: Fast-spreading variants of the coronavirus that causes Covid-19, SARS-CoV-2, contain mutations that allow the virus to escape some of the immune response created naturally or by vaccination. A new study by a team of researchers has revealed important details about how these escape mutations work.
The scientists at Scripps Research, along with collaborators in Germany and the Netherlands, whose research appears in Science, used structural biology techniques to map with high resolution how important classes of neutralizing antibodies bind to the original pandemic strain of SARS-CoV-2 – and how the process is disrupted by mutations found in new variants first discovered in Brazil, the United Kingdom, South Africa and India.
The study also highlights that several of these mutations are clustered in one site, known as the "receptor binding site", on the peak protein of the virus. Other sites on the receptor binding domain are not affected.
"One implication of this study is that when designing next-generation vaccines and antibody therapies, we should consider paying more attention to other vulnerable sites on the virus that are usually unaffected by the mutations found in variants of concern," says co. lead author Meng Yuan, PhD.
Yuan is a postdoctoral fellow in senior author Ian's lab Wilson, DPhil, Hansen professor of structural biology and chair of the integrative structural and computer biology division at Scripps Research.
How & # 39; worrisome variants & # 39; escape the immune response
SARS-CoV-2 "variants of concern" include UK B.1.1.7 variants, South Africa B.1.351 variants, Brazil P.1 variants and India B.1.617 variants . Some of these variants seem to be more contagious than the original Wuhan tribe. Recent studies have shown that antibody responses generated by natural infection against the parent strain or via vaccination are less effective in neutralizing these variant strains.
Because of the variants' potential to spread and cause disease – perhaps in some cases despite vaccination – scientists are urging to discover how the variants manage to escape much of the body's previous immune response, including the antibody response.
In the study, the researchers mainly focused on three mutations in the SARS-CoV-2 spike protein: K417N, E484K and N501Y. These mutations are found alone or in combination in most of the major SARS-CoV-2 variants. All mutations are found in the SARS-CoV-2 receptor binding site, where the virus attaches to host cells.
The researchers tested representative antibodies from the main classes that target the general area in and around the receptor binding site. They found that many of these antibodies lose their ability to effectively bind and neutralize the virus when the mutations are present.
Using structural imaging techniques, the team then mapped the relevant part of the virus on an atomic scale to investigate how the mutations affect places where antibodies would otherwise bind and neutralize the virus.
"This work provides a structural explanation why antibodies elicited by Covid-19 vaccines or natural infection by the original pandemic strain are often ineffective against these worrisome variants," says Wilson.
Approaching vulnerable points
The findings suggest that while antibody responses to the SARS-CoV-2 receptor binding site can be very potent in neutralizing the native Wuhan strain, certain variants can escape – ultimately necessitating updated vaccines.
At the same time, the study underscores the fact that the three major viral mutations, of which SARS-CoV-2 is inherently susceptible to development, do not alter other vulnerable sites on the virus outside of the receptor binding site. Specifically, the researchers showed that virus neutralizing antibodies targeting two other regions outside the receptor binding site were largely unaffected by these three mutations.
This suggests that future vaccines and antibody-based treatments could provide broader protection against SARS-CoV-2 and its variants by raising or using antibodies against parts of the virus that lie outside the receptor binding site. The researchers note that broad protection against variants may be needed if, as seems likely, the virus becomes endemic in the human population.
The Wilson laboratory and collaborators in this study continue to study the responses of human antibodies to variants of concern and hope to find strategies for broad protection against not only SARS-CoV-2 and its variants, but also against SARS-CoV -1 and other related emerging coronaviruses.