Structural details of how SARS-CoV-2 variants escape the immune response


Rapidly spreading variants of the COVID-19-causing coronavirus SARS-CoV-2 carry mutations that allow the virus to escape part of the immune response generated naturally or through vaccination. A new study by scientists from Scripps Research together with colleagues in Germany and the Netherlands has revealed important details about how these escape mutations work.

The scientists whose study appears in scienceused 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 that were first introduced in Brazil, UK, have been proven to be South Africa and India.

Research also highlights that several of these mutations are clustered at a site known as the “receptor binding site” on the virus’ spike protein. Other sites in the receptor binding domain are not affected.

“One implication of this study is that as we develop next-generation vaccines and antibody therapies, we should consider focusing on other vulnerable parts of the virus that tend not to be affected by the mutations found in worrying variants “says co – lead author Meng Yuan, PhD.

Yuan is a postdoctoral fellow in the lab of lead author Ian Wilson, DPhil, Hansen Professor of Structural Biology and Chair of the Department of Integrative Structural and Computational Biology at Scripps Research.

How “Concerning Variants” Escape the Immune Response

SARS-CoV-2 “worrying variants” include the British B.1.1.7 variants, the South African B.1.351 variants, the Brazilian P.1 variants and the Indian B.1.617 variants. Some of these variants appear to be more contagious than the original Wuhan tribe. Recent studies have shown that antibody responses generated by natural infection of the original strain or by vaccination are less effective in neutralizing these variant strains.

Given the potential of the variants to spread and cause disease – possibly in some cases despite vaccination – scientists feel it is imperative to find out how the variants manage to escape much of the previous immune response in the body, including the antibody response .

In the study, researchers mainly focused on three mutations in the SARS-CoV-2 spike protein: K417N, E484K, and N501Y. Alone or in combination, these mutations are found in most of the important SARS-CoV-2 variants. All mutations are located at 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 at atomic resolution to study how the mutations affect sites where antibodies would otherwise bind and neutralize the virus.

“This work provides a structural explanation for why antibodies generated by COVID-19 vaccines or natural infection by the original pandemic strain are often ineffective against these worrying variants,” says Wilson.

Focus on weak spots

The results suggest that while antibody responses to the SARS-CoV-2 receptor binding site can be very effective in neutralizing the original Wuhan strain, certain variants can escape – which may require updated vaccines.

At the same time, the study underscores the fact that the three most important viral mutations, to which SARS-CoV-2 appears to be naturally susceptible to development, do not change other vulnerable parts of the virus outside the receptor binding site. Specifically, the researchers showed that virus-neutralizing antibodies targeting two other areas outside the receptor binding site were largely unaffected by these three mutations.

This suggests that future vaccines and antibody-based treatments could offer broader protection against SARS-CoV-2 and its variants by raising or using antibodies against parts of the virus that are outside the receptor binding site. The researchers note that broader protection against variants may be needed if the virus is likely to become endemic in the human population.

The Wilson laboratory and the staff of this study continue to investigate the responses of human antibodies to worrying variants and hope to find strategies for comprehensive protection not only against SARS-CoV-2 and its variants, but also against SARS-CoV-1 and other related, Identify newly emerging coronavirus variants.

Republished with permission of the Scripps Research Institute.


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