Fast-spreading variants of the COVID-19-causing coronavirus, SARS-CoV-2,
carry mutations that enable the virus to escape some of the immune response
created naturally or by vaccination. A new study from scientists at Scripps
Research, along with collaborators in Germany and the Netherlands, has
revealed key details of how these escape mutations work.
The scientists, whose study appears in Science, used structural biology
techniques to map at 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 detected in
Brazil, the United Kingdom, South Africa and India.
The research also highlights that several of these mutations are clustered
in one site, known as the “receptor binding site,” on the spike protein of
the virus. Other sites on the receptor binding domain are unaffected.
“An implication of this study is that, in designing next-generation vaccines
and antibody therapies, we should consider increasing the focus on other
vulnerable sites on the virus that tend not to be affected by the mutations
found in variants of concern,” says co-lead author Meng Yuan, PhD.
Yuan is a postdoctoral research associate in the laboratory of senior author
Ian Wilson, DPhil, Hansen Professor of Structural Biology and Chair of the
Department of Integrative Structural and Computational Biology at Scripps
Research.
How ‘variants of concern’ escape immune response
SARS-CoV-2 “variants of concern” include the UK’s B.1.1.7 variants, South
Africa’s B.1.351 variants, Brazil’s P.1 variants and India’s B.1.617
variants. Some of these variants appear to be more infectious than the
original Wuhan strain. Recent studies have found that antibody responses
generated through natural infection to the original 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 consider it urgent to discover
how the variants manage to escape much of the prior immune response in the
body, including the antibody response.
In the study, the researchers focused mainly on three mutations in the
SARS-CoV-2 spike protein: K417N, E484K and N501Y. Alone or in combination,
these mutations are found in most major SARS-CoV-2 variants. All of the
mutations are found in the SARS-CoV-2 receptor binding site, which the where
the virus attaches to host cells.
The researchers tested representative antibodies from the major 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
portion of the virus at atomic-scale resolution to examine how the mutations
affect sites where antibodies otherwise would bind and neutralize the virus.
“This work provides a structural explanation for why antibodies elicited by
COVID-19 vaccines or natural infection by the original pandemic strain are
often ineffective against these variants of concern,” Wilson says.
Zeroing in on points of vulnerability
The findings suggest that while antibody responses to the SARS-CoV-2
receptor binding site can be very potent in neutralizing the original Wuhan
strain, certain variants are able to escape—perhaps eventually necessitating
updated vaccines.
At the same time, the study underlines the fact that the three key viral
mutations, which SARS-CoV-2 seems inherently prone to develop, do not alter
other vulnerable sites on the virus outside the receptor binding site. The
researchers specifically 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
provide broader protection against SARS-CoV-2 and its variants by eliciting
or utilizing antibodies against parts of the virus that lie outside the
receptor binding site. The researchers note that broad protection against
variants may be necessary if, as seems likely, the virus becomes endemic in
the human population.
Reference:
Yuan M, Huang D, Lee C-CD, et al. Structural and functional ramifications of
antigenic drift in recent SARS-CoV-2 variants. Science. 2021. doi:
10.1126/science.abh1139