As the COVID-19 pandemic continues, so too does the evolution of SARS-CoV-2. The emerging variants have varied properties, some of which may be able to evade our immune system better than their predecessors. This diminishes the efficacy of vaccines and antiviral monoclonal antibodies.

Some researchers are searching for universal viral targets—those that would remain unchanged in all variants—to target those areas of the virus that are resilient to viral evolution.

Shown in red, blue, and green are three of the coldspots on the virus spike that are targeted by the newly discovered antibodies. [IRB, Bellinzona, CH]

Now, a group of researchers used coldspot-guided antibody discovery (a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change) to identify antibodies directed toward highly conserved viral epitopes that recognize all SARS-CoV-2 variants and other coronaviruses.

This work is published in Science Immunology, in the article, “Human neutralizing antibodies to cold linear epitopes and subdomain 1 of the SARS-CoV-2 spike glycoprotein.”

Screening through over 10 million coronavirus sequences, researchers discovered areas of the spike protein of the virus that were remarkably conserved.

Filippo Bianchini and Virginia Crivelli, PhD students at IRB (Bellinzona, Switzerland) in the lab of professor Davide Robbiani. [IRB, Bellinzona, CH]

“We call these ‘coldspots’,” said Virginia Crivelli, a PhD student in the lab of Davide Robbiani, MD, PhD, at the Institute for Research in Biomedicine (IRB), Università della Svizzera italiana (USI), in Bellinzona, Switzerland. “Most of the virus is rapidly changing, but we discovered 15 regions that do not.”

By analyzing samples from COVID-19 convalescent individuals, they found that some had antibodies specific for the coldspots.

“These antibodies are very rare,” said Filippo Bianchini, a PhD student in the Robbiani lab at the IRB. “But thanks to a new method, we were able to find them.”

The antibodies blocked virus infection in laboratory experiments, even to the latest variants of concern, and protected from disease in preclinical models.

Specifically, the authors noted, “Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four genera, including the nine human coronaviruses, through recognition of a conserved motif that includes the S2´ site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization and, like fp.006 and hr2.016, protects mice expressing human ACE2 against infection when present as a bispecific antibody.”

Will the new antibodies be effective against the next coronavirus(es)? “It is likely that new coronaviruses that infect humans will emerge,” said Robbiani, head of the laboratory of immunology and infectious disease and IRB director. “Our findings indicate that it may be already possible to develop countermeasures that are broadly effective against present and also future coronaviruses.”

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