New antibody approach blocks several coronaviruses and resists mutations

An international team of scientists has developed a new approach that uses antibodies that work together to prevent infection from several coronaviruses, including SARS-CoV-2. This approach is more resilient to viral evolution and offers valuable insight for developing the next generation of coronavirus vaccines and therapeutics.

LA JOLLA, CA—Coronaviruses, like the COVID-19-causing SARS-CoV-2, have spike proteins on their surfaces that shapeshift over time in a process called antigenic drift. This continual drifting means the mutating virus may eventually escape the protective immune response fighting against its earlier versions. The potential for escape mutants raises concerns about the long-term efficacy of the current vaccine and antibody strategies used to prevent and treat coronavirus infection.

To address these concerns, an international team of scientists have characterized a new “cross-neutralizing antibody” approach resilient to the spike protein’s tendency to shapeshift in a study published in Cell Host & Microbe on May 12, 2021.

Coronaviruses have caused several pandemics and epidemics in the past twenty years, including the COVID-19 pandemic. Vaccines and therapeutic antibodies have been invaluable in preventing and treating COVID-19. Still, they may not remain as effective as the virus changes or as different coronaviruses transmit from animals to humans.

“These viruses are constantly evolving to outmaneuver our immune systems,” says senior author Ian Wilson, PhD, of Scripps Research. “We must develop new approaches that are resilient to this continual shift. Cross-neutralizing antibodies offer a potential solution; they target the sites on the virus’s spike protein that change the least and can neutralize multiple coronaviruses within the same family.”*

The spike proteins, which resemble the tines of a crown (or corona in Latin), give coronaviruses their name and are shared among the whole family. They are also the key that allows the virus to enter and infect human cells, which makes them the primary target when blocking infection. Wilson and his colleagues have identified specific antibody binding sites within the spike protein that are more robust and less malleable to changes. These sites are also shared across multiple coronavirus subtypes that could cause human disease.

The new study details the structure and viral binding interactions of CV38-142, a cross-neutralizing antibody. It can block various coronaviruses, including those that infect humans, bats, and pangolins, by binding to one of these less malleable sites on the receptor binding domain of the spike protein. Although there are a few differences in the specific interactions between CV38-142 and its binding site on different coronaviruses like SARS-CoV and SARS-CoV-2 spike proteins, the binding looks essentially the same thanks to water molecules that come in to assist these interactions. This mechanism likely helps the CV38-142 antibody to remain more robust and resist antigenic drift. They also noted that the bivalent (two-pronged) CV32-142 antibody was more effective at neutralizing the coronaviruses than its fragmented version, likely because it binds multiple neighboring spike proteins.

Notably, the researchers found that CV32-142 could be combined with other neutralizing antibodies that bind to different conserved sites on the spike protein, such as COVA1-16. This combined antibody approach greatly enhances neutralization and was effective against the concerning new variants, B.1.1.7 and B.1.351, that escaped neutralization by many potent monoclonal antibodies, including some in Emergency Use Authorization.

“The receptor binding site can be quite different on each coronavirus and their evolving variants,” said Wilson. “Combining cross-neutralizing antibodies is a promising option to provide better protection against this range of potential disease-causing viruses in the long term.”

By characterizing the new antibody’s detailed structure and interactions with the viral proteins, the scientists provide valuable understanding that can be used to design the next generation of coronavirus vaccines and therapeutics.

Authors of the study, “A combination of cross-neutralizing antibodies synergizes to prevent SARS-CoV-2 and SARS-CoV pseudovirus infection”, are Hejun Liu, Deli Huang, Sandhya Bangaru, Fangzhu Zhao, Chang-Chun D. Lee, Linghang Peng, Shawn Barman, Xueyong Zhu, David Nemazee, Dennis R. Burton, Marit J. van Gils, Rogier W. Sanders, Hans-Christian Kornau, S. Momsen Reincke, Harald Prüss, Jakob Kreye, Nicholas C. Wu, Andrew B. Ward, and Ian A. Wilson.

This work was supported by funding from the Bill and Melinda Gates Foundation (OPP1170236 and INV-004923), The National Institute of Health (R00 AI139445 and R01 AI132317), and the German Research Foundation 

*This sample press release was written by me, independent of any institution. Quotes were made up by me for the purpose of creating this portfolio piece.