A new study out this week from Houston Methodist explains clever ways the BA.1 and BA.2 omicron variants escape antibodies, contributing to the ability of these variants to spread rapidly and to be so successful in infecting people with the COVID-19 virus.

The findings of this study are described in a paper titled “Antibody escape and cryptic cross-domain stabilization in the SARS-CoV-2 Omicron spike protein,” appearing April 18 in the preprint journal bioRxiv. Jimmy D. Gollihar, PhD, with the Houston Methodist Department of Pathology and Genomic Medicine, and Kamyab Javanmardi, PhD candidate, and Ilya Finkelstein, PhD, with the Department of Molecular Biosciences at The University of Texas at Austin, are the corresponding authors on the study.

Being able to pinpoint some ways the BA.1 and BA.2 omicron variants are able to evade detection by antibodies, making them more contagious than anything before, could lead to new therapeutic targets and help update vaccine formulations, Gollihar said. Doing so also could make variants identifiable by the immune system so it can better fend off omicron infections.

The researchers found that these two dominant sublineages of omicron have unprecedented numbers of spike protein mutations, with BA.1 having 33 and BA.2 having 29. These mutations are what lead to their increased transmissibility and enhanced ability to evade the immune system. These results reveal previously unknown mechanisms by which the virus avoids being detected by the immune system.

“One of the surprising findings in this study was that many mutations with critical roles in immune escape in previous variants of SARS-CoV-2 do not play the same roles in immune escape in omicron, and, in some cases, the effects of these mutations are completely reversed,” said Gollihar, who is the head of antibody discovery and accelerated protein therapeutics in Houston Methodist’s Center for Infectious Diseases. “The virus also appears to be stabilizing itself to allow for more mutations to evade our immune systems.”

He said this study is the first to systematically dissect each of the omicron mutations across the entirety of the spike protein. Previous studies miss contextual and long-range interactions across the protein.

“We developed a comprehensive map showing various mechanisms of immune escape by omicron that allows us to identify which antibodies retain neutralization activity against the virus,” Gollihar said. “This and future work will enable clinicians to make informed decisions about the use of monoclonal antibody therapy and aid in the development of next-generation vaccines.”

Having this new information about key features of omicron’s spike protein mutations and how they synergize, Gollihar and his team say it’s possible that the continuing accumulation of mutations may set the stage for greatly altering the equilibrium and stability of the spike protein in a way that allows for new, more virulent strains to develop. Understanding this evolution is critical, they say, to better inform future therapeutic targets and vaccine formulations, as the SARS-CoV-2 virus will continue to evolve with new variants inevitably arising and spreading.

Looking forward, they add, the strategy used in this study also will be applicable to future zoonotic outbreaks and other microbial pathogens, providing a powerful platform for investigating evolutionary trajectories of infectious agents and engineering appropriate and adaptable vaccines.

“We will continue to monitor the virus for changes in the spike protein and add new antibodies to test as they are discovered. Continuing to do so will allow us to design better probes for antibody discovery in hopes of engineering new therapeutics by finding potent neutralizing antibodies across all variants,” Gollihar said. “We have also recently expanded the platform to other pathogens where we hope to stay ahead of other potential outbreaks.”

Gollihar, Javanmardi and Finkelstein’s collaborators on this study were Thomas H. Segall-Shapiro, Daniel R. Boutz, Randall J. Olsen and James M. Musser with the Houston Methodist Research Institute; Charlie D. Johnson, Ankur Annapareddy, Chia-Wei Chou and Andrew D. Ellington with UT Austin; and Scott Weaver, Xuping Xie, Hongjie Xia and Pei-Yong Shi with the University of Texas Medical Branch.

This project was supported by the Houston Methodist Academic Institute Infectious Diseases Fund and many generous Houston philanthropists, including Carole Walter Looke and Jim Looke with their gift to the Laboratory of Antibody Discovery and Accelerated Protein Therapeutics within the Houston Methodist Research Institute’s Center for Infectious Diseases.