A new approach to mapping viral mutations that "escape" leading clinical antibodies has revealed mutations in the SARS-CoV-2 virus that allow it to evade treatments, including a single amino-acid mutation that fully escapes Regeneron's antibody cocktail. These maps, say the authors, demonstrate that prior characterization of escape mutations was incomplete. They will also help to enable immediate interpretation of the effects of the mutations cataloged by viral genomic surveillance, say the authors.
Several antibodies are in use or under development as therapies to treat COVID-19. As new SARS-CoV-2 variants emerge, it is important to predict whether they will remain susceptible to antibody treatment. Most leading anti-SARS-CoV-2 antibodies target the viral receptor-binding domain (RBD), which facilitates binding to the ACE2 receptor on host cells.
Tyler Starr and colleagues recently developed a scanning method to map how mutations to the RBD affect its recognition by antibodies. Here, Starr and colleagues leveraged this approach to show how mutations to SARS-CoV-2's RBD affect binding by the antibodies in the REGN-COV2 cocktail and by Eli Lilly's antibody LY-CoV016. The authors focused on mutations to the SARS-CoV-2 RBD that do not strongly disrupt binding to the host receptor (ACE-2), to map how these mutations impact binding to the three anti-SARS-CoV-2 antibodies. The maps identified mutations that escape antibody binding, including, surprisingly, a single mutation that escapes both antibodies in the Regeneron antibody cocktail.
To determine if the escape maps could inform analysis of viral evolution in infected humans, the authors examined deep sequencing data from a persistently infected patient who was treated with REGN-COV2 at day 145 after diagnosis with COVID-19. The analysis identified resistance mutations that arose in this patient. Three of the four escape mutations identified by Starr and team had not been identified in Regeneron's viral cell-culture selections, say the authors, illustrating an advantage of complete maps as used here.
The complete maps also permitted the researchers to assess what escape mutations are already present among circulating SARS-CoV-2. After examining all human-derived SARS-CoV-2 sequences available as of 11 January 2021, they report a substantial number of RBD mutations that escaped one or more of the antibodies are in circulation.
Starr, T.N., et al. (2021) Prospective mapping of viral mutations that escape antibodies used to treat COVID-19. Science. doi.org/10.1126/science.abf9302.