SARS-CoV-2 evolution in an immunocompromised host reveals shared neutralization escape mechanisms.

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Individuals develop similar antibody responses to SARS-CoV-2.
• The viral spike (S) protein's receptor-binding domain (RBD) is a key target for neutralizing antibodies.
• Understanding viral evolution against common immune responses is crucial for developing effective countermeasures.

Purpose of the Study:

• To investigate how SARS-CoV-2 RBD evolves under immune pressure from common antibody responses.
• To identify specific mutations conferring resistance to neutralizing antibodies.
• To assess the implications of these mutations for the efficacy of S-directed countermeasures.

Main Methods:

• Studied viral evolution in a persistently infected immunocompromised individual.
• Utilized antibody Fab/RBD structural analysis to predict resistance mutations.
• Employed pseudotype assays to confirm antibody resistance conferred by identified mutations.
• Tested resistance against antibodies from convalescent donors and clinically used monoclonal antibodies.

Main Results:

• Identified late-stage S protein RBD mutations that confer resistance to a common class of SARS-CoV-2 neutralizing antibodies.
• Demonstrated resistance against polyclonal serum from multiple healthy convalescent donors and against clinically relevant monoclonal antibodies.
• Found that affinity maturation is not essential for wild-type virus neutralization but is critical for neutralization breadth.

Conclusions:

• Mutations identified in evolved SARS-CoV-2 variants can confer resistance to broadly neutralizing antibodies.
• These findings predict the emergence of antibody-resistant variants and have significant implications for the long-term efficacy of vaccines and therapeutics targeting the SARS-CoV-2 spike protein.
• The study highlights the dynamic interplay between viral evolution and the host immune response.