Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations

Frauke Muecksch, Yiska Weisblum, Christopher O. Barnes, Fabian Schmidt, Dennis Schaefer-Babajew, Zijun Wang, Julio C. Julio, Andrew I. Flyak, Andrew T. DeLaitsch, Kathryn E. Huey-Tubman, Shurong Hou, Celia A. Schiffer, Christian Gaebler, Justin Da Silva, Daniel Poston, Shlomo Finkin, Alice Cho, Melissa Cipolla, Thiago Y. Oliveira, Katrina G. MillardVictor Ramos, Anna Gazumyan, Magdalena Rutkowska, Marina Caskey, Michel C. Nussenzweig, Pamela J. Bjorkman, Theodora Hatziioannou, Paul D. Bieniasz

Research output: Contribution to journalArticlepeer-review

162 Scopus citations

Abstract

Antibodies elicited by infection accumulate somatic mutations in germinal centers that can increase affinity for cognate antigens. We analyzed 6 independent groups of clonally related severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) Spike receptor-binding domain (RBD)-specific antibodies from 5 individuals shortly after infection and later in convalescence to determine the impact of maturation over months. In addition to increased affinity and neutralization potency, antibody evolution changed the mutational pathways for the acquisition of viral resistance and restricted neutralization escape options. For some antibodies, maturation imposed a requirement for multiple substitutions to enable escape. For certain antibodies, affinity maturation enabled the neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. Antibody-antigen structures revealed that these properties resulted from substitutions that allowed additional variability at the interface with the RBD. These findings suggest that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.
Original languageEnglish (US)
Pages (from-to)1853-1868.e7
JournalImmunity
Volume54
Issue number8
DOIs
StatePublished - Aug 10 2021
Externally publishedYes

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology
  • Immunology and Allergy

Fingerprint

Dive into the research topics of 'Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations'. Together they form a unique fingerprint.

Cite this