Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations
Schiffer, Celia A.
Nussenzweig, Michel C.
Bjorkman, Pamela J.
Bieniasz, Paul D.
UMass Chan AffiliationsSchiffer Lab
Department of Biochemistry and Molecular Pharmacology
Amino Acids, Peptides, and Proteins
Immunology of Infectious Disease
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AbstractAntibodies 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.
Muecksch F, Weisblum Y, Barnes CO, Schmidt F, Schaefer-Babajew D, Wang Z, C Lorenzi JC, Flyak AI, DeLaitsch AT, Huey-Tubman KE, Hou S, Schiffer CA, Gaebler C, Da Silva J, Poston D, Finkin S, Cho A, Cipolla M, Oliveira TY, Millard KG, Ramos V, Gazumyan A, Rutkowska M, Caskey M, Nussenzweig MC, Bjorkman PJ, Hatziioannou T, Bieniasz PD. Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations. Immunity. 2021 Aug 10;54(8):1853-1868.e7. doi: 10.1016/j.immuni.2021.07.008. Epub 2021 Jul 30. PMID: 34331873; PMCID: PMC8323339. Link to article on publisher's site