Abstract
Understanding the evolution of antibody immunity following heterologous SAR-CoV-2 breakthrough infection will inform the development of next-generation vaccines. Here, we tracked SARS-CoV-2 receptor binding domain (RBD)-specific antibody responses up to six months following Omicron BA.1 breakthrough infection in mRNA-vaccinated individuals. Cross-reactive serum neutralizing antibody and memory B cell (MBC) responses declined by two- to four-fold through the study period. Breakthrough infection elicited minimal de novo Omicron-specific B cell responses but drove affinity maturation of pre-existing cross-reactive MBCs toward BA.1. Public clones dominated the neutralizing antibody response at both early and late time points, and their escape mutation profiles predicted newly emergent Omicron sublineages. The results demonstrate that heterologous SARS-CoV-2 variant exposure drives the evolution of B cell memory and suggest that convergent neutralizing antibody responses continue to shape viral evolution.
Competing Interest Statement
C.I.K. is a former employee and holds shares in Adimab. LLC. P.K., H.L.D., E.R.C., and J.C.G. are current employees and hold shares in Adimab LLC. L.M.W. is an employee and holds shares in Invivyd Inc. T.N.S. and J.D.B. consult with Apriori Bio. J.D.B. has consulted for Moderna and Merck on viral evolution and epidemiology. D.R.B. is a consultant for IAVI, Invivyd, Adimab, Mabloc, VosBio, Nonigenex, and Radiant. C.I.K. and L.M.W. are inventors on a provisional patent application describing the SARS CoV 2 antibodies reported in this work. T.N.S. and J.D.B. may receive a share of intellectual property revenue as inventors on Fred Hutchinson Cancer Center optioned technology and patents related to deep mutational scanning of viral proteins. The other authors declare that they have no competing interests.
