Antibody affinity maturation and cross-variant activity following SARS-CoV-2 mRNA vaccination: Impact of prior exposure and sex

BACKGROUND: Limited knowledge exists regarding antibody affinity maturation following mRNA vaccination in naïve vs. COVID-19 recovered individuals and potential sex differences. METHODS: We elucidated post-vaccination antibody profiles of 69 naïve and 17 COVID-19 convalescent adults using pseudovirus neutralization assay (PsVNA) covering SARS-CoV-2 WA-1, variants of concern (VOCs) and variants of interest (VOIs). Surface Plasmon Resonance (SPR) was used to measure antibody affinity against prefusion spike and receptor binding domain (RBD) and RBD mutants. FINDINGS: Higher neutralizing antibodies were observed in convalescent vs. naïve adults against, WA-1, VOCs, and VOIs. Antibody binding to RBD and RBD mutants showed lower binding of post-vaccination sera from naïve compared with convalescent individuals. Moreover, we observed early antibody affinity maturation in convalescent individuals after one vaccine dose and higher antibody affinity after two doses compared with the naïve group. Among the naïve participants, antibody affinity against the SARS-CoV-2 prefusion spike was significantly higher for males than females even though there were no difference in neutralization titers between sexes. INTERPRETATION: This study demonstrates the impact of prior infection on vaccine-induced antibody affinity maturation and difference in antibody affinity between males and females. Further studies are needed to determine whether antibody affinity may contribute to correlates of protection against SARS-CoV-2 and its variants. FUNDING: The antibody characterization work described in this manuscript was supported by FDA's Medical Countermeasures Initiative (MCMi) grant #OCET 2021-1565 to S.K and intramural FDA-CBER COVID-19 supplemental funds. The SPARTA program was supported by the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH), Department of Health and Human Services contract 75N93019C00052, and the University of Georgia (US) grant UGA-001. T.M.R is also supported by the Georgia Research Alliance (US) grant GRA-001. The CTRU was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002378.