Binding and avidity signatures of polyclonal sera from individuals with different exposure histories to SARS-CoV-2 infection, vaccination, and Omicron breakthrough infections.

ABSTRACT

BACKGROUND: The number of exposures to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to vaccination antigens impact the magnitude and avidity of the polyclonal response. METHODS: We studied binding and avidity of different antibody isotypes to the spike, the receptor binding domain (RBD), and the nucleoprotein (NP) of wild type (WT) and BA.1 SARS-CoV-2 in convalescent, mRNA vaccinated, mRNA boosted, hybrid immune individuals, and in individuals with breakthrough cases during the peak of the BA.1 wave. RESULTS: We found an increase in spike binding antibodies and antibody avidity with increasing number of exposures to infection and/or vaccination. Nucleoprotein antibodies were detectible in convalescent individuals and a proportion of breakthrough cases, but displayed low avidity. Omicron breakthrough infections elicited high levels of cross-reactive antibodies between WT and BA.1 antigens in vaccinated individuals without prior infection directed against the spike and receptor binding domain (RBDs). The magnitude of the antibody response and avidity correlated with neutralizing activity against WT virus. CONCLUSIONS: The magnitude and quality of the antibody response increased with the number of antigen exposures, including breakthrough infections. However, cross-reactivity of the antibody response after BA.1 breakthroughs, was impacted by the number of prior antigenic exposures.