The magnitude and timing of recalled immunity after breakthrough infection is shaped by SARS-CoV-2 variants

Vaccination against SARS-CoV-2 protects from infection and improves clinical outcomes in breakthrough in-fections, likely reflecting residual vaccine-elicited immunity and recall of immunological memory. Here, we define the early kinetics of spike-specific humoral and cellular immunity after vaccination of seropositive individuals and after Delta or Omicron breakthrough infection in vaccinated individuals. Early longitudinal sampling revealed the timing and magnitude of recall, with the phenotypic activation of B cells preceding an increase in neutralizing antibody titers. While vaccination of seropositive individuals resulted in robust recall of humoral and T cell immunity, recall of vaccine-elicited responses was delayed and variable in magni-tude during breakthrough infections and depended on the infecting variant of concern. While the delayed kinetics of immune recall provides a potential mechanism for the lack of early control of viral replication, the recall of antibodies coincided with viral clearance and likely underpins the protective effects of vaccina-tion against severe COVID-19.

Automated summary

This study investigates the early kinetics of spike-specific humoral and cellular immunity after vaccination and breakthrough infections of seropositive individuals. The findings reveal that vaccination of seropositive individuals induces robust recall of immune responses, while recall of vaccine-elicited responses in breakthrough infections is delayed and variable, depending on the infecting variant.