Hybrid adaptive immunity to SARS-CoV-2 protects against breakthrough infection after COVID-19 vaccination in ALSPAC participants

Immunological memory to vaccination and viral infection involves coordinated action of B and T-cells, thus integrated analysis of these two components is critical for understanding their contributions to protection against breakthrough infections (BI). We investigated cellular and humoral immune responses to SARS-CoV-2 infection and/or COVID-19 vaccination in participants from the Avon Longitudinal Study of Parents and Children (ALSPAC). The magnitude of antibody and T-cell responses following the second vaccine dose was associated with protection against BI in participants with a history of SARS-CoV-2 infection (cases), but not in infection-naïve controls. Youden’s index thresholds for protection against BI were calculated for all immune measures. Anti-Spike IgG (>666.4 BAU/mL) and anti-nucleocapsid N pan Ig (>0.1332 BAU/mL) thresholds combined were 100% sensitive and 83% specific for cases without BI over 8-months follow-up. Collectively these results point to the superior protective effect of hybrid immunity and have implications for the design of next-generation COVID-19 vaccines.