Hybrid B- and T-Cell Immunity Associates With Protection Against Breakthrough Infection After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Avon Longitudinal Study of Parents and Children (ALSPAC) Participants.
Baum HE., Santopaolo M., Francis O., Milodowski EJ., Entwistle K., Oliver E., Hitchings B., Diamond D., Thomas AC., Mitchell RE., Kibble M., Gupta K., Di Bartolo N., Klenerman P., Brown A., Morales-Aza B., Oliver J., Berger I., Toye AM., Finn A., Goenka A., Davidson AD., Ring S., Molloy L., Lewcock M., Northstone K., Roth F., Timpson NJ., Wooldridge L., Halliday A., Rivino L.
BACKGROUND: Immunological memory to vaccination and viral infection involves the coordinated action of B and T cells; thus, integrated analysis of these 2 components is critical for understanding their respective contributions to protection against breakthrough infections (BIs) after vaccination. METHODS: We investigated cellular and humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or vaccination in 300 adult participants from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants were grouped by those with (cases) and without (controls) a history of SARS-CoV-2 infection. To provide a quantitative correlate for protection against BI in the 8-month period after the study, Youden index thresholds were calculated for all immune measures analyzed. RESULTS: 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-naive controls. Over 8 months of follow-up, 2 threshold combinations provided the best performance for protection against BI in cases: (i) anti-spike immunoglobulin G (IgG) (≥666.4 binding antibody units [BAU]/mL) combined with anti-nucleocapsid pan-immunoglobulin (pan-Ig) (≥0.1332 BAU/mL) and (ii) spike 1-specific T cells (≥195.6 spot-forming units/106 peripheral blood mononuclear cells) combined with anti-N pan-Ig (≥0.1332 BAU/mL). Both combinations offered 100% specificity for detecting cases without BI, with sensitivities of 83.3% and 72.2%, respectively. CONCLUSIONS: Collectively, these results suggest that hybrid B- and T-cell immunity offers superior protection from BI after coronavirus disease 2019 (COVID-19) vaccination, and this finding has implications for designing next-generation COVID-19 vaccines that are capable of eliciting immunity to a broader repertoire of SARS-CoV-2 proteins.