Anti-rubella IgG serum levels predict risk for SARS-CoV-2 breakthrough infectionsTo the Editor,

Despite recent advances in prophylactic vaccination, SARS-CoV-2 infections continue to cause significant morbidity. A better understanding of immune response differences between vaccinated individuals with and without later SARS-CoV-2 breakthrough infection is urgently needed. CoV-ADAPT is a prospective long-term study comparing humoral (anti-spike-RBD-IgG, neutralization capacity, avidity) and cellular (spike-induced T-cell interferon-γ release) immune responses in individuals vaccinated against SARS-CoV-2 at four different time points (three before and one after third vaccination). In this cohort study, 62 fully vaccinated individuals presented with SARS‑CoV-2 breakthrough infections vs 151 without infection 3-7 months following third vaccination. Breakthrough infections significantly increased anti-spike-RBD-IgG (p<0.01), but not spike-directed T-cell interferon-γ release (TC), antibody neutralization capacity or avidity. Anti-spike-RBD-IgG and antibody avidity decreased with age (p<0.01) and females showed higher anti-spike-RBD-IgG (p<0.01), and a tendency towards higher antibody avidity (p=0.051). The association between humoral and cellular immune responses previously reported at various time points was lost in subjects after breakthrough infections (p=0.807). Finally, a machine-learning approach based on our large immunological data set (a total of 49 variables) from different time points was unable to predict breakthrough infections (AUC: 0.55). In conclusion, distinct differences in humoral vs cellular immune responses in fully vaccinated individuals with or without breakthrough infection could be demonstrated. Breakthrough infections predominantly drive the humoral response without boosting the cellular component. Breakthrough infections could not be predicted based on immunological data, which indicates a superior role of environmental factors (e.g. virus exposure) in individualized risk assessment.

A document by Luise Erpenbeck. Click on the document to view its contents.

Background: Humoral and cellular immune responses to SARS-CoV-2 vaccines wane with time. In the COV‑ADAPT cohort, we recently studied both immunological components and their interdependencies following different vaccine combinations before (T1) and up to three months after second immunization (T2). This follow-up investigated the stability of long-term immune responses and aimed to identify predictive markers. Methods: We assessed humoral (anti-spike-RBD-IgG, neutralization capacity, avidity) and cellular (spike-induced T-cell interferon‑γ release) immune responses three-seven months after secondary vaccination (T3) in blood samples of 318 healthcare workers with previous homologous ChAdOx1 nCoV-19 (ChAdOx1), homologous BNT162b2 or heterologous ChAdOx1/BNT162b2 vaccinations. Results: At T3, homologous ChAdOx1 vaccination resulted in significantly lower anti-spike-RBD-IgG (152±151 BAU/ml) as compared to heterologous ChAdOx1/BNT162b2 (388±300 BAU/ml) and homologous BNT162b2 (435±327 BAU/ml). In all groups, anti-spike-RBD-IgG (T3) exceeded antibody levels before second vaccination (T1). T-cell interferon-γ release following heterologous ChAdOx1/BNT162b2 vaccination was significantly higher at T3 (1062±2083 mIU/ml) vs. T1 (680±1691 mIU/ml), yet did not differ significantly between the three groups at T3. Associations between humoral and cellular responses were found at T3 (all groups combined). Additionally, the early cellular response (at T1) was significantly associated with late (T3) humoral (ChAdOx1/BNT162b2, BNT162b2/BNT162b2) and cellular responses (all groups). In contrast to T2, neutralization capacity at T3 was significantly higher for ChAdOx1/BNT162b2 and BNT162b2/BNT162b2 vs. ChAdOx1/ChAdOx1. Conclusions: We identified (i) long-term interdependencies between the humoral and the cellular immune system, (ii) observed distinct waning dynamics following different vaccination regimes, and (iii) uncovered early T-cell responses as a useful predictor of long-term immune responses.