Systems biology analysis reveals distinct molecular signatures promoting immune responsiveness to the BNT162b COVID-19 vaccine [scRNA-seq]

Human immune responses to COVID-19 vaccines display a large heterogeneity of induced immunity and the underlying immune mechanisms for this remain largely unknown. Using a systems biology approach, we longitudinally profiled a unique cohort of female high and low responders to the BNT162b vaccine, who were known from previous COVID-19 vaccinations to develop maximum and minimum immune responses to the vaccine. We utilized high dimensional flow cytometry, bulk and single cell mRNA sequencing and 48-plex serum cytokine analyses. We revealed early, transient immunological and molecular signatures that distinguished high from low responders and correlated with B and T cell responses measured 14 days later. High responders featured a distinct transcriptional activity of interferon-driven genes and genes connected to enhanced antigen presentation. This was accompanied by a robust cytokine response related to Th1 differentiation. Both transcriptome and serum cytokine signatures were confirmed in two independent confirmatory cohorts. Collectively, our data contribute to a better understanding of the immunogenicity of mRNA-based COVID-19 vaccines, which might lead to the optimization of vaccine designs for individuals with poor vaccine responses. Single-cell transcriptome (scRNA-seq) of CD3-CD19- cells of COVID-19 vaccine high-responders (HR) and low-responders (LR) before the third (booster) COVID-19 vaccination with BNT162b (pre), as well as 24 hours (24h) and 48 hours (48h) after the vaccination were analyzed.