Systems biology analysis reveals distinct molecular signatures associated with immune responsiveness to the BNT162b COVID-19 vaccine

BACKGROUND: Human immune responses to COVID-19 vaccines display a large heterogeneity of induced immunity and the underlying immune mechanisms for this remain largely unknown. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: German Center for Infection Research, German Center for Lung Research, German Research Foundation, Excellence Strategy EXC 2155 "RESIST" and European Regional Development Fund.

• Odak, I.
• Riemann, L.
• Sandrock, I.
• Cossmann, A.
• Ramos, G. M.
• Hammerschmidt, S. I.
• Ritter, C.
• Friedrichsen, M.
• Hassan, A.
• Dopfer-Jablonka, A.
• Stankov, M. V.
• Weskamm, L. M.
• Addo, M. M.
• Ravens, I.
• Willenzon, S.
• Schimrock, A.
• Ristenpart, J.
• Janssen, A.
• Barros-Martins, J.
• Hansen, G.
• Falk, C.
• Behrens, G. M. N.
• Förster, R.