Systems biological assessment of human immunity to BNT162b2 mRNA vaccination

The emergency use authorization of two COVID-19 mRNA vaccines in less than a year since the emergence of SARS-CoV-2 represents a landmark in vaccinology(1,2). Yet, how mRNA vaccines stimulate the immune system to elicit protective immune responses is unknown. Here we used a systems biological approach to comprehensively profile the innate and adaptive immune responses of 56 healthy volunteers vaccinated with the Pfizer-BioNTech mRNA vaccine. Vaccination resulted in robust production of neutralizing antibodies (nAbs) against the parent strain and a variant of concern, B.1.351, and significant increases in antigen-specific polyfunctional CD4 and CD8 T cells after the second dose. There was also a robust innate response induced within the first 2 days of the booster vaccination, compared to the first dose. Specifically, there were strongly enhanced: (i) frequency of CD14(+)CD16(+) inflammatory monocytes; (ii) concentration of IFN-γ in the plasma, which correlated with enhanced pSTAT3 and pSTAT1 levels in monocytes and T cells; and (iii) transcriptional signatures of innate responses characteristic of antiviral responses, within 2 days following booster vaccination, compared to the primary response. Consistent with these observations, single-cell transcriptomics analysis of 242,479 leukocytes demonstrated a ~100-fold increase in the frequency of a myeloid cell cluster containing monocytes and dendritic cells, enriched in interferon-response transcription factors (TFs) and reduced in AP-1 TFs, only after the second immunization. Finally, we identified distinct molecular pathways of innate activation that correlate with CD8 T cell and nAb responses, and identify an early monocyte-related signature that was associated with the breadth of the nAb response against the B1.351 variant strain. Collectively, these data provide insights into the cellular and molecular responses induced by mRNA vaccines and demonstrate their capacity to prime the immune system to mount a more potent innate immune response following booster immunization.