Comparative multi-OMICS single-cell atlas of five COVID-19 (rAdVV and mRNA) vaccines describe unique and distinct mechanisms of action

COVID-19 vaccines based on a range of expression platforms have shown considerable protective efficacy, generating antibody and T cell immune responses. However, molecular pathways underpinning COVID-19 vaccine priming of immunity against the SARS-CoV-2 virus have not yet been explored extensively. This analysis is critical to optimization of future vaccination strategies, schedules, and combinations. Thus, we investigated a cohort of individuals pre- and post-vaccination to understand the humoral and cellular immune response against different COVID-19 vaccines, including recombinant adenoviral vector (rAdVV) and mRNA-based vaccines. Single-cell RNA sequencing allowed characterization of monocytes, T, NK and B cell activation at the transcriptomics/proteomic level, in response to different COVID-19 vaccines. Our data revealed that different COVID-19 vaccines elicit a unique and distinct mechanism of action. Specifically, we revealed that rAdVV vaccines negatively regulate CD4+ T cell activation, leukocytes chemotaxis, IL-18 signalling and antigen presentation by monocytes whilst mRNA vaccines positively regulate NKT cell activation, platelets activation and chemokine signalling pathways. An antigen-specific T cell response was already observed following the 1st vaccine dose and was not further augmented after the subsequent 2nd dose of the same vaccine and it was dependent on the type of vaccination used. Our integrated three layered-analyses highlights that COVID-19 vaccines evoke a strong but divergent immune response at the RNA, protein, and cellular levels. Our approach is able to pinpoint efficacy and mechanisms controlling immunity to vaccination and open the door for better vaccination which could induce innate and adaptive immunity equally in the long term. Key findingsO_LIDecrease in major three cell types classical and non-classical monocytes and NK type III cells after COVID-19 vaccination C_LIO_LIIndividual vaccination (AZ, JJ, MD, PB) has differential effect on various immune cell subsets and regulates unique cell populations, whilst no change was observed for CV vaccination C_LIO_LIrAdVV and mRNA vaccines have different mechanism of action for activation of lymphocytes and monocytes, respectively C_LIO_LIrAdVV vaccines negatively regulates CD4+ T cell activation, leukocytes chemotaxis, IL-18 signalling and antigen presentation whilst mRNA vaccines positively regulate NKT cell activation, platelets activation and chemokine signalling pathways. C_LIO_LIAn antigen-specific T cell response was prompted after the 1st vaccine dose and not augmented after the subsequent 2nd dose of the same vaccine. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/507666v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@11fd7eborg.highwire.dtl.DTLVardef@198a9c7org.highwire.dtl.DTLVardef@1b28735org.highwire.dtl.DTLVardef@1cadbb5_HPS_FORMAT_FIGEXP M_FIG C_FIG