Discrete Immune Response Signature to SARS-CoV-2 mRNA Vaccination Versus Infection

Abstract

Both SARS-CoV-2 infection and vaccination elicit potent immune responses. A number of studies have described immune responses to SARS-CoV-2 infection. However, beyond antibody production, immune responses to COVID-19 vaccines remain largely uncharacterized. Here, we performed multimodal single-cell sequencing on peripheral blood of patients with acute COVID-19 and healthy volunteers before and after receiving the SARS-CoV-2 BNT162b2 mRNA vaccine to compare the immune responses elicited by the virus and by this vaccine. Phenotypic and transcriptional profiling of immune cells, coupled with reconstruction of the B and T cell antigen receptor rearrangement of individual lymphocytes, enabled us to characterize and compare the host responses to the virus and to defined viral antigens. While both infection and vaccination induced robust innate and adaptive immune responses, our analysis revealed significant qualitative differences between the two types of immune challenges. In COVID-19 patients, immune responses were characterized by a highly augmented interferon response which was largely absent in vaccine recipients. Increased interferon signaling likely contributed to the observed dramatic upregulation of cytotoxic genes in the peripheral T cells and innate-like lymphocytes in patients but not in immunized subjects. Analysis of B and T cell receptor repertoires revealed that while the majority of clonal B and T cells in COVID-19 patients were effector cells, in vaccine recipients clonally expanded cells were primarily circulating memory cells. Importantly, the divergence in immune subsets engaged, the transcriptional differences in key immune populations, and the differences in maturation of adaptive immune cells revealed by our analysis have far-ranging implications for immunity to this novel pathogen.

Funding: We are grateful for support of this work from NYU Grossman School of Medicine. Work in Dr. Koralov’s laboratory was further supported by the NIH R01 grant (HL-125816), LEO Foundation Grant (LF-OC-20-000351), NYU Cancer Center Pilot Grant (P30CA016087), the Judith and Stewart Colton Center for Autoimmunity Pilot grant. Presented work was also supported by NIH grant R21 AI158997, R01 CA194864 and R01 CA212608 to S.K.; NIH grants AI114852 and AI082630 to R.S.H.; and AI148574 to M.J.M. TBB and NØ are supported by the Danish Cancer Society (Kræftens Bekæmpelse), the Danish Council for Independent Research (Danmarks Frie Forskningsfond) and the LEO Foundation.

Declaration of Interest: MJM reported potential competing interests: laboratory research and clinical trials contracts with Lilly, Pfizer (exclusive of the current work), and Sanofi for vaccines or MAB vs SARS-CoV-2; contract funding from USG/HHS/BARDA for research specimen characterization and repository; research grant funding from USG/HHS/NIH for SARS-CoV-2 vaccine and MAB clinical trials; personal fees from Meissa Vaccines, Inc. and Pfizer for Scientific Advisory Board service.

Ethical Approval: All studies were approved by the NYU Institutional Review Board (IRB #s 18-02035, 18-02037, 20-00463). This study was performed in accordance with the Declaration of Helsinki. All volunteers provided written informed consent prior to enrollment.