mRNA COVID-19 vaccine elicits potent adaptive immune response without the persistent inflammation seen in SARS-CoV-2 infection

SARS-CoV-2 infection and vaccination elicit potent immune responses. Our study presents a comprehensive multimodal single-cell dataset of peripheral blood of patients with acute COVID-19 and of healthy volunteers before and after receiving the SARS-CoV-2 mRNA vaccine and booster. We compared host immune responses to the virus and vaccine using transcriptional profiling, coupled with B/T cell receptor repertoire reconstruction. COVID-19 patients displayed an enhanced interferon signature and cytotoxic gene upregulation, absent in vaccine recipients. These findings were validated in an independent dataset. Analysis of B and T cell repertoires revealed that, while the majority of clonal lymphocytes in COVID-19 patients were effector cells, clonal expansion was more evident among circulating memory cells in vaccine recipients. Furthermore, while clonal αβ T cell responses were observed in both COVID-19 patients and vaccine recipients, dramatic expansion of clonal γδT cells was found only in infected individuals. Our dataset enables comparative analyses of immune responses to infection versus vaccination, including clonal B and T cell responses. Integrating our data with publicly available datasets allowed us to validate our findings in larger cohorts. To our knowledge, this is the first dataset to include comprehensive profiling of longitudinal samples from healthy volunteers pre/post SARS-CoV-2 vaccine and booster. ### Competing Interest Statement 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 SARSCoV2; contract funding from USG/HHS/BARDA for research specimen characterization and repository; research grant funding from USG/HHS/NIH for SARSCoV2 vaccine and MAB clinical trials; personal fees from Meissa Vaccines, Inc. and Pfizer for Scientific Advisory Board service. PS is listed as a coinventor on a patent application related to single cell technology used (US provisional patent application 62/515180). ### Clinical Trial Observational trials are not subject to registration requirements ### Funding Statement We are grateful for support of this work from NYU Grossman School of Medicine. Work in the Koralov 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 NO are supported by the Danish Cancer Society (Kraeftens Bekaempelse), the Danish Council for Independent Research (Danmarks Frie Forskningsfond) and the LEO Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: NYU Institutional Review Board I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data will be publicly available upon publication in peer reviewed journal.