Poor immunogenicity upon SARS-CoV-2 mRNA vaccinations in autoimmune SLE patients is associated with pronounced EF-mediated responses and anti-BAFF/Belimumab treatment.

• Type of Material: Article
• Authors: Caterina E Faliti, Emory University; Fabliha A Anam, Emory University; Narayanaiah Cheedarla, Emory University; Matthew C Woodruff, Emory University; Sabeena Y Usman, Emory University; Martin C Runnstrom, Emory University; Trinh T.P Van, Emory University; Shuya Kyu, Emory University; Hasan Ahmed, Emory University; Andrea Morrison-Porter, Emory University; Hannah Quehl, Emory University; Natalie S Haddad, Emory University; Weirong Chen, Emory University; Suneethamma Cheedarla, Emory University; Andrew S Neish, Emory University; John D Roback, Emory University; Rustom Antia, Emory University; Arezou Khosroshahi, Emory University; F. Eun-Hyung Lee, Emory University; Ignacio Sanz, Emory University
• Language: English
• Date: 2023-06-12
• Publisher: Emory University Libraries
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1101/2023.06.08.23291159
• Title of Journal or Parent Work: medRxiv
• Grant/Funding Information: This work was supported by National Institutes of Health grants: U54- 762 CA260563-01 Emory SeroNet (I.S., F.E.L.), U19-AI110483 Emory Autoimmunity Center of Excellence (I.S.).
• Keywords: pathology; diseases; SARS-CoV-2; cancer; human immunology; mRNA
• Research Categories: Biology, Microbiology; Health Sciences, Medicine and Surgery; Health Sciences, Pathology; Health Sciences, Oncology

Abstract

Novel mRNA vaccines have resulted in a reduced number of SARS-CoV-2 infections and hospitalizations. Yet, there is a paucity of studies regarding their effectiveness on immunocompromised autoimmune subjects. In this study, we enrolled subjects naïve to SARS-CoV-2 infections from two cohorts of healthy donors (HD, n=56) and systemic lupus erythematosus (SLE, n=69). Serological assessments of their circulating antibodies revealed a significant reduction of potency and breadth of neutralization in the SLE group, only partially rescued by a 3 rd booster dose. Immunological memory responses in the SLE cohort were characterized by a reduced magnitude of spike-reactive B and T cell responses that were strongly associated with poor seroconversion. Vaccinated SLE subjects were defined by a distinct expansion and persistence of a DN2 spike-reactive memory B cell pool and a contraction of spike-specific memory cTfh cells, contrasting with the sustained germinal center (GC)-driven activity mediated by mRNA vaccination in the healthy population. Among the SLE-associated factors that dampened the vaccine responses, treatment with the monoclonal antibody anti-BAFF/Belimumab (a lupus FDA-approved B cell targeting agent) profoundly affected the vaccine responsiveness by restricting the de novo B cell responses and promoting stronger extra-follicular (EF)-mediated responses that were associated with poor immunogenicity and impaired immunological memory. In summary, this study interrogates antigen-specific responses and characterized the immune cell landscape associated with mRNA vaccination in SLE. The identification of factors associated with reduced vaccine efficacy illustrates the impact of SLE B cell biology on mRNA vaccine responses and provides guidance for the management of boosters and recall vaccinations in SLE patients according to their disease endotype and modality of treatment.