Disease-associated B cells and immune endotypes shape adaptive immune responses to SARS-CoV-2 mRNA vaccination in human SLE

Caterina E Faliti; Trinh T P Van; Fabliha A Anam; Narayanaiah Cheedarla; M Elliott Williams; Ashish Kumar Mishra; Sabeena Y Usman; Matthew C Woodruff; Geoff Kraker; Martin C Runnstrom; Shuya Kyu; Daniel Sanz; Hasan Ahmed; Midushi Ghimire; Andrea Morrison-Porter; Hannah Quehl; Natalie S Haddad; Weirong Chen; Suneethamma Cheedarla; Andrew S Neish; John D Roback; Rustom Antia; Jennifer Hom; Christopher M Tipton; John M Lindner; Eliver Ghosn; Surender Khurana; Christopher D Scharer; Arezou Khosroshahi; F Eun-Hyung Lee; Ignacio Sanz

doi:10.1038/s41590-024-02010-9

Disease-associated B cells and immune endotypes shape adaptive immune responses to SARS-CoV-2 mRNA vaccination in human SLE

Nat Immunol. 2024 Nov 12. doi: 10.1038/s41590-024-02010-9. Online ahead of print.

Authors

Caterina E Faliti^{1

2}, Trinh T P Van^{1

2}, Fabliha A Anam^{1

2}, Narayanaiah Cheedarla³, M Elliott Williams⁴, Ashish Kumar Mishra⁵, Sabeena Y Usman^{1

2}, Matthew C Woodruff^{1

2}, Geoff Kraker⁶, Martin C Runnstrom⁷, Shuya Kyu⁷, Daniel Sanz^{1

2}, Hasan Ahmed⁸, Midushi Ghimire^{1

2}, Andrea Morrison-Porter⁷, Hannah Quehl⁷, Natalie S Haddad^{7

9}, Weirong Chen^{1

2}, Suneethamma Cheedarla³, Andrew S Neish³, John D Roback³, Rustom Antia⁸, Jennifer Hom^{1

2}, Christopher M Tipton^{1

2}, John M Lindner¹⁰, Eliver Ghosn¹, Surender Khurana⁵, Christopher D Scharer⁴, Arezou Khosroshahi^{1

2}, F Eun-Hyung Lee⁷, Ignacio Sanz^{11

12}

Affiliations

¹ Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA.
² Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA.
³ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
⁴ Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
⁵ Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration, Silver Spring, MD, USA.
⁶ Dotmatics, Inc., Boston, MA, USA.
⁷ Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, USA.
⁸ Department of Biology, Emory University, Atlanta, GA, USA.
⁹ MicroB-plex, Inc., Atlanta, GA, USA.
¹⁰ BioMed X Institute, Heidelberg, Germany.
¹¹ Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA. Ignacio.sanz@emory.edu.
¹² Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA. Ignacio.sanz@emory.edu.

PMID: 39533072
DOI: 10.1038/s41590-024-02010-9

Abstract

Severe acute respiratory syndrome coronavirus 2 mRNA vaccination has reduced effectiveness in certain immunocompromised individuals. However, the cellular mechanisms underlying these defects, as well as the contribution of disease-induced cellular abnormalities, remain largely unexplored. In this study, we conducted a comprehensive serological and cellular analysis of patients with autoimmune systemic lupus erythematosus (SLE) who received the Wuhan-Hu-1 monovalent mRNA coronavirus disease 2019 vaccine. Our findings revealed that patients with SLE exhibited reduced avidity of anti-receptor-binding domain antibodies, leading to decreased neutralization potency and breadth. We also observed a sustained anti-spike response in IgD^-CD27^- 'double-negative (DN)' DN2/DN3 B cell populations persisting during memory responses and with greater representation in the SLE cohort. Additionally, patients with SLE displayed compromised anti-spike T cell immunity. Notably, low vaccine efficacy strongly correlated with higher values of a newly developed extrafollicular B and T cell score, supporting the importance of distinct B cell endotypes. Finally, we found that anti-BAFF blockade through belimumab treatment was associated with poor vaccine immunogenicity due to inhibition of naive B cell priming and an unexpected impact on circulating T follicular helper cells.

Abstract

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