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

• Published in: Nature immunology
• Main Authors: Faliti, Caterina E., Van, Trinh T. P., Anam, Fabliha A., Cheedarla, Narayanaiah, Williams, M. Elliott, Mishra, Ashish Kumar, Usman, Sabeena Y., Woodruff, Matthew C., Kraker, Geoff, Runnstrom, Martin C., Kyu, Shuya, Sanz, Daniel, Ahmed, Hasan, Ghimire, Midushi, Morrison-Porter, Andrea, Quehl, Hannah, Haddad, Natalie S., Chen, Weirong, Cheedarla, Suneethamma, Neish, Andrew S., Roback, John D., Antia, Rustom, Hom, Jennifer, Tipton, Christopher M., Lindner, John M., Ghosn, Eliver, Khurana, Surender, Scharer, Christopher D., Khosroshahi, Arezou, Lee, F. Eun-Hyung, Sanz, Ignacio
• Format: Journal Article
• Language: English
• Published: 12-11-2024
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-024-02010-9

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.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.