Background: Systemic Lupus Erythematosus (SLE) patients exhibit B-cell abnormalities. Although there are concerns about reduced antibody responses to SARS-CoV-2 vaccines, detailed data on B-cell-specific responses in SLE remain scarce. Understanding the responsiveness to novel vaccine-antigens, and boosters number, is important to avoid unnecessary prolonged isolation of immunocompromised individuals. Objectives: To assess humoral and antigen-specific B-cell subset responses, including changes in isotype switching, prior to and after several doses of SARS-CoV-2 vaccines. Methods: Blood samples were obtained prior to and after SARS-CoV-2 vaccination from cross-sectional and longitudinal cohorts of previously uninfected patients with SLE. Healthy participants receiving SARS-CoV-2 vaccines were recruited as controls. We measured serum antibody titres, their neutralizing capacity, and vaccine-specific memory B cells subsets. Results: Impaired IgG, IgA, and neutralizing responses against the original and various SARS-CoV-2 variants were observed following two doses of vaccine in SLE patients. Follow-up booster doses increased humoral responses compared to baseline, but they remained lower, with poorer neutralisation capacity against most strains, compared to healthy individuals after three or more doses. Analysis of memory B-cells subsets in SLE patients revealed an increase of SARS-CoV-2-specific isotype unswitched IgM+ over SARS-CoV-2-specific isotype switched IgG+/IgA+memory B-cells compared to healthy individuals. Culturing healthy naive B-cells with high levels of IFNα, a hallmark of SLE pathogenesis, prevented B-cells from switching to IgG under IgG-polarizing conditions. Conclusions: SLE patients' protection against SARS-CoV-2 is overall impaired compared to healthy individuals and is associated with a class switch defect possibly due to chronic exposure of B-cells to IFNα.

The authors have declared no competing interest.

Funding: This study was funded by a LUPUS UK grant (185431), (186075) (186987) and Versus Arthritis (17603) awarded to C.Mauri.

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:

This study involves human participants and was obtained from the UCLH Health Service Trust ethics committee, under REC reference no. 14/SC/1200. Patients gave informed consent to participate in the study before taking part.

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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors