INTRODUCTION

As scientific advances have been applied with unprecedented speed during the COVID-19 pandemic, physicians and their patients have pivoted from treatment of infection and passive immunization to full-scale preventative measures, particularly in high-risk individuals (1, 2). Patients with systemic lupus erythematosus (SLE) comprise a unique population with regard to risk for infection and outcomes associated with SARS–CoV-2, given underlying demographics, associated organ damage, and comorbidities. In addition, medications commonly used to treat SLE have been associated with an increased risk of death from COVID-19 (3). Early data provided evidence that patients with SLE have a high risk of hospitalization from COVID-19, with factors including race/ethnicity, comorbidities such as cardiovascular disease and renal insufficiency, and higher body mass index identified as independent predictors of hospitalization (1, 4). Further raising concern, infection was reported to be associated with flares of disease (5). In subsequent studies, patients with SLE and confirmed COVID-19 were demonstrated to generate and maintain serologic responses despite the use of a variety of immunosuppressants (6). These data provided reassurance regarding the efficacy and durability of humoral immunity and protection against reinfection with SARS–CoV-2, as well as potential insights into the efficacy of active immunization in SLE patients.

Since the phase III clinical studies of all 3 vaccines excluded patients treated with immunosuppressants or immune-modifying drugs within 6 months of enrollment, data on SLE are virtually absent (7-9). Furthermore, given the potential for disease flares following immunization, it is not surprising that a recent study reported hesitancy for vaccination in patients with rheumatic diseases, including SLE (10). Accordingly, the current study was initiated to address these critical gaps and examine the efficacy of these promising COVID-19 vaccines in patients with SLE. This was accomplished by evaluating a multiethnic/multiracial cohort of SLE patients using assessments of serologic responses which were compared to healthy controls. The assays included antibodies to the spike protein receptor-binding domain (RBD), virus-neutralizing antibodies, and antigen-specific T cell production of interferon-γ (IFNγ), both prior to and after vaccination. Factors associated with the level of responsiveness were sought. In addition, SLE disease activity pre- and postvaccination was measured, as well as the rate of flare postvaccination.

DISCUSSION

To our knowledge, this is the first reported study focused on patients with SLE who received full regimens of a COVID-19 vaccine, and overall IgG antibody responses against the SARS–CoV-2 spike protein RBD were significantly decreased compared to vaccinated controls, with 28.8% of patients generating responses falling below the lowest level observed in the healthy controls. Receiving any immunosuppressive agent other than antimalarials and having a normal anti-dsDNA antibody level prior to vaccination were identified as independent predictors for poor response to the COVID-19 vaccine. Seroreactivity to the SARS–CoV-2 spike RBD strongly correlated with the functional SARS–CoV-2 microneutralization assay and correlated with the ELISpot assay. Overall, there was no change in SLEDAI score pre- and postvaccination, with 11.4% of patients having a flare and 1.3% of those flares being severe, supporting the relative safety of the vaccination in SLE patients.

The finding of anti-dsDNA antibodies positively correlating with higher responses to COVID-19 vaccination was initially unexpected, especially given that this finding persisted even after controlling for medication use. Moreover, disease activity per se was not associated with more effective seroreactivity. It could be hypothesized that the presence of anti-dsDNA antibodies is a proxy of elevated type I IFN activity in these patients. Indeed, studies have shown that high IFNα activity in patients with SLE is associated with the presence of disease-specific autoantibodies, such as anti-dsDNA (18). These autoantibodies can form immune complexes, further stimulating type I IFN production (19). Besides their potent antiviral properties, type I IFNs induce the maturation and activation of myeloid dendritic cells, and promote B cell survival and differentiation into antibody-producing cells (20, 21). These considerations support the hypothesis that those with stronger responses to the COVID-19 vaccines could have higher baseline type I IFN activity, due to its potential to enhance antibody responses to foreign antigens. Thus, patients with anti-dsDNA antibodies, despite receiving immunosuppressive therapy, may be more likely to develop a strong humoral response to the COVID-19 vaccines. Alternatively, these analyses did not account for patient adherence to medication or the possibility that elevated dsDNA antibodies reflects inefficacy of immunosuppression, which might account for these findings. These potential insights merit further investigation.

Given the exclusion of patients receiving immunosuppressants from the regulatory vaccine studies, several groups have already explored the influence of immunosuppressive medications on the response to vaccination. Boyarsky et al evaluated patients with organ transplants and reported that antimetabolite maintenance immunosuppression was associated with an absent or reduced anti-RBD spike response after the first dose of the vaccine (22). A follow-up study from the same group in 658 transplant recipients who received the second dose of the SARS–CoV-2 mRNA vaccine showed an increase in seroreactivity in response to the second dose; however, poor responses were associated with antimetabolite immunosuppressive treatment (23).

Concordant with our results, several studies have shown decreased vaccine-induced seroreactivity in patients with rheumatic diseases. In 123 such patients, including 24 with SLE, those receiving MMF or rituximab were less likely to develop an antibody response to the spike protein after the first dose of the SARS–CoV-2 mRNA vaccine; these findings were confirmed in a larger study of 404 patients, including 87 with SLE, after the second dose (24, 25). In an analysis of 26 patients with chronic inflammatory diseases (CIDs) that included 2 patients with SLE who were receiving HCQ, SARS–CoV-2 antibodies were significantly lower in patients, compared to controls, after both doses of BNT162b2 or mRNA-1273. No patients experienced a disease flare after both doses of the vaccine (26). A large study of 133 patients with CIDs, including 15 patients with SLE, who received an mRNA vaccine showed that patients with CIDs had a 3-fold reduction in anti–spike protein IgG response with B cell depletion, glucocorticoids, and antimetabolites (27). A subsequent analysis of 89 patients that included 10 patients with SLE showed that rituximab was associated with impaired serologic response to the SARS–CoV-2 vaccine (28). Haberman et al demonstrated that MTX adversely affected both the humoral and cellular immune responses to COVID-19 mRNA vaccines in patients with immune-mediated inflammatory diseases (29). A large study from Furer et al that included 101 patients with SLE showed that older age and treatment with glucocorticoids, rituximab, MMF, and abatacept were associated with reduced immunogenicity as measured by serum IgG antibody levels against SARS–CoV-2 spike S1/S2 proteins 2–6 weeks after vaccination (30). Our study showed that receiving any non-antimalarial immunosuppressive therapy was independently associated with decreased response to COVID-19 vaccines in patients with SLE.

In addition to concerns regarding inefficient immune responses to COVID vaccination, it may be the case that vaccination induces increased autoantibody production and disease activity. As speculated by Tang et al, delivery of mRNA encoding S protein via the vaccine, likely degraded by normal cellular processes, could interact with a number of cytoplasmic RNA-binding proteins involved in the posttranscriptional regulation of inflammation and result in worsening SLE (5). Similarly, RNA vaccines may trigger Toll-like receptors, generating further production of type I IFN, already well-recognized to be elevated in most SLE patients (19). It has been reported that influenza vaccines triggered a transient increase in several autoantibody specificities in 72 SLE patients, with a flare rate of 19.4% within 6 weeks postvaccination; 10 (13.9%) were mild/moderate and 4 (5.6%) were severe (31). In a study evaluating SLE flares after immunization against poliomyelitis, only 4 of 73 patients (5%) experienced flares (32). In aggregate, despite apprehensions, the data presented herein did not support significantly increased anti-dsDNA antibody production or flares postvaccination. These results are consistent with a recent study which showed that the majority of vaccinated SLE patients had no change or decrease in disease activity after COVID-19 vaccination as measured by the SLEDAI (30).

Our study has several limitations. Similar to other studies evaluating potential surrogate markers for vaccine efficacy, it is premature to assign a threshold level of protection based on either the IgG response to the anti-RBD of SARS–CoV-2 spike protein or the microneutralization assay given the number of controls. There was vaccine hesitancy among patients in the NYU Lupus Cohort, in large part due to concern regarding the potential effect on lupus activity, and thus the patients in this study may not be fully representative of the patients seen in our cohort. While known prior COVID-19 infection was accounted for in all patients, it remains possible that asymptomatic or mild infection occurred between prevaccine blood draw and vaccination, which could influence subsequent seroreactivity. While this study included 90 patients with SLE, the number of patients receiving individual medications was too small to draw any definitive conclusions about their effects on vaccine response in SLE patients, and in our analyses, receiving any non-antimalarial immunosuppressive agent was ultimately the strongest predictor of a poor antibody response to the COVID-19 vaccines. Another limitation of the work is the absence of a direct comparator of SLE flare rates over the same time period. It also remains possible that a perceived SLE flare could have been a vaccine side effect.

This study has several strengths. In contrast to previous reports, the focus was limited to patients with SLE and assessed the COVID-19 vaccines’ effects on lupus-specific disease activity with availability of a validated disease index pre- and postvaccination in the majority of patients. Flares were rare, with only 1.3% being severe. These data are reassuring and support the notion that vaccines do not exacerbate disease activity, a finding that should hopefully alleviate vaccine hesitancy. Our study assessed 2 surrogate markers for B cell reactivity and a surrogate for T cell–mediated responses. Although the latter was limited to fewer patients, it was particularly applied to evaluate those with lower humoral responses and reinforced the concern about vaccine efficacy in a subset of these individuals.

In summary, in a multiracial/multiethnic study of SLE patients receiving a complete COVID-19 vaccine regimen, nearly 30% had a low response. Having a normal anti-dsDNA antibody level and taking any immunosuppressive medication other than antimalarials were independently associated with a decreased vaccine response. While minimal protective antibody levels remain unknown, these results, supported by other studies, raise concerns for our lupus patients, many of whom rely on medications to maintain low disease activity. Accordingly, the next phase of scientific inquiry and advance should focus on protocols addressing additional vaccination. Reassuringly, severe disease flares are infrequent, which should encourage patients to consider vaccination.

ACKNOWLEDGMENTS

The authors would like to thank the patients who participated in the study. They would also like to acknowledge Ranit Shriky and Rebecca Cohen for their assistance with regulatory matters and Benjamin Wainwright for his contributions to the manuscript.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Izmirly had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design

Izmirly, Kim, Samanovic, Fernandez-Ruiz, Haberman, Scher, Mulligan, Clancy, Buyon.

Acquisition of data

Izmirly, Samanovic, Fernandez-Ruiz, Ohana, Deonaraine, Engel, Masson, Cornelius, Herati, Guttmann, Blank, Plotz, Haj-Ali, Banbury, Stream, Hasan, Ho, Rackoff, Blazer, Tseng, Belmont, Saxena, Mulligan, Clancy, Buyon.

Analysis and interpretation of data

Izmirly, Kim, Samanovic, Fernandez-Ruiz, Xie, Belmont, Saxena, Mulligan, Clancy, Buyon.