Impact of BNT162b2 mRNA anti-SARS-CoV-2 vaccine on interferon-alpha production by plasmacytoid dendritic cells and autoreactive T cells in patients with systemic lupus erythematosus: The COVALUS project

Abstract

Objective: To evaluate the specific response of SLE patients to BNT162b2 vaccination and its impact on autoimmunity defined as in vivo production of interferon-alpha (IFNα) by plasmacytoid dendritic cells (pDCs) and autoreactive immune responses.

Methods: Our prospective study included SLE patients and healthy volunteers (HV) who received 2 doses of BNT162b2 vaccine 4 weeks apart. Subjects under immunosuppressive drugs or with evidence of prior COVID-19 were excluded. IgG anti-Spike SARS-CoV-2 (anti-S) antibodies, anti-S specific-B cells, anti-S specific T cells, in vivo INF-α production by pDCs, activation marker expression by pDCs and autoreactive anti-nuclear T cells were quantified before first injection, before second injection, and 3 and 6 months after first injection.

Results: Vaccinated SLE patients produced significantly lower IgG antibodies and specific B cells against SARS-CoV-2 as compared to HV. In contrast, anti-S T cell response did not significantly differ between SLE patients and HV. Following vaccination, the surface expression of HLA-DR and CD86 and the in vivo production of IFNα by pDCs significantly increased in SLE patients. The boosted expression of HLA-DR on pDCs induced by BNT162b2 vaccine correlated with the overall immune responses against SARS-CoV-2 (anti-S antibodies: r = 0.27 [0.05-0.46], p = 0.02; anti-S B cells: r = 0.19 [-0.03-0.39], p = 0.09); anti-S T cells: r = 0.28 [0.05-0.47], p = 0.016). Eventually, anti-SARS-CoV-2 vaccination was associated with an overall decrease of autoreactive T cells (slope = - 0.00067, p = 0.015).

Conclusion: BNT162b2 vaccine induces a transient in vivo activation of pDCs in SLE that contributes to the immune responses against SARS-CoV-2. Unexpectedly BNT162b2 vaccine also dampens the pool of circulating autoreactive T cells, suggesting that vaccination may have a beneficial impact on SLE disease.

Keywords: Plasmacytoid dendritic cells; SARS-CoV-2; Systemic lupus erythematosus; Type-1 interferon; mRNA vaccine.

Fig. 1

SARS-CoV-2-specific immune responses following vaccination Anti-Spike IgG blood titer measured in BAU/mL by ELISA in SLE patients (in blue) compared to HV (in red). Points represents the mean and error bars the standard error of the mean (A). Blood concentrations of anti-S specific B cell measured by flow cytometry using tetramers of biotinylated spike-protein associated to fluorescent streptavidin. Points represented the mean and error bars the standard error of the mean (B). Correlation between anti-spike IgG blood level and anti-S specific B cells in SLE and HV at all the time points. Pearson's coefficient is provided (C). T cell response to SARS-CoV-2 vaccine measured by flow cytometry as the percentage of CD154+/IFNγ+ among CD4 cells after stimulation with a pool of peptides covering the sequence of Spike protein. For each time Ti, we represented here the delta Ti- T0 to take into account background and basal signal (D). Points represented the mean and error bars the standard error of the mean* p < 0.05 **p < 0.001 ***p < 0.001.

Fig. 2

Impact of BNT162b2 vaccine on ex vivo IFNα production by pDCs and pDCs activation. Percentage of IFNα2b production by circulating pDCs during follow-up. In blue, SLE patients, in red HV (A). Activation markers on circulating pDCs during study follow-up measured by mean fluorescence intensity ratio of HLA-DR (B) and CD86 (C) in flow cytometry. Correlation between pDCs activation measured by HLA-DR gMFI on pDCs at M1 and M3 in SLE and HV and anti-S IgG blood level (D), anti-S specific B cells (E) and anti-S specific T cells (F) *p < 0.05 **p < 0.001 ***p < 0.001.

Fig. 3

Autoreactive-specific immune responses following vaccination Anti-dsDNA IgG blood levels among SLE patients during follow-up. Box plot represents the median and the interquartile range of patients with detectable anti-dsDNA Ab at baseline [left-panel]. Points and lines represent the individual levels of each included patients at each visit [right-panel] (A). Complement fraction C3 and C4 blood level among SLE patients during follow-up. Points represents the mean and error bars the standard deviation (B). SLE disease activity measured by SLEDAI-2k during follow-up (C). Autoreactive anti-nuclear specific T cell activity among SLE patients and HV during follow-up defined as the percentages of activated (double positive CD154+/CD69+) cells among non-naïve CD4 T cells after stimulation with a pool of nuclear antigens. Time-associated slope is significantly negative in a linear mixed-effect model in the SLE group: (β for fixed-effect of time in the linear mixed-effect model = -0.00067, p=0.015). Points represented the mean and error bars the standard error of the mean (D).