LAUSR

The immunogenicity of severe acute respiratory syndrome coronavirus2 (SARSCoV2) spike mRNAcontaining lipid nanoparticles (LNPs) vaccines (such as BNT162b2 and mRNA1273) has been extensively studied. It was found that following BNT162b2 or mRNA1273 vaccination, injected mRNALNPs are incorporated by dendritic cells (DC). These DC traffic to the draining lymph nodes where they present SARSCoV2 spike antigens and prime CD4 and CD8 T cells. Primed CD4 T cells then differentiate into either Type 1 Thelper cells (Th1) or T follicular helper (Tfh) spikespecific T cells. These Tfh play a pivotal role by initiating and maintaining strong germinal centre reactions, which eventually lead to the generation of spikespecific memory B cells and of longlived plasma cells, resulting in the secretion of binding and neutralising antibodies (Abs) against the spike protein. It should be noted that this germinal centre formation is enhanced by LNPs which, in addition to their role of carrier, act as a strong adjuvant. Regulatory T cells (Tregs) are key regulators of immune reactions. These CD4 T cells are characterised by the constitutive expression of the transcription factor forkhead box protein 3 (FoxP3) and the interleukin (IL)2 receptor α chain CD25. However, they have a low expression of the IL7 receptor CD127. Previous work on the impact of Tregs on vaccination showed that a subset of Tregs, termed follicular regulatory T cells (Tfr) regulate Tfh cells and control unspecific growth of the germinal centre response during a T celldependent immune reaction. Further, in the absence of adjuvants, transient Tregs depletion favours DC maturation in the draining lymph nodes after immunisation with the SARSCoV2 spike antigen. This results in the production of spikespecific CD4 and CD8 T cells producing interferongamma. However, there is only limited data on the impact of Tregs on mRNALNPs vaccine immunogenicity. Indeed, systems biology (i.e. multiomics) analyses did not observe an induction of Tregs following BNT162b2 vaccination, although higher levels of phosphorylated signal transducer and activator of transcription 1 (pSTAT1) and pSTAT3 in Tregs were observed 1 day after the second vaccine administration. In addition, no correlations were found between baseline Treg counts and Ab response to BNT162b2 vaccination in allogeneic haematopoietic stem cell transplant recipients while positive correlations were observed with memory B cells, naive CD4 T cells and Tfh cell counts. In comparison to healthy controls, patients with multiple myeloma (MM) have a lower serological response to SARSCoV2 mRNA vaccine. This is particularly true in patients given Bcell maturation antigen (BCMA)targeted therapies and in those given the antiCD38 monoclonal Ab (mAb). CD38 is a transmembrane glycoprotein that is highly expressed on MM cells as well as on normal plasma cells. It is thus not unexpected that antiCD38 mAb affect serological response to mRNA vaccines. AntiCD38 mAbs have additional immunomodulatory effects by depleting CD38 Treg cells, known to be more immunosuppressive than the CD38 Treg, and eliminating regulatory Band myeloidderived suppressor cells. In addition, Tfr (and particularly programmed cell deathprotein 1 [PD1] Tfr) express high levels of CD38, suggesting that their destruction by Received: 11 February 2022 | Accepted: 14 February 2022