IgM antibodies derived from memory B cells are potent cross-variant neutralizers of SARS-CoV-2

Abstract

Humoral immunity to SARS-CoV-2 can be supplemented with polyclonal sera from convalescent donors or an engineered monoclonal antibody (mAb) product. While pentameric IgM antibodies are responsible for much of convalescent sera’s neutralizing capacity, all available mAbs are based on the monomeric IgG antibody subtype. We now show that IgM mAbs derived from immune memory B cell receptors are potent neutralizers of SARS-CoV-2. IgM mAbs outperformed clonally identical IgG antibodies across a range of affinities and SARS-CoV-2 receptor-binding domain epitopes. Strikingly, efficacy against SARS-CoV-2 viral variants was retained for IgM but not for clonally identical IgG. To investigate the biological role for IgM memory in SARS-CoV-2, we also generated IgM mAbs from antigen-experienced IgM+ memory B cells in convalescent donors, identifying a potent neutralizing antibody. Our results highlight the therapeutic potential of IgM mAbs and inform our understanding of the role for IgM memory against a rapidly mutating pathogen.

Dynamics of SARS-CoV-2 VOC neutralization and novel mAb reveal protection against Omicron

“…We identified that a previously described human Mab, Mab297 (Hale et al, 2022; Rodda et al, 2021), effectively neutralizes Omicron variants BA.1 and Omicron BA.2, the Delta variant, and the ancestral SARS-CoV-2/WA-1. In our assays, the single antibody performed better than the Regeneron REGN10987/10933 mAB cocktail comprised of two different Mabs that do not neutralize these Omicron variants.…”

“…In fact, we found that the ND values from the Omicron BA.1 PRNT 50 assay were increased by approximately 54-fold when comparing sera from 2-dose versus 3-dose vaccine regimen. These observations demonstrate that vaccine boost delivers a significant and functional enhancement in protective antibody levels against both Omicron BA.1 and ancestral virus infection in boosted persons.We identified that a previously described human Mab, Mab297(Hale et al, 2022;Rodda et al, 2021), effectively neutralizes Omicron variants BA.1 and Omicron BA.2, the Delta variant, and the ancestral SARS-CoV-2/WA-1. In our assays, the single antibody performed better than the Regeneron REGN10987/10933 mAB cocktail comprised of two different Mabs that do not neutralize these Omicron variants.…”

Acute and long-term immune responses to SARS-CoV-2 infection in unvaccinated children and young adults with inborn errors of immunity

“…This is not surprising since >50% of IEI patients in our cohort suffered from a humoral or combined underlying immunodeficiency. This may mean that the immediate protection against a reinfection is weaker in such patients with lower levels of seroprotection, not only for IgG but also for IgM, whose role in protecting against reinfection or crossreactivity against other SARS-CoV-2 variants has been described (76). Nevertheless, and prior to vaccination, only 2 patients were reinfected.…”

The response to BTN62b2 booster doses demonstrates that serum antibodies do not predict the establishment of immune B-cell memory in common variable immune deficiencies

“…The frequency and function of peripheral IgM MBCs are predictive of the T-independent response to polysaccharide vaccines and clinical outcomes 6,39 and, as confirmed here, in the absence of IgM MBCs, patients with CVIDs have a more severe disease with a significantly higher frequency of chronic lung disease and immune dysregulation 39 . Moreover, IgM MBCs may play a crucial role in COVID-19, as monoclonal antibodies derived from IgM MBCs from patient's convalescent from the infection with the Wuhan virus are potent neutralizers not only for the wild-type strain, but also for its emerging viral variants 38 . Similarly, antibodies derived from IgM MBCs were able to neutralize the H1N1 influenza virus to which the donor had never been exposed 61 .…”

“…In control individuals, IgM MBCs with low affinity for the viral spike protein serve as substrates for the generation of high-affinity MBCs that are class-switched and are mainly of the IgG isotype 25,37 . Recently, it has been suggested that antibodies produced by IgM MBCs may play an important role in the defense against SARS-CoV-2, as demonstrated by the potent neutralizing activity of IgM monoclonal antibodies cloned from MBCs of individual convalescent from COVID-19 38 .…”