A human antibody reveals a conserved site on beta-coronavirus spike proteins and confers protection against SARS-CoV-2 infection

Abstract

Broadly neutralizing antibodies (bnAbs) to coronaviruses (CoVs) are valuable in their own right as prophylactic and therapeutic reagents to treat diverse CoVs and, importantly, as templates for rational pan-CoV vaccine design. We recently described a bnAb, CC40.8, from a coronavirus disease 2019 (COVID-19)-convalescent donor that exhibits broad reactivity with human beta-coronaviruses (β-CoVs). Here, we showed that CC40.8 targets the conserved S2 stem-helix region of the coronavirus spike fusion machinery. We determined a crystal structure of CC40.8 Fab with a SARS-CoV-2 S2 stem-peptide at 1.6 Å resolution and found that the peptide adopted a mainly helical structure. Conserved residues in β-CoVs interacted with CC40.8 antibody, thereby providing a molecular basis for its broad reactivity. CC40.8 exhibited in vivo protective efficacy against SARS-CoV-2 challenge in two animal models. In both models, CC40.8-treated animals exhibited less weight loss and reduced lung viral titers compared to controls. Furthermore, we noted CC40.8-like bnAbs are relatively rare in human COVID-19 infection and therefore their elicitation may require rational structure-based vaccine design strategies. Overall, our study describes a target on β-CoV spike proteins for protective antibodies that may facilitate the development of pan-β-CoV vaccines.

Broadly neutralizing antibodies target the coronavirus fusion peptide

“…Therefore, these sites are worth exploring as targets for novel COVID-19 vaccines and therapeutics that retain efficacy against new variants and protect against a wider range of coronaviruses. Progress in this direction has started with recent studies identifying several mAbs that target the conserved stem helix (12)(13)(14)(15)(16) and using unbiased approaches to screen for mAbs of interest (17)(18)(19)(20). Here we undertake a large-scale survey of the binding landscape of broadly reactive mAbs against coronaviruses.…”

Broadly neutralizing and protective nanobodies against diverse sarbecoviruses

“…Additional cross-neutralizing SARS-CoV-2 and SARS-CoV-1 antibodies targeting to other faces of RBD have also been identified such as those to the cliff face (S2H97 and 6D60), top face (S2X146), and outer face (S309 and BG10-19) (Figure S5). Recently, a human antibody with broad reactivity to human beta-coronaviruses has been isolated that targets the conserved S2 stem-helix, raising the possibility of development of pan-β-CoV therapies and vaccines 62 . More importantly, these cross-neutralizing and pan-β-CoV antibodies can be substantially boosted by mRNA vaccines, particularly in individuals with pre-existing SARS-CoV-1 or SARS-CoV-2 infection 63–65 .…”

Broadly Neutralizing Antibodies to SARS-CoV-2 Provide Novel Insights Into the Neutralization of Variants and Other Human Coronaviruses

“…One plausible reason behind this pattern might be the high immune selection pressure elicited by nAbs targeting these key regions during natural infection in the host or vaccinated individuals ( Garcia-Beltran et al., 2021 ). In contrast, no mutation is reported in the broadly conserved fusion peptide and stem-helix regions of the S2 domain of SARS-CoV-2 VOCs/VOIs ( Pinto et al., 2021 ; Dacon et al., 2022 ; Hurlburt et al., 2022 ; Zhou et al., 2022b ) ( Figure 1E ) which are also recognized by the host’s immune system during natural infection ( Wang et al., 2021 ). The sequence of the fusion peptide region is identical in all SARS-CoV-2 variants and highly conserved across human coronaviruses ( Dacon et al., 2022 ) ( Figure 1E ).…”

“…Interestingly, a rare class of nAbs (e.g. S2P6, CV3-25, and CC40.8) targeting the pan-β-CoVs conserved hydrophobic regions (stem-helix region) involved in the fusion machinery neutralizes not only all SARS-CoV-2 variants but also pan-β-CoVs ( Pinto et al., 2021 ; Zhou et al., 2022b ; Hurlburt et al., 2022 ). Though these stem-helix specific nAbs neutralize pan-β-CoVs at a higher concentration (IC 50 >1μg/ml), these bnAbs have shown in vivo protective efficacy at low-dose against all 3 major human infecting coronaviruses that include SARS-CoV, MERS-CoV and SARS-CoV-2 ( Zhou et al., 2022a ) suggesting antibody effector functions via their Fc-region may be playing a role in virus clearance.…”