Broadly neutralizing antibodies target the coronavirus fusion peptide

Abstract

The potential for future coronavirus outbreaks highlights the need to develop strategies and tools to broadly target this group of pathogens. Here, using an epitope-agnostic approach, we identified six monoclonal antibodies that bound to spike proteins from all seven human-infecting coronaviruses. Epitope mapping revealed that all six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. Two antibodies, COV44-62 and COV44-79, broadly neutralize a range of alpha and beta coronaviruses, including SARS-CoV-2 Omicron subvariants BA.1 and BA.2, albeit with lower potency than RBD-specific antibodies. In crystal structures of Fabs COV44-62 and COV44-79 with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine at the S2' cleavage site. Importantly, COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings identify the fusion peptide as the target of the broadest neutralizing antibodies in an epitope-agnostic screen, highlighting this site as a candidate for next-generation coronavirus vaccine development.

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 ).…”

“…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 ). NAbs targeting these two regions block fusion machinery by preventing S2 domain refolding from the pre- to the post-fusion state.…”

“…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. Lastly, clinical evaluation is awaited for recently identified a new class of conserved fusion peptide-directed antibodies (COV44-62 and COV44-79) with the broadest neutralization potential against both α-CoVs and β-CoVs ( Dacon et al., 2022 ).…”

“…Dacon et. al., screening identified only 2% of 211 mAbs showed broad reactivity to at least two other non-SARS β-CoVs, suggesting that frequency of fusion peptide targeted mAbs are lower than stem-helix mAbs ( Dacon et al., 2022 ). Overall, these studies suggest that nAb cocktails that include relatively conserved least mutated RBD regions, fusion peptides, and stem-helix regions targeting nAbs could be effective against evolving SARS-CoV-2 variants and human coronavirus outbreaks that may arise in the future.…”

Omicron BA.2 Lineage, the “Stealth” Variant: Is It Truly a Silent Epidemic? A Literature Review

“…These mAbs target the fusion peptide region, which plays a critical role during coronavirus invasion, has an identical sequence in all SARS-CoV-2 VOCs, and is highly conserved. However, these mAbs have a significantly low in vitro neutralization potency that may be due to their relatively weak binding to the intact spike, which is enhanced only when the S1 cap is removed [57]. Many analyses are currently under revision, and one of them states that LY-CoV1404 (also known as bebtelovimab) displays potent neutralizing activity against numerous variants, including the BA.2 subvariant, as it retains binding activity to the spike proteins despite several underlying RBD mutations (K417N, L452R, E484K, and N501Y) [58].…”