Engineered Immunogens to Elicit Antibodies Against Conserved Coronavirus Epitopes

Abstract

Immune responses to SARS-CoV-2 primarily target the receptor binding domain of the spike protein, which can readily mutate to escape acquired immunity. Other regions in the spike S2 subunit, such as the fusion peptide and the stem helix, are highly conserved across sarbecoviruses and recognized by broadly reactive antibodies, providing hope that targeting these epitopes by vaccination could offer protection against both current and emergent viruses. Here we employed computational modeling to design epitope scaffolds that display the fusion peptide and the stem helix epitopes. The engineered proteins bound both mature and germline versions of multiple broad and protective human antibodies with high affinity. Binding specificity was confirmed both biochemically and via high resolution crystal structures. Finally, the epitope scaffolds showed potent engagement of antibodies and memory B-cells from subjects previously exposed to SARS-CoV2, illustrating their potential to elicit antibodies against the fusion peptide and the stem helix by vaccination.

SARS-CoV-2 Omicron XBB lineage spike structures, conformations, antigenicity, and receptor recognition

“…Structural modeling showed that the epitopes of the fusion peptide targeting antibodies DH1058.1 and DH1294, and stem helix targeting antibody DH1057.1, are not fully accessible for antibody binding on the pre-fusion SARS-CoV-2 S protein (Gobeil et al, 2022, Kapingidza et al, 2023). Despite this, measurable binding of the SARS-CoV-2 S protein to these antibodies can be observed by SPR and ELISA, suggesting antibody-induced local refolding of the S protein structure to expose the antibody eptiopes.…”

“…Having a more durable RBD may bode well for the current booster. Additionally, compared to the other Omicron variants tested, the XBB.1.5 S protein showed increased antibody accessibility to subdominant S2 subunit epitopes, particularly at the stem helix region, which may better enable elicitation of potentially protective antibodies that target these regions (Pinto et al, 2021, Kapingidza et al, 2023).…”

A library-on-library screen reveals the breadth expansion landscape of a broadly neutralizing betacoronavirus antibody

“…While S2P6 neutralizes antigenically distinct betacoronavirus (β-CoV) strains including SARS-CoV-2, antibody binding data suggest that it arose in response to HCoV-OC43 infection and gained cross-reactivity to other β-CoV strains via SHMs 10 . Given that stem helix peptide is a target for the development of broadly protective coronavirus vaccines 35 , it is important to understand the evolutionary trajectories that lead to breadth expansion of bnAbs to the stem helix peptide.…”