CVR - Coronavirus Vaccines R&D Roadmap

Milestone
2.3.a

Spike protein epitopes

In progress
High priority

Identify epitopes other than the RBD area of the Spike protein that generate protective humoral immunity and are conserved across virus types.

Progress Highlights

See CVR Scholar Hub page: Broadly Conserved Coronavirus Epitopes

S1 subunit outside of the RBD (N-terminal domain, NTD)

Conserved across SARS-CoV-2 variants.

Antibodies targeting the NTD can block viral entry and enhance Fc-mediated effector functions.

S1 subunit outside of the RBD (Subdomain 1, SBD)

Conserved across SARS-Cov-2 variants; important for stabilizing the overall conformation of the spike protein when in the perfusion state. Antibodies targeting RBD reduce the conformational flexibility of the spike protein.

S1 subunit upstream of the furin cleavage site

Conserved region in sarbecoviruses that may regulate spike cleavage, and generates a strong IgG response.

S2 subunit (fusion peptide)

Highly conserved across all betacoronaviruses; critical for virus-cell membrane fusion.

Antibodies targeting this S2 region can block membrane fusion and viral entry into host cells.

S2 subunit (fusion loop) 

Broader epitope region than fusion peptide that is conserved 62-98% across human coronaviruses, but highly conserved across SARS-CoV-2 variants. Similar mechanism to fusion loop antibodies (preventing viral fusion and entry

S2 subunit (heptad repeat 1, HR1)

Conserved across SARS-CoV-2 variants, with high sequence similarity in SARS-CoV-1 and MERS-CoV.

Antibodies targeting HR1 can block conformational changes required for membrane fusion

S2 subunit (heptad repeat 2, HR2)

More moderately conserved than HR1. 

Antibodies targeting HR2 inhibit the formation of the six-helix bundle that is necessary for fusion.

S2 subunit (stem helix)

Conserved across all coronaviruses

Antibodies targeting the Stem Helix can prevent fusion and entry.

S2 subunit (upstream helix)

Highly conserved across SARS-CoV-2 variants, moderately conserved across betacoronaviruses 

Antibodies targeting the Upstream Helix can block conformational changes, locking the spike protein in its pre-fusion conformation.

S2 subunit (fusion peptide proximal region, FPPR)

Adjacent to the Fusion Peptide, and conserved across SARS-Cov-1 variants and other coronaviruses, including SARS-CoV-1 and MERS-CoV

Antibodies targeting FPPR prevent conformational changes of the spike protein required for fusion and viral entry. Especially strong binding affinity when combined with Fusion Peptide-targeting antibodies

S2 subunit downstream of the furin cleavage site with downstream function

Conserved across sarbecoviruses. Generates broadly protective IgG response. 

S2 subunit (hinge region connecting HR1 and the central helix)

Conserved across SARS-CoV, MERS-CoV, HCoV-OC43, and HCoV-HKU1. 

Antibody binding to the hinge region prevents viral entry through an Fc-mediated response.

S2 subunit (engineered stabilized stem) 

Hsieh 2024 created a stabilized S2 stem construct for vaccination that provided potent neutralization across multiple sarbecoviruses.