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TitleThe buried S2 apex of SARS-CoV-2 spike elicits an immunodominant germline-restricted public antibody response.
Journal, issue, pagesbioRxiv, Year 2026
Publish dateFeb 19, 2026
AuthorsSuncheol Park / Jacob Mischka / Nisreen Okba / Anass Abbad / Meng Yuan / Komal Srivastava / Charles Gleason / Lubbertus C F Mulder / Jeffrey Copps / Katrina Saam / Sandhya Bangaru / Florian Krammer / Ian A Wilson / Viviana Simon / Andrew B Ward
PubMed AbstractThe continued mutational pressure on the SARS-CoV-2 S1 subunit underscores the need to target the conserved S2 region for pan-coronavirus vaccine development. A detailed molecular understanding of S2- ...The continued mutational pressure on the SARS-CoV-2 S1 subunit underscores the need to target the conserved S2 region for pan-coronavirus vaccine development. A detailed molecular understanding of S2-directed immune responses is therefore essential. In this study, we identified the S2 apex as the most immunodominant epitope within the S2 subunit, eliciting robust antibody responses despite occlusion by S1, using electron-microscopy-based polyclonal epitope mapping (EMPEM) of plasma from infected and vaccinated individuals. Structure-guided sequence analysis with antibody databases revealed that antibodies targeting a poorly characterized S2 Apex-B site form a convergent public clonotype, which is predominantly derived from the IGHV3-30 germline with a 14-residue CDRH3 containing a G/S-G-S/N-Y motif. This clonotype is extensively expanded, accounting for up to 40% of total spike-reactive antibody sequence counts in individual vaccinated donors. This study elucidates the molecular basis the high-frequency elicitation of this non-neutralizing clonotype emphasizing that its immunodominance acts as a primary hurdle for universal coronavirus vaccines and underscore the need for precision antigen design to redirect immunity toward more potent neutralizing targets.
External linksbioRxiv / PubMed:41756886 / PubMed Central
MethodsEM (single particle)
Resolution2.75 - 24.0 Å
Structure data

EMDB-73884, PDB-9z80:
SARS-CoV-2 S2 in complex with polyclonal Fab_Donor1
Method: EM (single particle) / Resolution: 3.17 Å

EMDB-74737, PDB-9zt5:
SARS-CoV-2 S2 in complex with polyclonal Fab-B_Donor3
Method: EM (single particle) / Resolution: 3.21 Å

EMDB-74738, PDB-9zt6:
SARS-CoV-2 S2 in complex with polyclonal Fab-B_Donor8
Method: EM (single particle) / Resolution: 2.83 Å

EMDB-74739, PDB-9zt7:
SARS-CoV-2 S2 in complex with COV2-2509
Method: EM (single particle) / Resolution: 3.11 Å

EMDB-74740, PDB-9zt8:
Stabilized SARS-CoV-2 S2 apo
Method: EM (single particle) / Resolution: 2.75 Å

EMDB-75193: SARS-CoV-2 spike S2 subunit in complex with polyclonal Fabs (Apex-A epitope)
Method: EM (single particle) / Resolution: 22.0 Å

EMDB-75194: SARS-CoV-2 spike S2 subunit in complex with polyclonal Fabs (Apex-B epitope)
Method: EM (single particle) / Resolution: 24.0 Å

EMDB-75295, PDB-10mu:
SARS-CoV-2 S2 in complex with polyclonal Fab_Donor2
Method: EM (single particle) / Resolution: 3.16 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • severe acute respiratory syndrome coronavirus 2
KeywordsVIRAL PROTEIN/Immune System / SARS-CoV-2 / Coronavirus / Immune system / antibody / VIRAL PROTEIN / VIRAL PROTEIN-Immune System complex / VIRUS

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