Defining the Antigenic Topology and Prospective Binding Breadth of Vaccination-induced SARS-CoV-2 Neutralizing Antibodies

Early plasmablast-derived human monoclonal antibodies from primary mRNA vaccination show potent spike RBD/NTD neutralization, but variant-associated mutations more often impact antibodies to immunodominant regions than those targeting a conserved NTD hydrophobic pocket.

• Why it matters: Viral evolution continually challenges how broadly vaccine-elicited neutralizing antibodies can recognize and inhibit emerging SARS-CoV-2 variants, despite prior epitope maps from structural studies.
• What they did: The study structurally and functionally characterized a panel of early plasmablast-derived monoclonal antibodies using cryo-electron microscopy, variant-binding analyses, and viral-fusion inhibition assays, focusing on antibodies to RBD and NTD.
• The result: Antibodies to immunodominant RBD/NTD regions are linked to higher escape sensitivity, while conserved NTD hydrophobic-pocket antibodies show broader reactivity and neutralize via distinct mechanisms, informing which structural features may better withstand variant evolution.

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