Structural and biochemical insights into HCV envelope proteins for germline-targeting vaccines.

GL-reverted VH1-69 bnAbs recognize the E2 core domain in a manner similar to mature Abs, revealing conserved epitope engagement prior to affinity maturation.

• Why it matters: Understanding germline recognition is crucial for designing effective HCV vaccines that elicit broadly neutralizing antibodies, addressing the challenge of immune response bias.
• What they did: Researchers determined high-resolution structures of GL-reverted VH1-69 bnAbs bound to E2, engineered E2 variants to improve GL Ab interactions, and tested their engagement with naive B cells.
• The result: Enhanced E2 variants increased affinity but did not improve naive B cell engagement, indicating a key constraint in GL-targeting strategies and guiding future vaccine design principles.