Structural basis for cross-group recognition of an influenza virus hemagglutinin antibody that targets postfusion stabilized epitope

Plasticity of influenza virus hemagglutinin (HA) conformation increases an opportunity to generate conserved non-native epitopes with unknown functionality. Here, we have performed an in-depth analysis of human monoclonal antibodies against a stem-helix region that is occluded in native prefusion yet exposed in postfusion HA. A stem-helix antibody, LAH31, provided IgG Fc-dependent cross-group protection by targeting a stem-helix kinked loop epitope, with a unique structure emerging in the postfusion state. The structural analysis and molecular modeling revealed key contact sites responsible for the epitope specificity and cross-group breadth that relies on somatically mutated light chain. LAH31 was inaccessible to the native prefusion HA expressed on cell surface; however, it bound to the HA structure present on infected cells with functional linkage to the Fc-mediated clearance. Our study uncovers a novel non-native epitope that emerges in the postfusion HA state, highlighting the utility of this epitope for a broadly protective antigen design. Author summaryInduction of broadly protective antibodies is a clue to combat the antigenic variation of influenza virus. In this context, directing the antibody specificity toward the conserved hemagglutinin (HA) epitopes is a rational approach; however, it is hampered by virus strategies to hide the vulnerable sites. Here, we show a novel non-native epitope that emerges in the postfusion HA state with unique structure, denoted as kinked loop-helix. Antibody toward this epitope is accessible to HA on infected cells, demonstrating an exposure of the vulnerable sites during viral replication. In-depth structural analysis uncovers how antibody adapts to the conserved non-native epitope and provide cross-group protection, with an implication to rational design of broadly protective immunogens.

Automated summary

This study analyzed human monoclonal antibodies against a stem-helix region in influenza virus hemagglutinin (HA), which is concealed in the native prefusion state but exposed in the postfusion state. The LAH31 antibody showed cross-group protection by targeting a unique kinked loop epitope in the postfusion state. Structural analysis revealed key contact sites responsible for the epitope specificity and cross-group breadth. This study uncovered a non-native epitope in the postfusion state, highlighting its potential for broadly protective antigen design.