Biology subjects

Wittenborn, L. E.

Publications and source records attributed to Wittenborn, L. E..

2 recordsLinked to original sources

bioRxiv2025

Structure basis for distinct protective mechanisms of IGHV3-23 antibodies targeting influenza hemagglutinin stem

Characterization of antibodies targeting the conserved stem domain of influenza hemagglutinin (HA) is critical for developing broadly protective countermeasures against influenza virus. From a phage display human antibody library, this study discovers three group 1 HA-specific stem antibodies, namely HB31, HB34, and HB315, all of which are encoded by IGHV3-23. While HB31 and HB34 have minimal neutralization activity in vitro, their Fc-mediated effector functions lead to better in vivo protection than the potently neutralizing HB315. Consistently, cryo-EM analysis suggests that HB31 and HB34 have a higher Fc accessibility than HB315, based on their epitopes and approaching angles. HB31 and HB34 engage a pocket in the upper HA stem that is rarely targeted by known HA stem antibodies, whereas the epitope of HB315 involves the lower stem. Overall, our findings provide insights not only into the structure-function relationship of HA stem antibodies, but also into the design of next-generation influenza therapeutics.

immunology↗

bioRxiv2025

Evolution of antibody cross-reactivity to influenza H5N1 neuraminidase from an N2-specific germline

The ongoing spread of highly pathogenic avian influenza H5N1 clade 2.3.4.4b virus in animals and its occasional spillover to humans have raised concerns about a potential H5N1 pandemic. Although recent studies have shown that pre-existing human antibodies can recognize H5N1 neuraminidase, the molecular basis of how this cross-reactivity develops remains poorly understood. In this study, we used a phage display antibody library derived from 245 healthy donors to isolate an antibody, HB420, that cross-reacts with neuraminidases of human H3N2 and avian H5N1 clade 2.3.4.4b viruses and confers protection in vivo. Cryo-EM analysis reveals that HB420 targets the neuraminidase active site by mimicking sialic acid binding through a single Asp residue. Furthermore, the inferred germline of HB420 is N2-specific but acquires cross-reactivity to H5N1 neuraminidase through somatic hypermutation. Overall, our findings provide insights into how neuraminidase antibody evolves breadth, which has important implications for the development of broadly protective influenza vaccines.

immunology↗