Influenza virus hemagglutinin head–stem interface epitope (HA head–stem interface)

The influenza virus hemagglutinin (HA) head–stem interface epitope is a highly conserved, normally occluded antigenic site located at the junction of the globular head (HA1) and the stalk (HA2) domains (McCarthy et al., 2024). Unlike the immunodominant but highly variable regions of the HA head, this interface remains relatively invariant across diverse influenza A subtypes, including both Group 1 and Group 2 viruses (Bangaru et al., 2021). Antibodies targeting this epitope, such as the prototype S8V1-157, typically do not neutralize the virus in traditional in vitro assays because the site is hidden in the prefusion resting state of the HA trimer (McCarthy et al., 2024). However, they provide potent protection in vivo by engaging the epitope during transient conformational fluctuations or on the surface of infected cells, primarily through Fc-mediated effector functions like antibody-dependent cellular cytotoxicity (ADCC) (McCarthy et al., 2024; Bangaru et al., 2021). This epitope is a primary focus for the development of universal influenza vaccines and broadly neutralizing monoclonal antibody therapies aimed at providing long-lasting protection against seasonal drift and potential pandemic strains (McCarthy et al., 2024; PMC10760138).

Other names

HA head–stem junctionOccluded HA epitopeHA1–HA2 interface epitopeVestigial esterase domain (VED) interface

Binding to the conserved head–stem interface to trigger Fc-mediated effector functions, such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), and potentially inhibiting the conformational rearrangements required for viral-host membrane fusion (McCarthy et al., 2024; Bangaru et al., 2021).