Influenza virus hemagglutinin (HA) stem (HA stem)

Influenza virus hemagglutinin (HA) is a critical class I fusion glycoprotein located on the viral surface, responsible for mediating host cell entry by binding to sialic acid receptors and facilitating membrane fusion (Krammer & Palese, 2013, Nature Reviews Drug Discovery). The HA molecule is structurally divided into a highly variable globular head and a more conserved stem (or stalk) region. While traditional seasonal vaccines primarily elicit antibodies against the head to block attachment, the HA stem is the focal point for developing "universal" influenza vaccines due to its high sequence conservation across diverse Influenza A and B subtypes (Erbelding et al., 2018, Journal of Infectious Diseases). Antibodies targeting the HA stem typically neutralize the virus by sterically inhibiting the pH-induced conformational changes required for the fusion of the viral envelope with the endosomal membrane (Corti et al., 2011, Science). Furthermore, these stem-directed antibodies often engage immune effector cells via their Fc regions to induce antibody-dependent cellular cytotoxicity (ADCC), providing an additional layer of protection (DiLillo et al., 2014, Nature Medicine). Broadly neutralizing antibodies, such as CR9114, have demonstrated the potential for cross-lineage protection against both Influenza A and B viruses by targeting this conserved region (Dreyfus et al., 2012, Science). Consequently, the HA stem is a high-priority target for therapeutic monoclonal antibodies and next-generation vaccines aimed at providing broad and durable protection against influenza.

Other names

Hemagglutinin stalkHA stalk domainHA2 subunitConserved HA stem epitopeHA stalk

Inhibition of the pH-triggered conformational change of the hemagglutinin protein, which prevents the fusion of the viral envelope with the host endosomal membrane (Corti et al., 2011, Science). Some antibodies also block the proteolytic cleavage of the HA0 precursor into HA1 and HA2 subunits. Additionally, stem-directed antibodies often mediate protection through Fc-receptor-dependent mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) (DiLillo et al., 2014, Nature Medicine).