Influenza A virus hemagglutinin head domain lateral patch and non-receptor binding site epitopes (HA head LP/non-RBS)

The Influenza A virus hemagglutinin (HA) head domain lateral patch and non-receptor binding site (non-RBS) epitopes are conserved regions on the globular head of the HA protein, which is the primary surface glycoprotein of the influenza virus [1, 2]. While most neutralizing antibodies target the highly variable receptor-binding site (RBS) to block viral attachment, the lateral patch and other non-RBS sites, such as the trimer interface, remain relatively stable across different viral strains and subtypes [3, 4]. These epitopes have become focal points for the development of universal influenza vaccines and broadly neutralizing antibodies (bnAbs) that can provide protection against both seasonal drift and potential pandemic shifts [5, 6]. Antibodies targeting the lateral patch, such as CL6649 and H7.HK1, can neutralize the virus by disrupting the loops involved in receptor contact or by sterically hindering viral entry [1, 2]. Other non-RBS antibodies, like FluA-20, target occluded epitopes at the trimer interface and function by physically disrupting the integrity of the HA trimer [3]. Despite their potential, these sites are often immunosubdominant, meaning the immune system naturally favors the variable RBS, and some sites are only accessible during transient "breathing" of the HA protein [4, 5]. Therapeutic strategies aim to overcome these challenges by using immunogens designed to focus the immune response on these conserved "supersites of vulnerability" [1, 7].

Other names

Lateral patchHA head interfaceNon-RBS head epitopesVestigial esterase domain epitopesOccluded head epitopesTrimer interface epitopesHA1 lateral patch

Neutralization of viral infectivity by blocking viral entry, disruption of hemagglutinin trimer stability, and induction of antibody-dependent cell-mediated cytotoxicity (ADCC).