[4] Additionally, HA is responsible for the fusion of the viral envelope with the late endosomal membrane once exposed to low pH (5.0–5.5).

[5] The name "hemagglutinin" comes from the protein's ability to cause red blood cells (i.e., erythrocytes) to clump together (i.e., agglutinate) in vitro.

[12] Neuraminidase has 11 known subtypes; hence, influenza viruses are named according to the combinations of HA and NA proteins expressed (e.g., H1N1 and H5N2).

The hemagglutinin of the H5N1 virus has been associated with its high degree of pathogenicity, apparently due to its ease of conversion to an active form by proteolysis.

[20] The HA trimer is synthesized as inactive precursor protein HA0 to prevent any premature and unwanted fusion activity and must be cleaved by host proteases in order to be infectious.

[citation needed] This so-called "fusion peptide" that was released as pH is lowered, acts like a molecular grappling hook by inserting itself into the endosomal membrane and locking on.

[26] Since hemagglutinin is the major surface protein of the influenza A virus and is essential to the entry process, it is the primary target of neutralizing antibodies.

This is because these antibodies bind near the top of the hemagglutinin "head" (blue region in figure above) and physically block the interaction with sialic acid receptors on target cells.

Therefore, antibodies targeting this region can block key structural changes that eventually drive the membrane fusion process, and therefore are able to achieve antiviral activity against several influenza virus subtypes.

Rodent and nonhuman primate models given the immunogen produced antibodies that could bind with HAs in many influenza subtypes, including H5N1.

[35] When the HA head is present, the immune system does not generally make bNAbs (broadly neutralizing antibodies).

[citation needed] A 2016 vaccine trial in humans found many broadly neutralizing antibodies targeting the stem produced by the immune system.