Viral Proteins Can Be Inhibited by Anti-Flu Antibodies

The basis of a universal flu vaccine may be formed by antibodies that inhibit a second viral protein as well as the 1 that they bind, according to a team of National Institutes of Health (NIH) investigators.

Furthermore, the viral neuraminidase can be inhibited by antibodies that recognize the viral surface protein hemagglutinin, which can enhance antibody neutralization of the virus and the activation of innate immune cells with anti-viral activity.

"Hemagglutinin stem-specific antibodies are perhaps the most promising approach for improving the duration and effectiveness of influenza vaccination," the authors wrote. "It is therefore critical to better understand how anti-stem antibodies provide protection from the virus."

Located on the surface of the influenza virus, hemagglutinin and neuraminidase are yin-yang proteins. While neuraminidase is an enzyme that releases budding progeny virions from the cell surface that remain attached from the hemagglutinin binding, hemagglutinin mediates virion attachment and fusion with host cell membranes.

Consisting of a head domain that contains the receptor binding site that attaches to host cell membranes, hemagglutinin also connects a stem domain that links the head to the virion membrane. Currently, antibodies that recognize the hemagglutinin head are induced, which prevent its ability to mediate viral entry.

To escape existing antibodies, the hemagglutinin head experiences rapid mutation. Consequently, this creates vaccine-resistant strains of the influenza virus annually, which in turn creates the “yearly mad dash” to formulate a matched vaccine.

In contrast, the hemagglutinin stem domain is much more resistant to mutations, which supplies a target for universal flu vaccines. Dozens of studies in animal models have shown this.

By inhibiting hemagglutinin cell fusion activity, stem-binding antibodies can block viral entry into host cells. However, they also disrupt the release of newly replicated virions via blockages of neuraminidase molecules that are close to hemagglutinin on the virion.

The ability of anti-stem antibodies to inhibit neuraminidase enabled animals to better survive a severe influenza infection have been shown in mice experiments. This effect may be significantly due to the role that neuraminidase normally plays in preventing the activation of innate immune cells with anti-viral activity, according to Yewdell and colleagues.

Additionally, investigators found the neuraminidase inhibitor oseltamivir (Tamiflu), which is approved by the US Food and Drug administration (FDA), further supports the idea since the medication boosts the ability of anti-stem antibodies to activate immune cells exposed to the influenza virus.

“Studying how anti-HA antibodies interfere with NA function, we found a trick to enable us to modulate the magnitude of the effect: changing the length of the stalk that supports the NA functional domain,” Yewdell told MD Magazine®. “This enabled us to show that protection in mice depends on stem length which in turn implicates blocking NA as a critical feature of anti-stem antibody immunity.”

Looking forward, Yewdell plans to determine which innate immune cell subsets participate in stem antibody protection in mice. These could be various types of natural killer cells, macrophages, dendritic cells. He hopes to eventually extend the findings to humans, but this is much easier written than achieved.