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Tweaking influenza’s sugar attachment

Published online 7 February 2020

Scientists are investigating whether changes to the position of a sugar molecule on the influenza virus could lead to improved flu vaccines.

Letizia Diamante

Cryo-electron microscopy model of the engineered HA stem nanoparticle. The nanoparticle core appears in teal, while the HA stems appear in maroon.
Cryo-electron microscopy model of the engineered HA stem nanoparticle. The nanoparticle core appears in teal, while the HA stems appear in maroon.
VRC, NIAID
A specific change in the position of a sugar molecule on the surface of the influenza virus alters the immune response in mice. The finding provides new insights into the role of this sugar in conferring immunity against influenza, and could lead to new tools in vaccine design. 

Hemagglutinin (HA) is a glycoprotein, comprising a head and a stem, which is attached to the surface of influenza viruses. It mediates viral attachment to, and infection of, target cells. 

Current influenza vaccines focus on triggering the production of neutralizing antibodies against the HA head region, but must be updated every winter since the head mutates rapidly as viruses evolve. In contrast, the HA stem is highly conserved across multiple strains of influenza virus, and is thus a promising target for a universal vaccine.

 Hemagglutinin is classified into two groups, with one of the main differences being the position of a sugar molecule, called glycan, bound to its stem. Little is known, however, how this difference affects the immune response. 

Scientists at the National Institutes of Health, USA, in collaboration with a researcher at Qatar University, prepared nanoparticles coated with mutated influenza A virus H1N1 HA stems, where the stem belonged to group 1 HA, but with a glycan attached as in group 2 HA. This variant could bind to antibodies that recognize group 2 HAs, but was unable to bind to group 1-specific broadly neutralizing antibodies. 

45% of mice immunized with the new nanoparticles survived infection with H7N9 influenza A virus, which has group 2 HA; whereas only 5-10% of mice survived when they were immunized with nanoparticles covered with unmodified group 1 HA stems. Antibodies collected from the blood of mice immunized with the new nanoparticles were injected prophylactically into mice that had never been exposed to influenza viruses. This conferred protection to the unexposed mice against H7N9.

“We were pretty surprised initially to observe such clear immunological differences between the unmodified and the glycan-modified HA stem nanoparticles,” say Masaru Kanekiyo and Barney S. Graham of the Vaccine Research Center at the US National Institute of Allergy and Infectious Diseases.

“The position of sugar molecules is currently not considered in vaccine design, but this work shows that it is a critical determinant of adaptive immunity against seasonal influenza,” says virologist, Yohei Yamauchi of the University of Bristol, UK, who was not involved in this study.

The researchers are now looking into alternative options to regain the lost immunity against group 1 HA with their engineered nanoparticles.

doi:10.1038/nmiddleeast.2020.23


Boyoglu-Barnum, S. et al. Glycan repositioning of influenza hemagglutinin stem facilitates the elicitation of protective cross-group antibody responses. Nat. Commun. 11, 791 (2020).