Universal stabilization of the influenza hemagglutinin by structure-based redesign of the pH switch regions

Abstract

Significance Influenza hemagglutinin (HA) is a prototypical class I fusion protein and a major component of current flu vaccines. HA is a metastable glycoprotein and undergoes conformational changes to the so-called postfusion state. Stabilization of the prefusion conformations of fusion proteins has proven to be a key success factor for the induction of efficacious immune response and stabilization has become a grand challenge in structural vaccinology. The study shows that three stabilizing mutations in two important pH-sensitive switch regions involved in the early refolding process impede refolding of the prefusion HA. Based on the substitutions of these highly conserved and buried HA residues a generally applicable stabilization strategy for all subtypes of group 1 and 2 influenza A HA was developed.