National Academy of Sciences, Proceedings of the National Academy of Sciences, 6(119), 2022
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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.