Turning off the pH-switch for improved influenza vaccine production

What is it about?

Flu vaccines generally rely on the expression of a conformationally correct pre-fusion trimer form of the Influenza Hemagglutinin (HA) protein to induce an effective immune response, and the success of such vaccines is hampered by HA’s unstable quaternary structure and low expression levels. In order to stabilize HA’s pre-fusion trimer form, Fin J. Milder et al. targeted its pH-sensitive regions that initiate HA’s conformational changes to its post-fusion state. They found that trimeric HA could be stabilized by substitution of three residues within two pH sensitive regions—H26W in pHS1 and K51I + E103I in pHS2—and used X-ray crystallography to show how these substitutions stabilized the pre-fusion trimer and impeded its refolding. The researchers found that this stabilization strategy was broadly applicable to a wide range of group 1 and 2 influenza A HAs, including from potentially pandemic strains, when combined with occasional “repair” of rare amino acids, a process where these amino acids were mutated back to subtype consensus. The authors suggest that the identification of this stabilization and repair approach that is generally applicable to all group 1 and 2 influenza A HA trimers could potentially help improve the development and efficacy of influenza vaccines.

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Why is it important?

Stabilization and repair of Influenza Hemagglutinin (HA) is generally applicable to all group 1 and 2 influenza A HA trimers could potentially help improve the development and efficacy of influenza vaccines.

Perspectives