"Breathing" Hemagglutinin Reveals Cryptic Epitopes for Universal Influenza Vaccine Design

Abstract

A universal vaccine against influenza remains a critical target, and efforts have recently focused on the stem of the hemagglutinin glycoprotein. In this issue of Cell and a related Cell Host & Microbe article, three studies identify broad protective epitopes in the hemagglutinin head domain that are exposed by trimer "breathing."

Figure 1

The Cryptic Epitopes Exposed by Virus “Breathing” (A) The occluded epitope on influenza HA. Canonically, three HA molecules form a compact trimer as one unit on the virus surface (left). In the studies discussed here, the “breathing” of the HA trimer exposes a concealed epitope by breathing, which can be recognized by protective antibodies. The HA molecules are displayed in surface representation. The HA1 molecules are colored in white, pink, and pale blue, while the HA2 molecules are colored in gray. The epitope is presented by the representative structure of targeting HA-interfaced antibody-HA complex (H3-S5V2-29). The antibody heavy chain and light chain are colored in marine and pale blue, respectively. The conserved epitopes among the antibodies in the three papers are shown in green, the conserved epitopes among human antibodies are colored in orange, and the epitope of S5V2-29 is colored in deep purple. (B) The epitopes of a representative RBS-targeted antibody (C05, PDB 4FQR), cross-binding of group 1 and group 2 HA stem antibody (CT-149, PDB: 4UBD), binding within group 1 HA stem (CR6261, PDB: 3GBM), and binding within group 2 HA stem (AF4H1K1, PDB: 5Y2L) are colored in red. (C) The envelope glycoproteins (E proteins) on mature and immature DENV display different conformations. E dimers are observed on the mature DENV, while E trimers are presented on immature DENV particles. The exposed epitope can be recognized by breathing envelope glycoproteins on DENV. Several antibodies recognized the cryptic epitope on E proteins have been identified (1A1D-2, 4E11, 2H12, E111, and 3E31), and we take 1A1D-2 as an example to show the hidden epitope on the DENV particle. The E proteins are displayed by surface representation, with domains I, II, and III in red, yellow, and blue, respectively. The heavy chain and light chain of antibody 1A1D-2 are colored in green and cyan. The structure of mature particle and breathing DENV are based on PDB: 3J27 and 2R6P, respectively. (D) The structures of E protein dimer on mature and breathing DENV particles and the 1A1D-2-E complex, with the same colors as in (C).