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. 2019 Apr 8;219(Suppl_1):S38-S45.
doi: 10.1093/infdis/jiy696.

Immunodominance and Antigenic Variation of Influenza Virus Hemagglutinin: Implications for Design of Universal Vaccine Immunogens

Seth J Zost  1 , Nicholas C Wu  2 , Scott E Hensley  1 , Ian A Wilson  2   3
Affiliations

Immunodominance and Antigenic Variation of Influenza Virus Hemagglutinin: Implications for Design of Universal Vaccine Immunogens

Seth J Zost et al. J Infect Dis. .

Abstract

Influenza viruses routinely acquire mutations in their hemagglutinin (HA) and neuraminidase (NA) glycoproteins that abrogate binding of pre-existing antibodies in a process known as antigenic drift. Most human antibodies against HA and NA are directed against epitopes that are hypervariable and not against epitopes that are conserved among different influenza virus strains. Universal influenza vaccines are currently being developed to elicit protective responses against functionally conserved sites on influenza proteins where viral escape mutations can result in large fitness costs [1]. Universal vaccine targets include the highly conserved HA stem domain [2-12], the less conserved HA receptor-binding site (RBS) [13-16], as well as conserved sites on NA [17-19]. One central challenge of universal vaccine efforts is to steer human antibody responses away from immunodominant, variable epitopes and towards subdominant, functionally conserved sites. Overcoming this challenge will require further understanding of the structural basis of broadly neutralizing HA and NA antibody binding epitopes and factors that influence immunodominance hierarchies of human antibody responses.

Keywords: antibody response; immune imprinting; influenza virus; vaccine design; virus evolution.

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Figures

Figure 1.
Figure 1.
Immunodominance of primary responses and recall responses against influenza hemagglutinin (HA). (A) The HA head domain (pink) is immunodominant in primary responses, whereas antibodies against the stem domain (blue) are rare. (B–C) Antibodies against the HA head remain dominant after exposure to antigenically similar (B) and antigenically drifted (C) seasonal viral strains. Antibodies elicited by antigenically drifted seasonal influenza virus strains often have high levels of somatic hypermutations that allow recognition of altered epitopes. (D–E) Antibodies against new pandemic viral strains tend to be more dominant initially against the (D) conserved HA stem, and (E) rare conserved epitopes, if any, in the HA head. Memory B cells producing antibodies against these conserved epitopes are preferentially boosted upon exposure to new pandemic viral strains. The color similarity of the HA head domain represents the similarity of the antigenicity in all figure panels.
Figure 2.
Figure 2.
Structural variation in the hemagglutinin (HA) stem and neighboring regions. Structures of HA protein from subtypes that have caused human infection are aligned by the helix A (HA2 residues 38–55) in the stem region: H1 (PDB 3LZG) [53], H2 (PDB 3KU5) [93], H3 (PDB 4FNK) [16], H5 (PDB 4BGW) [94], H6 (PDB 4XKD) [95], H7 (PDB 4LN6) [96], H9 (PDB 1JSD) [97], H10 (PDB 4XQ5) [98]. Zoomed-in views for several structural features of interest are shown. PDB, Protein Data Bank.
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