Changed epitopes drive the antigenic drift for influenza A (H3N2) viruses

Abstract

Background: In circulating influenza viruses, gradually accumulated mutations on the glycoprotein hemagglutinin (HA), which interacts with infectivity-neutralizing antibodies, lead to the escape of immune system (called antigenic drift). The antibody recognition is highly correlated to the conformation change on the antigenic sites (epitopes), which locate on HA surface. To quantify a changed epitope for escaping from neutralizing antibodies is the basis for the antigenic drift and vaccine development.

Results: We have developed an epitope-based method to identify the antigenic drift of influenza A utilizing the conformation changes on epitopes. A changed epitope, an antigenic site on HA with an accumulated conformation change to escape from neutralizing antibody, can be considered as a "key feature" for representing the antigenic drift. According to hemagglutination inhibition (HI) assays and HA/antibody complex structures, we statistically measured the conformation change of an epitope by considering the number of critical position mutations with high genetic diversity and antigenic scores. Experimental results show that two critical position mutations can induce the conformation change of an epitope to escape from the antibody recognition. Among five epitopes of HA, epitopes A and B, which are near to the receptor binding site, play a key role for neutralizing antibodies. In addition, two changed epitopes often drive the antigenic drift and can explain the selections of 24 WHO vaccine strains.

Conclusions: Our method is able to quantify the changed epitopes on HA for predicting the antigenic variants and providing biological insights to the vaccine updates. We believe that our method is robust and useful for studying influenza virus evolution and vaccine development.

Figure 1

Overview of our method for the antigenic drift. (A) The overview of our method. (B) The structural locations of selected 64 critical amino acid positions on five epitopes (Epitope A in red; B in purple; C in orange; D in cyan; E in green). The sialic acid is in green. All structures are presented by using PyMOL.

Figure 2

The relationships between number of changed epitopes and antigenic variants on 4 models. (A) The first model considered an epitope as changed if there is at least one mutation within it. (B) The second model considered an epitope as changed if there are at least two mutations within it. (C) The third model considered an epitope as changed if there are at least two critical mutations within it. (D) The fourth model was derived from model three and further defined "1+" type if there are at least 2 and 3 critical mutations in epitope A and B. respectively.

Figure 3

The changed-epitope composition and antigenic variants on 4 models. (A) Model one. (B) Model two (C) Model three. (D) Model four.

Figure 4

The HA/antibody structure and interface. (A) The antibody (pale green) and HA trimer (PDB code 1KEN). (B) The interface of the antibody and HA. The selected critical positions on epitope B and the CDRs in the heavy (red) and light (pink) chains of the antibody are labelled.

Figure 5

The epitope evolution and antigenic drift. (A) The distributions of variant ratios of WER and Smith vaccine strains from 1982-1983 to 2009 seasons. 10 seasons with emerging variants and followed by the update of WER strain in the next season are labelled (red arrow) (B) The average hamming distances (HD) of 5 epitopes from 1982-1983 to 2009 seasons.