The molecular basis of influenza virus antigenic change

Influenza viruses escape antibody-mediated neutralization by accumulating amino acid substitutions in the hemagglutinin surface protein, necessitating frequent updates of the influenza vaccine. Previous studies identified more than 130 potentially important amino acid positions that could cause antibody escape upon mutation. The 20 amino acids that could theoretically occupy each of these positions imply a seemingly endless number of possibilities to escape from antibody recognition. For this thesis the exact amino acid changes responsible for antigenic change of influenza viruses in the past were identified, with the ultimate goal to provide new insights in the evolution of influenza viruses that will help to improve selection of vaccine strains.

All major antigenic differences were due to one or very few substitutions on a small number of key positions near the domain ofthe hemagglutinin responsible for binding to the host cell, and generally involved substantial alterations of the biophysical properties of the amino acids. It was shown that the ability of key substitutions to cause antigenic change is largely independent of the amino acid context, and that substitutions similar to those that caused antibody escape in the past are potentially important for future antigenic change of the influenza viruses responsible for the 2009 influenza pandemic.

These results indicate that the possibilities for influenza viruses to escape antibody-mediated neutralization are limited and that genetically vastly different influenza viruses have analogous ways to change antigenically. The small number of critical positions and restricted amino acid usage decimates the number of possible escape variants from thousands to dozens and thus substantially increases the possibility to predict the antigenic component of influenza virus evolution.