Molecular basis of immune escape by A(H9N2) avian influenza viruses

I’ve been working with collaborators at the University of Glasgow and the Avian Influenza Group at the Pirbright Institute on the genetic basis of antigenic variation among avian influenza viruses. We’ve uploaded a manuscript to bioRxiv on “The molecular basis of A(H9N2) avian influenza viruses”. Thomas Peacock and I share the lead authorship on this work, we’ve used a combination of experimental and computational approaches to explore the genetic basis of immune escape by these viruses.

A(H9N2) viruses are an economically important pathogen of poultry across much of Asia, the Middle East, and North and West Africa. They play a crucial role at the human-animal interface, particularly in China where they are the most common flu subtype in poultry. A(H9N2) viruses pose a threat to human health, both as a zoonotic agent in their own right, but also as an important donor of genes to novel reassortant viruses that may infect humans.

Like other flu subtypes, vaccine effectiveness is persistently challenged by the emergence of novel antigenic variants. Current understanding of antigenic variation among A(H9N2) viruses is largely derived from a handful of monoclonal antibody (mAb) escape mutant studies. These studies have identified a variety of amino acid substitutions that allow mutant viruses to grow in the presence of an antibody that targets a specific area of the virus.

Our main findings:

  1. Many mAb escape mutations are absent, or very rare, among sequenced A(H9N2) viruses.
  2. Several others had no significant effect on chicken antisera binding (mutations that result in extra glycosylation were a notable exception).
  3. Modelling antigenic and genetic data from circulating viruses identifies several novel amino acid substitutions that could explain antigenic variation in the field.
  4. Substitutions enabling immune escape by increasing glycosylation or receptor-binding avidity had the largest impacts on chicken antisera binding.
  5. Modelling and examination of sequence data suggests that of these two mechanisms of immune escape, modulation of avidity likely plays a greater role in evolution in nature.

Flu virus: egg-adaptation, dN/dS ratios and phylogeny

In recent years there has been increasing attention paid to the consequences of egg-adaptation of influenza viruses. To remain effective, the flu vaccine is regularly updated to ensure that it remains a good antigenic match to circulating viruses. The H3N2 component of the vaccine has recently been less effective than expected, despite the vaccine strain being well-matched to circulating strains. This is partly due to changes that occur when the vaccine is grown in chicken eggs.

Continue reading “Flu virus: egg-adaptation, dN/dS ratios and phylogeny”

Protein structure and antigen attractiveness

Great efforts are made to understand what makes particular areas of a pathogen protein attractive to the immune system. A better understanding of the biophysical and structural features that underpin antibody-recognition of antigens may allow us to infer the relative importance of the different areas (epitopes) recognised by antibodies and to predict which mutations are most likely to result in new pathogen strains able to evade pre-existing immunity.

Continue reading “Protein structure and antigen attractiveness”