Description of Research Expertise

Research Interests
-influenza virus
-antigenic drift
-vaccines

Key words: Influenza virus, antigenic drift, viral pathogenesis, viral receptors, antibody specificity, vaccines

Description of Research
Seasonal influenza virus poses a major threat to the human population, contributing to over 30,000 annual deaths in the United States alone. Influenza virus rapidly escapes pre-existing humoral immunity by accumulating mutations in the viral surface proteins hemagglutinin (HA) and neuraminidase (NA). This process, termed “antigenic drift”, creates antigenically distinct viruses, making it difficult to predict which types of viruses will predominate during any given flu season. Understanding the underlying mechanisms that promote antigenic drift is a key scientific and public health challenge.
For decades, the leading hypothesis has posited that certain individuals mount restricted neutralizing antibody responses that enable the virus to undergo sequential selection. This established paradigm is largely based on in vitro and in ovo studies that examined how influenza virus mutates in the presence of monoclonal antibodies.

Revisiting a mouse model of antigenic drift established in the 1950’s, we found that influenza virus rapidly accumulates HA mutations that increase receptor binding avidity when confronted with polyclonal antibodies in vivo. Passaging such mutant viruses in naïve mice selects for viruses with additional HA mutations that restore receptor binding avidities to wild-type levels. Surprisingly, many receptor-modulating mutations are located in antigenic sites of HA, in many cases at a considerable distance from the defined receptor binding pocket. Therefore, a major driving force of influenza virus antigenic drift is likely related to how the virus interacts with cellular receptors rather than how the virus interacts with individual antibodies.

All of these studies have been completed using a mouse-adapted influenza strain. Do other subtypes of influenza virus utilize similar mechanisms? Does the 2009 pandemic H1N1 virus utilize similar mechanisms? We assume that most individuals mount polyclonal antibody responses that support the growth of mutants with high receptor binding avidity, but the reality is that very little is known about the types of antibody repertoires elicited by natural influenza virus infection and/or vaccines. Do certain individuals mount restricted antibody responses or are multi-epitope responses the norm? At the end of the day, the best way to combat antigenic drift is to create a broadly neutralizing vaccine that is effective against antigenically diverse strains. Can increasing our knowledge of influenza virus antibody repertoires allow us to design immunogens that selectively elicit immune responses to conserved antigens?

It certainly is an exciting time to study influenza viruses! Potential rotation projects include but are not limited to:

1. Model antigenic drift of 2009 pandemic H1N1 virus in mice
2. Determine immunodominance hierarchy of antibody responses induced by inactive IAV vaccine
3. Develop novel immunogens that elicit antibody responses to conserved regions of HA
4. Determine if receptor binding avidity influences antigenic drift of other groups of viruses
5. Determine if receptor specificity alters pathogenicity of influenza viruses

Lab Personnel
Colleen Sullivan (technician)
Jaclyn Myers, Ph.D. (postdoc)
Yang Li (MD/PhD student/MVP)
Susi Linderman (PhD student/IGG)