Stalking influenza

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Abstract
Influenza A virus causes seasonal flu epidemics and periodic worldwide pandemics (e.g., the 1918 Spanish flu, which caused ≈50 million deaths). The viral surface protein HA is the primary target of neutralizing Abs in natural infections (1). At any given time there are a limited number of viral strains circulating in humans, restricting widespread immunity to a small subset of potential viruses. Yearly seasonal epidemics arise from antigenic drift in the sequence of HA of currently circulating viruses, whereas pandemics are caused by the emergence of new, antigenically divergent viruses to which there is little to no immunity in the population (i.e., antigenic shift). The worldwide spread of a new H1N1 virus in 2009 caused the first recorded pandemic in more than 40 years. Current influenza vaccines are primarily produced from killed virus and mimic natural infection, inducing strain-specific, mainly HA-based, neutralization. Vaccine is produced from representative circulating strains grown in chicken eggs in a months-long process. Recent efforts aim to produce a broader influenza vaccine that focuses on common neutralization epitopes shared by multiple influenza strains. Such a vaccine should target a variety of influenza strains and better combat pandemics. A study published in PNAS describes an exciting strategy toward developing a broader influenza vaccine (2). HA is trimeric and comprises a receptor-binding surface subunit (HA1) and a transmembrane subunit (HA2) that mediates entry after exposure to low pH in the endosome. Decades of HA structural characterization have defined the steps of membrane fusion and the epitopes of neutralizing Abs (Fig. 1) (1). HA is produced as a single-chain precursor with an HA1 cap covering an HA2 stalk. Cleavage leads to burial …