Sera from Individuals with Narrowly Focused Influenza Virus Antibodies Rapidly Select Viral Escape Mutations In Ovo

Abstract

Influenza viruses use distinct antibody escape mechanisms depending on the overall complexity of the antibody response that is encountered. When grown in the presence of a hemagglutinin (HA) monoclonal antibody, influenza viruses typically acquire a single HA mutation that reduces the binding of that specific monoclonal antibody. In contrast, when confronted with mixtures of HA monoclonal antibodies or polyclonal sera that have antibodies that bind several HA epitopes, influenza viruses acquire mutations that increase HA binding to host cells. Recent data from our laboratory and others suggest that some humans possess antibodies that are narrowly focused on HA epitopes that were present in influenza virus strains that they were likely exposed to in childhood. Here, we completed a series of experiments to determine if humans with narrowly focused HA antibody responses are able to select for influenza virus antigenic escape variants We identified three human donors that possessed HA antibody responses that were heavily focused on a single HA antigenic site. Sera from all three of these donors selected single HA escape mutations during passage experiments, similar to what has been previously reported for single monoclonal antibodies. These single HA mutations directly reduced binding of serum antibodies used for selection. We propose that new antigenic variants of influenza viruses might originate in individuals who produce antibodies that are narrowly focused on HA epitopes that were present in viral strains that they encountered in childhood. Influenza vaccine strains must be updated frequently since circulating viral strains continuously change in antigenically important epitopes. Our previous studies have demonstrated that some individuals possess antibody responses that are narrowly focused on epitopes that were present in viral strains that they encountered during childhood. Here, we show that influenza viruses rapidly escape this type of polyclonal antibody response when grown by acquiring single mutations that directly prevent antibody binding. These studies improve our understanding of how influenza viruses evolve when confronted with narrowly focused polyclonal human antibodies.

Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2

“…Our data further show that RBD-12GS-I53–50 elicited Ab responses targeting several of the non-overlapping epitopes recognized by neutralizing Abs that have been identified in the RBD. Such polyclonal responses targeting multiple distinct epitopes might explain the magnitude of neutralization observed and should minimize the risk of selection or emergence of escape mutations ( Davis et al, 2018 ; Lee et al, 2019 ). Finally, the high production yield of RBD-I53–50A components and the robust stability of the antigen-bearing RBD nanoparticles suggests that these will likely be more amenable to large-scale manufacturing than the SARS-CoV-2 S-2P trimer, which expresses poorly and is unstable ( Edwards et al, 2020 ; Hsieh et al, 2020 ; McCallum et al, 2020 ).…”

Earliest infections predict the age distribution of seasonal influenza A cases

“…Foundational work on the theory of original antigenic sin demonstrated that an individual’s immune response to influenza vaccination is biased toward antigens similar to those encountered in childhood ( Davenport and Hennessy, 1956 ). In some cases, this may result in a narrow antibody response focused on a single epitope ( Davis et al, 2018 ). This phenomenon has been suggested to explain an unexpected decrease in vaccine effectiveness (VE) in the middle-aged in the 2015–2016 influenza season ( Skowronski et al, 2017b ; Flannery et al, 2018 ).…”

Asynchrony between virus diversity and antibody selection limits influenza virus evolution

“…The observation that immune escape can be reliably be selected for in egg (Davis et al, 2018) and mouse (Hensley et al, 2009) passage experiments and yet appears rare in reinfected experienced humans is unsurprising in light of our view that influenza virus evolution is limited more by the failure of selection pressure and antigenic diversity to coincide than by the absence of either.…”