Biophysical insights into immunoglobulin interactions with influenza viral proteins

Influenza viruses cause a significant burden across the globe leading to thousands of mortalities annually. It remains challenging to acquire long-lasting immunity against influenza viruses due to the rapid rate of mutation within circulating strains and limited protection provided by seasonal flu vaccines. While the generation of influenza-specific antibodies provides a major source of protection against viral infection, our understanding of how biophysical properties of antibody-antigen interaction influence antibody protection against influenza viruses remains elusive. To address these challenges, we first developed imaging-based approaches in combination with computational models to elucidate the extent and mechanism of antibody inhibition of influenza virus assembly and release. We found that, depending on the binding orientation and target location of the antibodies, multivalent antibodies could adopt two “crosslinking” modes to achieve inhibition of viral shedding. Additionally, by establishing an in vitro system to mimic the competition between soluble antibodies and B cell receptors, we identified physical constraints that could limit effective B cell responses during repeated exposures to influenza viral antigens. Particularly, we found that membrane-proximal viral epitopes are at an inherent disadvantage for B cell recognition, due to steric hindrance by both directly and non-directly competing antibodies. Together, these insights call attention to the multi-faceted roles of antibodies in generation of long-lasting protection against influenza viral infection, highlighting the importance of optimizing epitope accessibility in current vaccine design strategies.