Immune focusing to a broadly protective subdominant viral epitope by antigen engineering

Abstract

Viral glycoproteins are under constant immune surveillance by human adaptive immune responses and rapidly evolve to evade host pressure. Antigenic variation including glycan introduction or removal is among the mechanisms of escape from host immunity. Understanding how glycosylation affects immunodominance on complex antigens may help describe underlying B-cell biology. We systematically engineered glycans onto the influenza virus hemagglutinin (HA) to determine how the resulting B cell responses of normal mice were altered by characterizing molecular features of the elicited humoral immunity. We found that glycan addition changed the initially diverse repertoire into an epitope-focused, more genetically restricted response. Structural analyses showed that one of three enriched gene families targeted a previously subdominant and hitherto uncharacterized epitope at the head interface. Mouse challenge studies showed Fc-dependent protection. Thus, glycan engineering in context of influenza HA, can redirect host adaptive immune responses by exposing subdominant epitopes. These results have potential implications for next-generation viral vaccines aimed at directing B-cell responses to preferred epitope(s). Support or Funding Information This research was supported by NIH grant P01 AI089618. Atomic model of the hyperglycosylated HA immunogen This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.