Nanovaccines Displaying the Influenza Virus Hemagglutinin in an Inverted Orientation Elicit an Enhanced Stalk-Directed Antibody Response.

Despite the availability of licensed vaccines, influenza causes considerable morbidity and mortality worldwide. Current influenza vaccines elicit an immune response that primarily targets the head domain of the viral glycoprotein hemagglutinin (HA). Influenza viruses, however, readily evade this response by acquiring mutations in the head domain. While vaccines that target the more conserved HA stalk may circumvent this problem, low levels of anti-stalk antibodies are elicited by vaccination, possibly due to the poor accessibility of the stalk domain to B cell receptors. In this work, we demonstrated that nanoparticles presenting HA in an inverted orientation generated ten-fold higher anti-stalk antibody titers after a prime immunization and five-fold higher anti-stalk titers after a boost than nanoparticles displaying HA in its regular orientation. Moreover, nanoparticles presenting HA in an inverted orientation elicited a broader anti-stalk response that reduced mice weight loss and improved survival after challenge to a greater extent than nanoparticles displaying HA in a regular orientation. Refocusing the antibody response towards conserved epitopes by controlling antigen orientation may enable the design of broadly protective nanovaccines targeting influenza and other pathogens with pandemic potential. This article is protected by copyright. All rights reserved.