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 antistalk antibodies are elicited by vaccination, possibly due to the poor accessibility of the stalk domain to B cell receptors. In this work, it is demonstrated that nanoparticles presenting HA in an inverted orientation generate tenfold higher antistalk antibody titers after a prime immunization and fivefold higher antistalk titers after a boost than nanoparticles displaying HA in its regular orientation. Moreover, nanoparticles presenting HA in an inverted orientation elicit a broader antistalk response that reduces mouse weight loss and improves survival after challenge to a greater extent than nanoparticles displaying HA in a regular orientation. Refocusing the antibody response toward conserved epitopes by controlling antigen orientation may enable the design of broadly protective nanovaccines targeting influenza viruses and other pathogens with pandemic potential.

Automated summary

Despite licensed vaccines being available, influenza still leads to significant illness and death globally. Current vaccines mainly target the head domain of the viral protein hemagglutinin (HA), but influenza viruses can easily evade this response by acquiring mutations in the head domain. This study demonstrates that nanoparticles presenting HA in an inverted orientation generate higher levels of antibodies and a broader immune response against the conserved stalk domain, providing better protection against the virus. By controlling antigen orientation, it may be possible to design nanovaccines that offer broad protection against influenza and other potential pandemic pathogens.