The influenza virus is a medically significant respiratory virus that infects up to 100 million people per season and entails a mortality rate of 500,000 individuals per year. Due to antigenic evolution, the virus is able to evade the host immune system on a seasonal basis, rendering current vaccination modalities suboptimal. Recently, the Young lab has employed a clamp stabilization domain to constrain the influenza hemagglutinin (HA) protein in its trimeric, prefusion conformation. This exposed highly conserved epitopes in the HA stem domain and has been shown to improve virus neutralization of seasonal strains ~4 fold and increase cross-reactivity to distantly related strains ~80 fold compared to current commercial inactivated vaccines. However, subunit vaccines remain typically poorly immunogenic and a significant response against the clamp stabilization domain was observed upon mouse immunization. Here, we employed a mIgG2a anti-clamp monoclonal antibody to form immune complexes with clamp-stabilized HA with the aim to (i) decrease the clamp-directed immunity through epitope shielding of the domain and (ii) increase immunogenicity of the subunit vaccine through Fc-mediated adjuvant activity.
It was found that sera from mice immunized with immune complexes displayed a shielding effect against the clamp domain coupled with redirection of mouse immunity to the HA ectodomain. Moreover, sera from the immune complexed immunized group (with no exogenous adjuvants) was capable of neutralizing a homosubtypic influenza virus strain and showed increased cross-reactivity towards distantly related influenza strains. However, immunization with immune complexes failed to invoke a significant Fc-mediated adjuvant activity. These results provide a potential pathway towards a subunit based broad spectrum influenza vaccine.