Incorporation of the TLR5-ligand flagellin in a recombinant Influenza A hemagglutinin vaccine provides enhanced immunogenicity and efficacy in vivo (47.2)

Abstract

Abstract The linkage between innate and adaptive immunity is well established. The recognition of specific pathogen associated molecular patterns (PAMPs) by members of the Toll-like receptor (TLR) family plays a prominent role in the activation of adaptive immune responses. Previously, we have demonstrated that the linkage of specific PAMPs with defined antigens provides more potent and protective antigen-specific responses in the absence of adjuvants or complex formulations. Here we utilized this approach to develop a recombinant protein based influenza vaccine. The TLR5 ligand flagellin was linked to hemagglutinin (HA) to generate a single component vaccine. The recombinant E. coli expressed protein is recognized by influenza-convalescent antisera, indicating that the HA portion of the fusion protein is properly folded and presents conformational epitopes. In mice, the recombinant vaccine induces strong humoral and cellular responses that are quantitatively and qualitatively superior to those observed when the antigen is delivered with alum or co-delivered with flagellin unlinked. Analysis of serum antibody responses reveals strong reactivity with cells infected with influenza A and the ability to inhibit viral entry in vitro. Moreover, immunization with the fusion protein fully protects BALB/c mice from a lethal intranasal challenge with influenza A. These data demonstrate that linkage of the TLR5-ligand flagellin with HA provides significant promise as a non-egg based approach in the development of novel vaccines to combat seasonal and pandemic influenza.