OTX015 flagellin is a TLR5 ligand consisting of domains where domain 1 contains the TLR5-binding site. We have demonstrated that the majority of conformational epitopes of the HA globular head of an H1N1 virus can be faithfully restored in a refolded fusion protein. Simultaneous antigen delivery and TLR5 signaling to the same antigen presenting cells are believed to result in enhanced antigen presentation and induction of humoral and cell-mediated immune responses. We have developed a panel of influenza vaccine formats which differ in the position of attachment of the HA globular heads fused to flagellin at different positions. Our initial vaccine formats fused the HA globular head of H1N1 subtypes to the carboxyl-terminus of flagellin. These seasonal vaccine candidates were highly immunogenic and protected mice against a lethal H1N1 influenza infection in mice. The C-terminal format of the A/Solomon Islands HA globular head vaccine has also been shown to be well-tolerated and immunogenic in humans. Subsequent development of pandemic H5N1 vaccines led to identification of a more efficacious LY294002 abmole bioscience alternative format of the vaccine, in which the HA globular head replaced the domain 3 of flagellin. VaxInnate has developed a flagellin fusion protein-based vaccine platform that effectively links innate and adaptive immunity. The flagellin portion of the fusion potentiates the immune response by triggering TLR5. The HA globular head contains the majority of HA neutralizing epitopes thereby eliciting a specific immune response against influenza virus. Induction of a potent antigen specific immune response requires the physical linkage of the antigen to flagellin, as codelivery of the 2 components failed to induce highly protective immunity to influenza and flavivirus infections in mice. We have previously demonstrated the excellent immunogenicity and efficacy of this vaccine platform when applied to either seasonal H1N1 or highly pathogenic avian influenza H5N1 in animal models. More recently we have demonstrated that a seasonal H1N1 vaccine, VAX125, is well tolerated and immunogenic in man. Importantly, this vaccine was extremely well tolerated and highly immunogenic in the typically poorly responsive elderly population. Here we report promising preclinical immunogenicity and efficacy results of three vaccine formats targeting 2009 pandemic H1N1 influenza.