In this proposal, we describe a plan for development of a novel rapid-acting mucosal vaccine candidate for influenza. This program explores a new concept in vaccine development and is the result of a collaborative venture between two companies- Apovia, Inc. of San Diego, CA and Corixa Corporation, based in Seattle, WA. Apovia has developed a particulate influenza virus antigen based on self-assembled virus-like particle (VLP) that bears a conserved influenza virus matrix protein (M2) epitope on its surface; vaccination with this VLP has demonstrated good protection in preclinical models. Corixa has developed a series of synthetic Toll-like receptor 4 (TLR4) agonists (AGPs), which, in extensive vaccine adjuvant evaluation studies, have been found to be highly complementary to Apovia's VLP technology. When delivered to the airway mucosa, the AGPs by themselves induce short-term protection against infectious challenge and serve as potent adjuvants for induction of mucosal and systemic immune responses. Preliminary studies have indicated that intranasal delivery of an AGP-containing influenza vaccine in three doses over a two-week period can stimulate both the innate and adaptive immune responses, as evidenced by continuous protection against lethal influenza virus challenge within 24 hours of the first dose. This vaccine candidate comprises several additional unique features including ease of manufacture, broad coverage of influenza virus subtypes (including known pandemic strains), and the potential for self-administration. This combination of """"""""nonspecific"""""""" approaches to influenza virus immunization, in which broad protection is sought at both the innate and adaptive levels, may ultimately prove to be a valuable adjunct to current type-specific immunization approaches. Herein, we propose a three-year development plan to identify a lead vaccine-adjuvant combination, carry out GMP manufacturing, toxicological and stability studies, and perform two human clinical trials to assess safety, immunogenicity, and protection against viral challenge at early and late timepoints. ? ?
