Seasonal influenza virus infections and influenza pandemics are responsible for high global mortality but current protection through vaccination is limited by seasonal variation and antigenic drift. In this proposal our goal is to develop a novel vaccine nano-platform and then utilize that platform to produce a universal influenza vaccine by exploiting the controlled presentation of conserved antigenic proteins (or protein fragments) from influenza. Vaccine therapies are based heavily on neutralizing antibodies specific for surface exposed hemagglutinin (HA), which prevent either the binding or the fusion step involved in virus entry of the cell. Vaccination, or influenza infection, can also induce influenza specific memory CD8 T cells, specific for internal influenza virus antigens such as the nucleoprotein (NP), that aid in clearance of viral infected infected cells and overall recovery in the event that neutralizing antibodies are unable to provide complete protection. Thus, eliciting neutralizing antibodies, specific for the conserved stalk region of the HA protein (csHA) and induction of selective CD8 T cell responses to the conserved NP, could be an excellent strategy for a universal influenza vaccine. We will develop a class of virus-like particles (VLPs), having nano-architectures that mimic the presentation of HA and NP antigenic fragments in influenza, in order to elicit specific immune responses towards the development of a universal influenza vaccine. We will build on strong preliminary results demonstrating both our ability to bioengineer these VLPs by encapsulation of NP on the interior and the ability of these materials to elicit a strong CD8 T cell-dependent recovery in mice challenged with up to 100x LD50 influenza. We will use the VLP, derived from the bacteriophage P22, to encapsulate NP fragments (and/or csHA) selectively on the interior and display csHA (and/or NP fragments) on the exterior surface of the P22 VLP in high copy number. The goal of this proposal is to integrate these two antigens (csHA and NP) with a highly engineer-able nano- platform to elicit protective immune responses in an effort aimed at the development of a universal influenza vaccine.
The overall relevance of this work lies in the development of a robust, modular, supramolecular platform for the spatially selective presentation of antigenic proteins and peptides, either on the inside or outside, designed to elicit specific protective immune responses. While this approach could be applied to a broad range of diseases, the focus of this application will be on developing a universal influenza vaccine based on directed immune responses to the conserved stalk of hemagglutinin (HA) and conserved nucleoprotein (NP) epitopes from influenza.
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