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 universal influenza vaccine by exploiting the controlled presentation of conserved antigenic proteins (or protein fragments) from influenza on a novel nano-platform. 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). 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 excellent components of a universal pan 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 that these materials 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI104905-02
Application #
8810290
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Salomon, Rachelle
Project Start
2014-02-20
Project End
2018-05-31
Budget Start
2014-02-20
Budget End
2014-05-31
Support Year
Fiscal Year
2014
Total Cost
$262,572
Indirect Cost
$45,689
Name
Indiana University Bloomington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
Rynda-Apple, Agnieszka; Harmsen, Ann; Erickson, Anfin S et al. (2014) Regulation of IFN-? by IL-13 dictates susceptibility to secondary postinfluenza MRSA pneumonia. Eur J Immunol 44:3263-72
Richert, Laura E; Rynda-Apple, Agnieszka; Harmsen, Ann L et al. (2014) CD11cýýý cells primed with unrelated antigens facilitate an accelerated immune response to influenza virus in mice. Eur J Immunol 44:397-408
Rynda-Apple, Agnieszka; Patterson, Dustin P; Douglas, Trevor (2014) Virus-like particles as antigenic nanomaterials for inducing protective immune responses in the lung. Nanomedicine (Lond) 9:1857-68
Patterson, Dustin P; LaFrance, Benjamin; Douglas, Trevor (2013) Rescuing recombinant proteins by sequestration into the P22 VLP. Chem Commun (Camb) 49:10412-4