Universal Influenza T Cell-Targeted Mucosal Vaccines
Abstract
An estimated 250,000-500,000 human deaths are caused each year by influenza, a respiratory viral infection. Young children and the elderly are at greatest risk of developing severe forms of disease associated with influenza infection. The major proteins present on the surface of the virus, hemagglutinin (HA) and neuraminidase (NA), undergo rapid mutation, but are also natural targets of human antibody responses produced by circulating B lymphocytes. For the past four decades, influenza vaccines have focused on inducing neutralizing antibodies reactive with seasonally circulating viruses. Classic neutralizing activity has been associated with HA- and NA-specific antibody reactivity. A major limitation of this approach is the focus on strain-specific immunity that rarely induces optimal immunity against drifted (mutated) strains emerging from one flu season to the next. Even during a single flu season, viral drift can occur, which may cause a seasonal influenza vaccine to be ineffective against the new strain (as occurred during the 2014-2015 flu season). New vaccines and strategies are needed to induce immunity against divergent influenza strains (evidenced by the Peer Reviewed Medical Research Program Area of Encouragement “Influenza: Development and testing of a universal influenza vaccine”). Two fundamentally different approaches are currently under investigation to induce long-term protective immunity against diverse influenza strains. One approach is to design a vaccine that induces B cells (antibodies) directed against conserved regions of surface HA. Another approach is to utilize advanced bioinformatics to identify short segments of proteins (peptides) present in nearly all influenza A strains, which are likely targets of another group of human lymphocytes, called T cells. CD8 T cells are able to recognize short sequences presented on the surface of an infected cell (known as “T cell epitopes”). Once activated in this manner, the CD8 T cell can secrete molecules that kill the target cell and prevent further viral spread. CD4 T cells, also known as helper T cells, recognize target sequences presented on the surface of other cells and secrete molecules that “help” both CD8 T cells and antibody-producing B cells develop optimally. We have already identified conserved influenza T cell targets (epitopes) that offered protection to “humanized” mice against infection with diverse types of influenza A viruses. Two areas of influenza and T cell-based vaccinology that have not been fully explored are vaccine formulation and delivery. It is known that both mucosal immunity and T cell immunity are important for protection against influenza infection. We propose now to develop an efficient vaccination platform to be delivered mucosally. In order for a T cell-based vaccine to be effective, the vaccine antigens must be processed and presented by antigen presenting cells (APC) to T cells. The most potent APCs are dendritic cells (DC). Thus, we propose to target our vaccines for specific uptake by DC. New methodologies allow us to generate replication-deficient adenovirus (Ad) vaccines that specifically and efficiently infect DC. Delivered mucosally, we postulate that DC-targeted recombinant Ad vaccines encoding conserved influenza T cell epitopes will induce immunity protective against influenza challenges. We will: (1) generate DC-targeted Ad vaccines encoding conserved influenza T cell epitopes, (2) test vaccine ability to induce proper T cell responses in humanized mice, and (3) determine whether the vaccines are protective (i.e., decrease in vivo viral replication and increase survival) using two distinct viral subtypes. We believe that the proposed work can lead to transformative influenza vaccine strategies, focusing on a paradigm-shifting concept of inducing broadly protective mucosal T cell responses. The resulting vaccine may be used alone to rapidly protect against emerging pandemic strains or c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810140
Entities
People
- Daniel Hoft
Organizations
- Saint Louis University
- United States Army