This U19 TRIAD Technology Development proposal describes an innovative program aimed at developing a high-performance, pro-inflammatory and non-tolerogenic vaccine delivery system based on the dendritic cell targeting anti-DEC-205 antibody. The success of anti-DEC-205 as a stimulator of strong inflammatory immune responses depends on co-administration of non-specific dendritic cell maturation factors. In their absence, anti- DEC-205 induces antigen-specific tolerance rather than immunity. Because of the dangers associated with nonspecific activation of the immune system, we propose to develop a modified pro-inflammatory and nontolerogenic anti-DEC-205 antibody. We have discovered a set of natural regulatory T-cell epitopes derived from human immunoglobulins that induce tolerance by stimulating regulatory T cells. We have verified experimentally that these epitopes generate antigen-specific expansion of regulatory T cells and suppress inflammatory immune responses. We hypothesize that regulatory T-cell epitopes contained in anti-DEC-205 promote a tolerogenic reaction that is only overcome through co-administration of non-specific immunostimulators. We expect that modification of these epitopes will significantly diminish tolerogenicity, enabling use of anti-DEC-205 as a stand-alone, high performance antigen delivery system. We will de-tolerize anti-DEC-205 by epitope modification in a two-stage process beginning first in a (humanized) mouse model system and progressing to human blood samples. Using TRIAD Toolkit Core immuno-informatics algorithms, we will reengineer anti-DEC-205 such that key amino acids in its regulatory T-cell epitopes are replaced with those that are experimentally shown to interfere with HLA binding. We will then (1) produce a set of antibody variants recombinantly conjugated to test antigens including vaccine candidates identified in TRIAD Research Projects, (2) identify de-tolerizing mutations that do not interfere with dendritic cell targeting, and (3) evaluate variants for reduced tolerogenicity, as well as for enhanced immunogenicity for vaccine antigens.

Public Health Relevance

This project will improve on a vaccine delivery vehicle targeted to cells that induce immune responses. Using computational and experimental methods, the vehicle will be optimally designed to eliminate portions that suppress immune responses. A more effective vehicle potentially will stimulate immune responses to prevent and treat disease through vaccination

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-KS-I)
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University of Rhode Island
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De Groot, Anne S; Ross, Ted M; Levitz, Lauren et al. (2015) C3d adjuvant effects are mediated through the activation of C3d-specific autoreactive T cells. Immunol Cell Biol 93:189-97
Zhang, Songhua; Desrosiers, Joseph; Aponte-Pieras, Jose R et al. (2014) Human immune responses to H. pylori HLA Class II epitopes identified by immunoinformatic methods. PLoS One 9:e94974
Dalal, Rahul S; Moss, Steven F (2014) At the bedside: Helicobacter pylori, dysregulated host responses, DNA damage, and gastric cancer. J Leukoc Biol 96:213-24
Bailey-Kellogg, Chris; Gutiérrez, Andres H; Moise, Leonard et al. (2014) CHOPPI: a web tool for the analysis of immunogenicity risk from host cell proteins in CHO-based protein production. Biotechnol Bioeng 111:2170-82
Mishra, Sasmita; Lavelle, Bianca J; Desrosiers, Joe et al. (2014) Dendritic cell-mediated, DNA-based vaccination against hepatitis C induces the multi-epitope-specific response of humanized, HLA transgenic mice. PLoS One 9:e104606
Pichu, Sivakamasundari; Ribeiro, Jose M C; Mather, Thomas N et al. (2014) Purification of a serine protease and evidence for a protein C activator from the saliva of the tick, Ixodes scapularis. Toxicon 77:32-9
Mishra, Sasmita; Losikoff, Phyllis T; Self, Alyssa A et al. (2014) Peptide-pulsed dendritic cells induce the hepatitis C viral epitope-specific responses of naïve human T cells. Vaccine 32:3285-92
Spero, Denice; Levitz, Lauren; De Groot, Anne S (2013) Report from the field: Overview of the Sixth Annual Vaccine Renaissance Conference. Hum Vaccin Immunother 9:1555-7
De Groot, Anne S; Ardito, Matthew; Terry, Frances et al. (2013) Low immunogenicity predicted for emerging avian-origin H7N9: implication for influenza vaccine design. Hum Vaccin Immunother 9:950-6
Koch, Manuel; Meyer, Thomas F; Moss, Steven F (2013) Inflammation, immunity, vaccines for Helicobacter pylori infection. Helicobacter 18 Suppl 1:18-23

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