The long-term goal of this project is to develop a highly active tetravalent vaccine to prevent Dengue Virus (DENV) infection using a novel vaccine delivery nanoparticle (PRINT-NP) platform with novel PAMP-based adjuvants. DENV infection has posed a serious global public health problem. No DENV vaccines are currently available, partly due to the lack of efficient vaccine delivery/adjuvants and of robust in vivo models of human vaccine responses and DENVl-4 infection. Due to the significant difference between mouse and human immune systems, humanized mice will play a critical role in evaluating human adjuvants, novel antigens and vaccine delivery platforms. Recent improved humanized mouse models have allowed stable reconstitution of a functional human immune system that have been increasingly used for evaluating and comparing human immune response to vaccination and to DENV infection. The AFC8-hu HSC/Hep/TEC mouse developed in the Su group with both human immune and liver cells is well-suited for evaluating human adjuvants and DENV vaccines and for studying DENV infection. With a stable human immune system from human HSC/TEC transplant, functional human immune cells are developed in all lymphoid/liver organs in AFC8-hu mice, which will provide an improved humanized mouse model for evaluating human vaccine response and DENV infection. Using humanized mouse models, we will model and develop novel PRINT-NP to deliver novel vaccine/adjuvant to human APC that induce efficient human protective immunity in vivo. Thus findings from this project will help to 1) identify top PRINT-NP for delivering human vaccines to induce human immunity;2) develop novel PAMP-based human adjuvants;3) define novel DENV antigens to induce neutralizing antibody (nAb);4) establish the humanized mouse model for studying DENV1-4 infection and evaluating DENV vaccines;and 5) identify top tetravalent DENV vaccines for further clinical development. The PRINT-NP and novel adjuvants platform can also be used in vaccine design against other emerging pathogens.

Public Health Relevance

The long-term goal of this project is to develop a highly active tetravalent vaccine to prevent Dengue Virus (DENV) infection using a novel vaccine delivery nanoparticle platform with novel adjuvants. The novel nanoparticle and adjuvants platform can also be used in vaccine design against other emerging pathogens

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109784-01
Application #
8657214
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Callaway, Justin B; Smith, Scott A; McKinnon, Karen P et al. (2015) Spleen Tyrosine Kinase (Syk) Mediates IL-1? Induction by Primary Human Monocytes during Antibody-enhanced Dengue Virus Infection. J Biol Chem 290:17306-20
Robbins, Gregory R; Roberts, Reid A; Guo, Haitao et al. (2015) Analysis of human innate immune responses to PRINT fabricated nanoparticles with cross validation using a humanized mouse model. Nanomedicine 11:589-99

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