Nasally administered vaccines have the potential to be effective, economical, needle-free methods of immunization able to induce both systemic and'mucosal immunity. Nasal immunization may allow for safe and effective vaccination against emerging infectious diseases and select agent pathogens. Although progress has been made in the development of nasal immunization strategies, a better understanding of the site(s) of delivery and mode(s) of action of adjuvants for nasally-administered vaccines is needed. It is not clear if nasal vaccine adjuvants exhibit adjuvant activity by activating the mucosal epithelium or immune cells in the subepithelial compartment. Additionally, while nasal immunization of mice induces systemic immune responses comparable in magnitude to those induced by parenteral immunization, nasal immunization of rabbits or non-human primates is not as effective as parenteral immunization for the induction of antigen- specific serum IgG. We postulate that the lack of efficacy of nasal immunization in rabbits and non-human primates is due to poor understanding of the immune inductive tissues of the upper respiratory tract in non- rodents and limited knowledge of the anatomical distribution of vaccines after nasal delivery and methods of controlling their residence time. Finally, nasal vaccines and adjuvants must be both effective and safe. Therefore, additional preclinical toxicity studies are needed to evaluate the safety of effective nasal vaccine formulations. Our long term goal is to develop safe and effective nasally administered vaccines for use in humans.
Our specific aims are:
Specific Aim One : Determine the mode of action of nasal vaccine adjuvants IL-1a and TLR4 ligand RC-529 AF. This will be addressed in a series of experiments to investigate if mucosal adjuvants activate (a) the mucosal stromal cells or (b) subepithelium dendritic cells or lymphocytes.
Specific Aim Two : Identify the anatomical site of delivery and time of clearance of vaccines when delivered nasally as aqueous or dry-powder formulations in mice, rats and rabbits and determine if delivery and clearance correlates with the induction of antigen-specific immunity in the systemic or mucosal compartment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI064879-04S1
Application #
8069023
Study Section
Special Emphasis Panel (ZRG1-VMD (01))
Program Officer
Khambaty, Farukh M
Project Start
2010-05-10
Project End
2011-01-31
Budget Start
2010-05-10
Budget End
2011-01-31
Support Year
4
Fiscal Year
2010
Total Cost
$137,589
Indirect Cost
Name
Duke University
Department
Pathology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Thompson, Joseph M; Whitmore, Alan C; Staats, Herman F et al. (2008) The contribution of type I interferon signaling to immunity induced by alphavirus replicon vaccines. Vaccine 26:4998-5003

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