The purpose of this application in response to PA-97-101, """"""""Basic mechanisms of vaccine efficacy"""""""", is to conduct basis research into mechanisms of vaccine-induced immunity in the lungs, using a highly pertinent and relevant tuberculosis infection model. An underlying motive is the plethora of new TB vaccine candidates currently being screened in mouse and guinea pig models, in which the Mycobacteria Research Laboratories [MRL] at Colorado State University are playing a central role. As the number of vaccine candidates tested has gradually increased, it has become increasingly apparent that fundamental information regarding vaccine strategies against this serious bacterial respiratory pathogen, particularly as it pertains to expression of immunity in the lungs, is almost completely lacking. Accordingly, this application proposes to address four major areas of concern, which in each case has the potential to derive important new information which may improve and broaden our overall approach to tuberculosis vaccination. These areas are [1] development of a widely applicable approach to identification of potential protein antigens, and specific application of this approach to the identification of key target antigens of Mycobacterium tuberculosis, an approach that will draw on our considerable experience in bacterial cultivation, antigen extraction, and proteomic analysis; [2] a further exploration of the potential for cytokine enhancement of vaccination, based on our recent success in this area; [3] work to determine the basis of down-regulation in vaccination, specifically in terms of interference with the BCG vaccine; and [4] the nature and antigenic targets of the CD8 T cell response in the lungs and the potential for CD8-directed vaccination strategies. These studies will exploit our extensive state of the art Level III biohazard facilities, our expertise in bulk cultivation and antigen purification, our new access to sophisticated cell sorting technology, and our demonstrated experience in using and developing the mouse low dose aerosol tuberculosis infection model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045707-05
Application #
6736264
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Sizemore, Christine F
Project Start
2000-05-01
Project End
2005-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
5
Fiscal Year
2004
Total Cost
$290,000
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Sambandamurthy, Vasan K; Derrick, Steven C; Hsu, Tsungda et al. (2006) Mycobacterium tuberculosis DeltaRD1 DeltapanCD: a safe and limited replicating mutant strain that protects immunocompetent and immunocompromised mice against experimental tuberculosis. Vaccine 24:6309-20
Junqueira-Kipnis, Ana Paula; Basaraba, Randall J; Gruppo, Veronica et al. (2006) Mycobacteria lacking the RD1 region do not induce necrosis in the lungs of mice lacking interferon-gamma. Immunology 119:224-31
Orme, Ian M (2006) Preclinical testing of new vaccines for tuberculosis: a comprehensive review. Vaccine 24:2-19
Orme, Ian M (2006) Safety issues regarding new vaccines for tuberculosis, with an emphasis on post-exposure vaccination. Tuberculosis (Edinb) 86:68-73
Orme, Ian M (2005) Tuberculosis vaccines: current progress. Drugs 65:2437-44
Skeiky, Yasir A W; Alderson, Mark R; Ovendale, Pamela J et al. (2005) Protection of mice and guinea pigs against tuberculosis induced by immunization with a single Mycobacterium tuberculosis recombinant antigen, MTB41. Vaccine 23:3937-45
Kipnis, Andre; Irwin, Scott; Izzo, Angelo A et al. (2005) Memory T lymphocytes generated by Mycobacterium bovis BCG vaccination reside within a CD4 CD44lo CD62 Ligandhi population. Infect Immun 73:7759-64
Taylor, Jennifer L; Ordway, Diane J; Troudt, Jolynn et al. (2005) Factors associated with severe granulomatous pneumonia in Mycobacterium tuberculosis-infected mice vaccinated therapeutically with hsp65 DNA. Infect Immun 73:5189-93
Orme, Ian M (2005) Current progress in tuberculosis vaccine development. Vaccine 23:2105-8
Irwin, Scott M; Izzo, Angelo A; Dow, Steven W et al. (2005) Tracking antigen-specific CD8 T lymphocytes in the lungs of mice vaccinated with the Mtb72F polyprotein. Infect Immun 73:5809-16

Showing the most recent 10 out of 30 publications