The highly infectious Gram-negative Brucella remains a global health threat and is responsible for the disease, brucellosis. In humans, B. melitensis is believed to be responsible for most infections, and it is naturally transmitted via ingestion of unpasteurized dairy products or aerosols of infected animal products resulting in infection of naso-oropharyngeal tissues. Although infection primarily occurs following a mucosal exposure, it can cause a systemic disease manifested by its flu-like symptoms. Despite aggressive antibiotic treatment, it can still result in a recurring sequelae evident as undulant fever and arthritis. Brucellae survival within the host is linked to its ability to evade intracellular recognition, thu, allowing them to sequester in various tissues. Vaccines that can recapitulate aspects of Brucella infection should prove effective in protecting against infection. Hence, we hypothesize that a vaccine that mimics aspects of natural mucosal B. melitensis infections and capable of stimulating cell-mediated immunity via the production of TNF-a and IFN-g will be protective against mucosal and systemic Brucella challenges. To enable this approach, we have recently developed a vaccine prototype that can confers complete protection in most cases with no detectable brucellae in spleens or lungs. Given the potency of this vaccine, we propose to test our hypothesis using two animal models to determine the efficacy of this vaccine against wild-type B. melitensis challenges. Studies in Specific Aim 1 will establish a mucosal (oral, nasal, or oral + nasal) immunization strategy for conferring protection to B. melitensis and to heterologous Brucella species. Studies in Specific Aim 2 will establish similar mucosal immunization strategy in goats, a natural host for B. melitensis, for conferring protection against B. melitensis-induced abortion. Studies in Specific Aim 3 will evaluate the biosafety of this vaccine to warrant future clinical testing. Thus, these studies will show that our oral/nasal vaccine can protect against Brucella challenges in two different experimental animal models.

Public Health Relevance

Brucellosis is the most common zoonotic disease worldwide, and this disease compromises mostly systemic tissues, including joints, spleen, and liver, requiring extended antibiotic treatment to clear the brucellae. The proposed studies will test the efficacy of our vaccine following its mucosal administration in two different animal models to learn how the induced T cells are protective against Brucella infections. The overall goal of this work is to show efficacy by our vaccine that can ultimately aid to reduce incidences of human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI123244-03
Application #
9398094
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Zou, Lanling
Project Start
2016-01-20
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Florida
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611