Chlamydia trachomatis infections are widespread throughout the World. This bacterial pathogen affects multiple organ systems producing acute symptomatology and persistent infections that can result in long-term sequelae. If implemented in a timely manner, antibiotic therapy is effective in controlling C. trachomatis infections. Unfortunately, many cases are asymptomatic, others are treated late, and/or are unsuccessfully managed. Efforts to produce a vaccine against trachoma were initiated decades ago. More recently, with the uncovering of the role of C. trachomatis in sexually transmitted infections, several laboratories have focused their efforts on producing a vaccine against genital infections. Our long-term goal is to engineer a vaccine that can protect against C. trachomatis infections. The hypothesis we want to test is that a vaccine formulated with the native major outer membrane protein (MOMP) of Chlamydia associated with amphipols (APols) can protect female mice against an intravaginal challenge. Generally, membrane proteins (MPs) are kept soluble in aqueous solutions using detergents. However, detergents tend to destabilize MPs, which can lead to the loss of protective conformational epitopes. APols are a novel type of polymeric surfactants that can substitute to detergents. They have been shown to be particularly favorable towards maintaining MP structure, function and stability. Our preliminary experiments indicate that candidate vaccines formulated with APol-trapped MOMP are more effective than their detergent-based equivalents. We propose to build on this observation by i) studying the stability and structure of MOMP/APol complexes in various types of vaccine formulations and ii) testing the protective effect of adjuvant-carrying APols. Indeed, as they associate permanently with MPs, APols can be used to deliver adjuvants to target cells concomitantly with antigenic MPs, which is expected to favor a strong systemic and mucosal immune response. Female mice will be challenged intravaginally and the course of the infection will be followed with vaginal cultures. Protection will be determined based on the number of animals with positive vaginal cultures and the severity and length of the infection. Subsequently, the mice will be mated to determine the fertility rates. In order to optimize the candidate vaccines, we will compare the immune response elicited by different vaccination protocols using various adjuvants linked in various ways to various APols, so as to modulate the release of the adjuvant in different cellular compartments. In conclusion, C. trachomatis infections are a major health problem in both developed and underdeveloped countries. The goal of this proposal is to formulate a vaccine with MOMP trapped by adjuvant-carrying APols. Decreasing the incidence and prevalence of these infections with a vaccine would have a major health impact worldwide. Furthermore, the development of vaccine formulations based on amphipol solubilized membrane proteins has the potential to impact a broad spectrum of pathogens.

Public Health Relevance

The goal of this proposal is to formulate a vaccine with MOMP trapped by adjuvant-carrying APols. Decreasing the incidence and prevalence of these infections with a vaccine would have a major health impact worldwide. Furthermore, the development of vaccine formulations based on amphipol solubilized membrane proteins has the potential to impact a broad spectrum of pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI092129-02
Application #
8324510
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
David, Hagit S
Project Start
2011-09-01
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$336,552
Indirect Cost
$79,352
Name
University of California Irvine
Department
Pathology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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