R01AI167629

Cervicovaginal Microbiome, Mucosal Immunity, and Pathogen Factors That Contribute to Spontaneous Clearance of Chlamydia trachomatis

Chlamydia trachomatis (CT) is the most commonly reported bacterial sexually transmitted infection in the U.S., and untreated infections are a major cause of adverse sequelae, including pelvic inflammatory disease, infertility, and ectopic pregnancy. Despite screening programs, infection rates continue to rise, likely due to the high incidence of asymptomatic infections in women and the recommended annual screening interval. While antibiotic therapy is curative, effective biomedical prevention strategies are lacking.

Most CT natural history studies focus on the short interval between screening and follow-up for treatment, typically 1-2 weeks. Few studies have had longer follow-up periods. Overall, these studies suggest that spontaneous clearance of CT (in the absence of antibiotic treatment) occurs in 11-44% of cases, but the mechanisms behind this clearance are poorly understood.

The vaginal microbiome (VMB) plays a major role in preventing CT acquisition and may also aid in CT clearance by reducing CT proliferation and promoting effective immune responses. Therefore, identifying modifiable vaginal microenvironmental features that contribute to spontaneous CT clearance could lead to novel interventions.

This proposal is submitted in response to PA-19-096 "Control of Sexually Transmitted Infections (STIs) through a Comprehensive Understanding of the Natural History of Infection". We propose to investigate the relationships between spontaneous CT clearance and VMB (structure, function, metabolome), mucosal immunity, and CT serovar-specific features.

To accomplish this, we will utilize archived cervicovaginal lavage samples collected from the Longitudinal Study of Vaginal Flora, which followed 3,620 cisgender women quarterly for one year. After the study concluded, the samples were retrospectively screened for CT, resulting in the identification of CT spontaneous clearance events (N=311) and persistence events (N=321).

The specific aims of this study will assess four domains that may drive the natural history of CT: 1) demographic, clinical, and behavioral factors, 2) vaginal microbiome and metabolome, 3) mucosal soluble markers of inflammation, and 4) CT serovar composition. Our experienced, multi-disciplinary team will adapt, refine, and apply modern methods in longitudinal epidemiology, utilizing machine learning and dimension-reduction techniques to analyze high-dimensional, multi-omic data.

Through this study, we aim to identify immunologic, metabolomic, and bacterial candidates that are associated with spontaneous CT clearance. The analysis of over 600 archived samples in this epidemiologic study presents the best available resource for identifying likely natural clearance and persistence mechanisms. The findings from these analyses will provide the cost-benefit justification for future confirmatory trials and experimental mechanistic studies.

The results of this study may lead to new CT vaccine approaches by pinpointing correlates of protection against clinically-relevant serovars and informing the choice of adjuvants for optimal immune response. Additionally, the data may aid in the design of antibiotic-sparing approaches, such as live biotherapeutic formulations, which could enhance CT control programs.

University Of Maryland, Baltimore

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Baltimore, Maryland 21201 United States

Single Zip Code

Control of Sexually Transmitted Infections (STIs) Through a Comprehensive Understanding of the Natural History of Infection (R01 Clinical Trial Not Allowed) (PA-19-096)

Amendment Since initial award the total obligations have increased 292% from $798,536 to $3,127,515.