The overarching goal of this application is to establish an integrated, interdisciplinary STI Cooperative Research Center (STI-CRC) uniquely positioned to adopt a synergistic approach bridging gaps to
- understand basic epidemiologic data on STI burden,
- understand STI natural history and burden of disease,
- advance basic science research for STI vaccines including development of appropriate animal models, high throughput antigen discovery and novel antigen delivery systems,
- conduct basic studies in clinical settings to expand the overall knowledge base on mucosal immunity in the genital tract; and
- evaluate the effectiveness of real-world STIs prevention and associated outcomes.
The investigators that come together to form this STI-CRC are international leaders in epidemiology, immunology, biostatistics and informatics and vaccine development, with particular expertise in HPV, CT and STI co-infections.
Sexually transmitted infections (STIs) represent a major cause of reproductive morbidity and mortality in women, at an estimated annual health care cost in the United States (US) of $16 billion. Of the 20 million new infections in the US each year, human papillomavirus (HPV) and Chlamydia trachomatis (CT) are by far the most common.
While asymptomatic in most women, both infections have the potential for serious adverse outcomes. Infection with one or more of 14 high-risk HPV genotypes is attributable to the development of nearly all invasive cervical cancer and its precursor lesions, cervical intraepithelial neoplasia (CIN). Excisional treatment of high-grade CIN in young childbearing women can result in serious pregnancy complications including preterm deliveries. Infection with HPV6/11, attributable to more than 90% of genital warts can have significant physical morbidity and psychosocial consequences especially in populations who are refractory to treatment and CT infection can cause serious complications such as pelvic inflammatory disease, ectopic pregnancy, and tubal infertility.
In the US, despite the availability of HPV and CT screening and treatment and in the case of HPV, efficacious first-generation vaccines, over 39.5 million women aged 14-59 years are estimated to be currently infected with HPV and in 2011, nearly 1.5 million cases of CT infection were reported to the US Centers for Disease Control and Prevention. Novel approaches are critical to understanding the continued high burden of these infections and the barriers to and successes of public health interventions.
Aim 1
To expand the scope of the University of New Mexico Interdisciplinary HPV Prevention Center (UNM-IHPC) by establishing the Epidemiology and Prevention Interdisciplinary Center for Sexually Transmitted Infections (EPIC-STI) through incorporating cooperative trans-disciplinary research approaches to address key gaps in the knowledge required to reduce the burden of preventable or treatable sexually transmitted infections, with a focus on HPV, CT and STI co-infections.
Aim 2
To fund and support 4 projects representing a spectrum of interdisciplinary and interactive research programs including: Project 1 will elucidate details of the development of protective immunity against CT infection using mouse and in vitro models to understand how long lasting CD4+ T cell-mediated immunity develops and traffics to protect against re-infection in the genital mucosa. Project 2 utilizes novel vaccine strategies based on virus-display technology to generate broad protection against HPV and CT infections in both single and combination vaccine strategies. Project 3 uses a mixed design approach to characterize the population-level burden of STI infection and co-infection and the individual-level within and between woman host response to CT infection by utilizing population-based cervical screening surveillance systems and a prospective cohort molecular epidemiologic study design. Project 4 employs woman-based information systems to delineate the population-based impact of HPV vaccination and changes to cervical cancer screening guidelines on sexually transmitted infections and associated disease outcomes.
Aim 3
To establish two cores that support the EPIC-STI and the interdisciplinary research approaches. Core A: Administrative Core to support coordination, communication, integration, collaboration and outreach that ensures the accomplishment of all Center goals; Core B: a Biostatistics and Bioinformatics Core to support the analysis of the high density data sets generated by the population-and laboratory-based programs and develop novel analytic approaches.
Aim 4
To implement Pilot Developmental Research Projects (DRPs) under approval of the NIAID STICRC Executive Committee with the goal of mentoring and enhancing new and junior investigators transitioning into independent STI research careers.
Expert panels have been convened over the past several years by the US Centers for Disease Control (CDC) and the World Health Organization (WHO) with a mandate to identify barriers to the effective prevention and control of sexually transmitted infections (STIs) and their disease sequelae, including the development of effective vaccines. Among the consensus agreement in research gaps was the need to:
- obtain better basic epidemiologic data on STI burden,
- improve our understanding of STI natural history and burden of disease,
- advance basic science research for STI vaccines including development of appropriate
- animal models, high throughput antigen discovery, and novel adjuvant and delivery systems, and
- conduct basic and translational studies in human clinical settings to expand the knowledge base on mucosal immunity in the genital tract. The goal of this application is to establish an integrated, interdisciplinary Center uniquely positioned to adopt a synergistic approach to bridging these and other research gaps. The investigators that comprise the EPIC-STI are internationally recognized leaders in molecular epidemiology, immunology, and
- vaccine development, with particular expertise in human papillomavirus (HPV) and Chlamydia trachomatis (CT) infections. The EPIC-STI will extend the successful model of the currently funded University of New Mexico -Interdsciplinary HPV Prevention Center (UNM-IHPC) to the epidemiologic description of the burden and impact of other common STIs and co-infections, the development of novel HPV and CT vaccines using broad spectrum epitope mapping and vaccine delivery via highly immunogenic virus like particle (VLP) platforms, and evaluation of the immune response to CT infections using complementary human and mouse studies.
The 4 Projects and 2 Cores funded through the EPIC-STI represent a highly integrated research program designed to accelerate translational research to improve the prevention and control of the major STIs and associated disease sequelae.
The EPIC-STI projects 1 and 3 will use complementary approaches to fill critical gaps in knowledge needed to improve our understanding of the development of protective host immune response to CT infection. A focus of these synergistic projects will be enhancing the understanding of the immune response at the genital mucosa, including characterization of memory T-cells tracking to the mucosa and how the mucosal immunological microenvironment interacts to affect trafficking or functioning of T-cell responses to CT infection using mouse models.
Project 3 provides a detailed and expansive characterization of soluble immune microenvironment in human CT infections and determines whether specific immunologic profiles change following antibiotic treatment and correlate with spontaneous resolution of infection versus susceptibility to reinfection. Translation of the findings from the human studies in Project 3 to animal studies in Project 1 serves to accelerate and refine the mouse model of CT infection and immunity. A core component of these two projects is to develop a more sound understanding of the character and variability of normal immune responses in order to identify deviations that result from infection or that may be associated with protection.
Traditionally vaccines have relied on one strategy - to mimic as closely as possible the immunological consequences of natural infection. Project 2 of the EPIC-STI will utilize a novel bacteriophage virus-like particle (VLP) display system that can be used for both vaccine identification and implementation. We have already used this platform to develop a next-generation HPV vaccine, and one aim of Project 2 is directed towards formulating this vaccine to address both US and global disparities in vaccine affordability and access in rural/remote populations.
This highly immunogenic VLP platform will also be employed in the CT components of this Project. CT vaccine candidates will be identified using a high-throughput and sensitive antigen discovery that employs sera resulting from Projects 1 and 3 in parallel with complementary bioinformatics strategies. Synergies will be furthered through the testing of lead vaccine candidates using Dr. Starnbach’s state-of-the-art CT infection model.
Professor, UNM HSC, Leader Project #2
Associate Professor, UNM HSC, Leader Project #3
Regent's Professor, UNM HSC,