Chlamydia is the most prevalent bacterial sexually transmitted infection (STI) in the world. There is no vaccine to prevent infection. However, researchers from the University of North Carolina at Chapel Hill, in partnership with colleagues at other sites in the U.S., Europe and Australia, will receive up to $10.7 million over five years from the National Institutes of Health (NIH) to move closer to identifying a vaccine candidate.
“Chlamydia can cause infertility and chronic pelvic pain in women, and infection has been linked to an increased risk for ovarian cancer,” says principal investigator Toni Darville, chief of the UNC Division of Pediatric Infectious Diseases, vice chair of pediatric research and a distinguished professor of pediatrics, microbiology and immunology at UNC’s School of Medicine. “Chlamydia is asymptomatic in 90 percent of men and women, leading to extremely high rates of infection. People don’t know they are infected, which is why a vaccine to prevent infection is so important. Women develop silent chronic infection and then present with infertility.”
The NIH’s National Institute of Allergy and Infectious Diseases (NIAID) awarded four U19 CRCs, or cooperative research centers, funding to develop vaccines for chlamydia, syphilis and gonorrhea. Darville will lead the UNC Chlamydia Vaccine Initiative STI CRC. While at the University of Pittsburgh, her team received funding from NIAID to study the T-cell Response Against Chlamydia in women, or TRAC, project. Since chlamydia multiplies inside host cells in a protective vacuole, a robust T-cell response is essential for protection. This new award will support TRAC2, which is the first of three main projects this new CRC will investigate.
In the first of these three projects, Darville and colleagues at the University of Pittsburgh will further study candidate vaccine antigens they identified in the previous TRAC project. The University of Pittsburgh will serve as the clinical core, enrolling 150 women at high risk of chlamydia infection into a longitudinal study. All women will be tested for this STI, and they will be treated with an antibiotic to clear the infection. They will then be followed at four time points over the next year to check for re-infection. Their samples will be sent to UNC for further T-cell antigen testing. Collaborators at the German Cancer Research Center in Heidelberg will examine the women’s antibody responses.
“Animals and people can develop partial or complete immunity to chlamydia after prolonged or repeated infection,” Darville said. “But many people can be infected over and over again, especially if their partner is not getting treated. We are trying to determine specific T-cell and antibody responses and the antigens recognized by immune cells of women who limit infection to their cervix, and those who remain uninfected over a year despite sexual exposure risk. This information will inform antigens and adjuvants for vaccine development. A preventative vaccine would greatly benefit women who suffer the brunt of disease due to this pathogen. Men rarely suffer negative effects of infection other than transmitting it to their partners.”
The second project is to test chlamydia vaccine candidates in animal models. Darville and partners will test antigens they previously found to be recognized by women’s T-cells, and other antigens identified through TRAC2 using viral vectors and nanoemulsion. The goal is to see which antigens and which delivery method elicit the best protective response against chlamydia in mice and guinea pig models. This second project will involve partners at UNC; Blue Willow Biologics in Ann Arbor, Michigan; Oxford University in England; and Queensland University of Technology in Australia.
The third project aims to determine non-invasive biomarkers that predict risk of upper genital tract infection in women acutely infected, as well as markers that predict risk of repeated infection. Such biomarkers could play a role in vaccine development by identifying women most likely to benefit from vaccination, and could also serve as surrogate endpoints of vaccine efficacy in future clinical trials. The partners involved in this project include colleagues at UNC, and N.C. State University.
In addition to Darville, other UNC faculty involved with the Chlamydia Vaccine Initiative CRC include Nilu Goonetilleke; Catherine O’Connell; and Xiaojing Zheng. UNC researchers are also sub-recipients of two of NIAID’s three other STI vaccine CRCs, including a project to identify a syphilis vaccine candidate with partners at the University of Connecticut, and a project to identify a gonorrheal vaccine candidate with partners at the Uniformed Services University of Health Sciences in Bethesda. These investigators include Arlene Seña; Jonathan Parr; Marcia Hobbs; Alex Duncan; and Rob Nicholas.