April is sexually transmitted infections (STI) awareness month, and Arlene Seña, MD, MPH, a researcher with the Institute for Global Health and Infectious Diseases, is sounding the alarm about the importance of syphilis prevention, testing, and treatment. U.S. syphilis cases have increased nearly 80% since 2018, a level not seen since 1950, while babies born with syphilis have surged 937% in the past decade.
“Syphilis is easy to cure with antibiotics such as benzathine penicillin and doxycycline in the early stages of infection, said Seña. “But we need better diagnostic methods and the ability to provide treatment to everyone who needs it. Despite many advances in infectious diseases, we’re still using primarily serological tests that were developed in the early 1900s to determine infection and response to therapy.”
Although syphilis has been around for centuries, Seña says research has been hindered because no one has been able to successfully culture the spirochete in vitro directly from clinical specimens. Meanwhile, testing can be complicated because of the disease’s complex progression into several distinct phases, each with specific clinical characteristics. It can also coexist with other STIs, such as genital herpes and HIV, which can present significant challenges in diagnosis and management.
“Many clinicians struggle with diagnosis because syphilis is the great masquerader and can be easily mistaken for other diseases. In fact, Sir William Osler, the father of modern medicine, coined the phrase ‘those who understand syphilis understand medicine,’ recognizing the many different ways the disease can present.”
Syphilis is caused by the bacterium Treponema pallidum subsp pallidum. Early symptoms of syphilis can include painless ulcers and sores that progress to body rashes involving the palms and soles, hair loss, muscle pain and fatigue. If untreated, syphilis can cause serious health issues, including blindness, deafness, paralysis, and damage to the heart and brain. Approximately 40% of babies born to women with untreated syphilis can be stillborn, or die from the infection as a newborn. They may also be born with serious health issues.
In 2012, there was only one case of congenital syphilis reported in North Carolina. In 2022, there were 55 reported cases. According to a CDC report, 9 in 10 cases of congenital syphilis could have been prevented with timely testing and adequate treatment during pregnancy in 2022. And as with HIV, racial, ethnic, sexual, and gender minorities are disproportionately affected.
New Frontiers: Diagnostics and Vaccine Development
Dr. Seña has been researching sexually transmitted diseases for more than 25 years. But she says the persistent and chronic nature of syphilis–one that can hide from the immune and affect other organ systems, yet be completely cured if treated early–is fascinating.
“Syphilis is not just an STI, it can lead to health conditions that damage the heart, brain, eyes, and other organs, and this damage may not show up for many years. Studying the immunological responses and pathogenesis of syphilis is critical for the development of improved diagnostics and treatments.”
Currently, the disease is diagnosed using a screening algorithm that involves multiple serum antibody tests, but these tests have limitations, including the inability to reliably distinguish between current and past infections, and difficulty determining cure after antibiotics.
Modern molecular techniques such as nucleic acid amplification systems and platforms, transcriptomics, proteomics and metabolomics have been developed and successfully applied to the diagnosis of infectious diseases. However, developers of potential syphilis diagnostics have had little to no access to high-quality syphilis patient specimens for advancing product development.
Dr. Seña is thus leading an NIH contract to develop a syphilis specimen biorepository, collecting clinical data and different sample types from patients with predominantly primary and secondary, or early latent syphilis from both domestic and international sites. The stored samples will be available for future use by industry and academic partners to advance syphilis diagnostics.
In the area of syphilis vaccine development, Dr. Seña has also been a Co-Project Director for the NIH STI Cooperative Research Center grant for syphilis vaccine development titled “Global sequence and surface antigenic diversity of T.pallidum outer membrane proteins.” The multidisciplinary study, which involved patients with syphilis enrolled from Malawi, China and Colombia, have shown that there is clearly genomic diversity in infecting strains worldwide. Genome sequencing methods conducted by Dr. Jonathan Parr’s UNC team and by other collaborating institutions have facilitated the assessment of specific outer membrane proteins as potential vaccine candidates. Seña also leads a Bill and Melinda Gates supported study to further explore the genomic epidemiology of T. pallidum strains infecting women and men in low- and middle-income countries to inform syphilis vaccine development.
“We have been able to better characterize the molecular epidemiology of circulating T. pallidum as well as evaluate for variability in the spirochete’s key outer membrane proteins from patient samples. These are critical steps in the development of a syphilis vaccine with global efficacy. The results of our studies have been shared in pre-print but our peer-reviewed manuscript is in press with important findings.”
Training and Education
Dr. Seña serves as a consultant to the North Carolina HIV/STD Prevention and Care Branch. She also contributes to the Center for Disease Control and Prevention’s STD Treatment Guidelines and serves theSoutheastern Prevention Training Center. She finds many clinicians today don’t understand syphilis and how to management it. She frequently responds to questions about clinical diagnosis and treatment.
“I’m not only interested in training our young learners, such as medical students, residents and fellows, but also training clinicians and practice about syphilis. Syphilis infections have continued to rise among both men and women, and it is clearly an infection that can lead to significant complications, especially in pregnant women and their infants.”
Dr. Seña says a collaborative approach that combines translational and clinical research, innovative diagnostics, biomedical prevention strategies, and public health strategies will be needed to address the global burden of syphilis.