Sequencing Syphilis Genomes in the Quest to Develop a Global Vaccine

The sexually transmitted infection, syphilis, has seen a global resurgence. In the US, there were 207,255 cases in 2022 according to the Centers for Disease Control (CDC), more than any time since the 1950s. Neonates, some of them stillborn, made up 3,755 of those cases. Internationally, other countries are seeing an upward trend as well.¹

Work around prevention, specifically a syphilis vaccine, would be an ideal solution to this global problem. One of the biggest challenges, however, is the Treponema pallidum (TPA) bacteria that causes syphilis, according to Jonathan Parr, MD, MPH, associate professor of medicine in the Division of Infectious Diseases at UNC.

“We are just learning about its genetic diversity worldwide, but already a lot is known about its ability to escape the immune system, which presents particular challenges for developing a vaccine in the sense that when we as humans are infected by this bacteria, our immune systems can slowly get infections under control in most cases, but don't clear the infection as a result,” Parr said. “To develop an effective vaccine, we have to do better than nature. So, I think one of the initial challenges is designing a vaccine that generates a robust immune response, but one that's capable, ideally, of clearing these infections and preventing infection.”

Parr says the other major challenge is societal and getting public buy-in from the populations who could benefit from a potential vaccine.

“There is increased skepticism as a result of the Tuskegee experiments. However, the majority of people, at least in my colleagues’ work—who were surveyed about this—they were interested and willing to participate in the syphilis vaccine development efforts that we're undertaking, as long as we can prove that we're trustworthy partners; that we're taking their concerns into account; that we engage them; that we truly listen to what they think about the process,” he said.

Parr is part of an international collaboration of researchers and physicians who have collected one of the most extensive genomic surveys of the syphilis bacterium to date and correlated the genetic data with clinical information about the patients who provided the samples. They are using the data to search for proteins on the surface of the microbe that don’t vary. Such stable proteins could be good targets for a vaccine. They published their findings in the Lancet Microbe.¹

This study enrolled participants from 4 countries, including Colombia, China, Malawi, and the US. Samples of TPA genomes from Africa and South America had been underrepresented in previous genetic studies and were a particularly valuable addition to the TPA genetic dataset according to the investigators.

Interestingly, TPA does not have much variation compared to other pathogens but there is more variation on the genes on the outer surface of the protein, explains Parr.

“Much of the variation that does exist in its genome occurs in genes that encode proteins that are placed on the outer surface of this bacteria. And these proteins are very important when we think about vaccine design, because you ideally want to see generation of antibody responses that have something to bind. And so while there is much less genetic diversity across the genome, there is still diversity in the proteins that matter most for vaccine development,” he said.

We're learning a lot about this stealth pathogen which infects people, escapes the human immune response, but we're making progress towards development of a vaccine in the lab and in preclinical trials. —Jonathan Parr, MD, MPH

Although there is limited variability in the genomes, Parr points out there are numerous subpopulations of TPA and in thinking about vaccine development they need to consider genetic diversity in different parts of the world.

“As we identify these subpopulations, we can start to drill down on what are their unique features, and how do these unique features make them better able to persist in different populations, in terms of the humans who are infected, but also the environments where they live.”

The investigators have secured funding to continue their efforts to develop a syphilis vaccine.

Reference
1. Searching for a Vaccine Against an Ancient Scourge. UNC press release. September 19, 2024. Accessed December 17, 2025.
https://globalhealth.unc.edu/2024/09/searching-for-a-vaccine-against-an-ancient-scourge/