How Connecticut Children’s is Advancing Syphilis Vaccine Research

Congenital Syphilis: The Risks for Newborns

Millions of individuals are infected with syphilis every year—including thousands of newborn babies. According to data from the Centers for Disease Control (CDC), cases of newborn syphilis increased nearly 700% between 2015 and 2024. For infants, the consequences of syphilis can be tragic.

“Syphilis is unique among the major bacterial STIs in its capacity for transplacental invasion, enabling direct fetal infection that can culminate in stillbirth,” said Dr. Hawley. Even in babies who survive, “there are a lot of downstream significant health problems that result from the infection,” she added.

In addition to prematurity and low birth weight, congenital syphilis can affect multiple parts of a baby’s body—including skin lesions, eye inflammation, abnormalities of the long bones, an enlarged spleen, and a highly infectious nasal discharge sometimes known as “snuffles.” Diagnosing syphilis in a newborn isn’t always straightforward, especially if the mother’s infection has gone undetected and untreated. 

“Some babies are born clearly symptomatic,” Dr. Hawley said. “Others look fine and go home, but then later become very sick and return to the hospital.” Testing is further complicated because newborns carry antibodies transferred from their mothers, which can make it difficult to distinguish active infection in the baby from maternal exposure.

Outsmarting a Stealth Pathogen: Understanding Treponema pallidum

Dr. Hawley, in collaboration with multiple researchers in the Spirochete Research Laboratories, has devoted her career to understanding the bacterium behind syphilis—Treponema pallidum—and using that knowledge to help develop a vaccine that could ultimately prevent the devastating outcomes of congenital syphilis. To understand the challenge facing Dr. Hawley’s research team, it helps to understand just how unusual T. pallidum is.

It belongs to a group of bacteria known as spirochetes, named for their distinctive spiral or wavelike shape. Over centuries of evolution, T. pallidum has become remarkably good at hiding from the human immune system. The outer membranes of many bacteria contain an abundance of proteins that the bacteria use for adhesion, acquiring nutrients, and other essential functions. Those proteins also give the immune system something to recognize and attack. 

But the surface of T. pallidum is different.

“It has a very reduced genome,” Dr. Hawley explained, “and as a result, the spirochete has either eliminated many of the proteins the immune system would normally recognize or hidden them beneath the surface, effectively shielding them from the host immune response.”

The few proteins that do remain exposed on its outer membrane are present in greatly reduced numbers. The result is what researchers call a “stealth pathogen,” a bacterium that can provoke a powerful immune response yet still hide in the body for years or even decades. For vaccine researchers, that creates a fundamental problem. A vaccine needs to teach the immune system what to attack, but T. pallidum offers few accessible targets. 

Finding New Targets for a Syphilis Vaccine

Dr. Hawley and other members of the Spirochete Research Laboratories are particularly interested in the scarce proteins that protrude through T. pallidum’s outer membrane. Those exposed areas could prove to be its Achilles heel. The team is studying candidate proteins that might be potential vaccine targets and examining the antibodies produced against them. Are the antibodies recognizing surface proteins? What are the functions of the targeted proteins being disrupted?

The team is also investigating which targets remain similar among strains circulating around the world, because a vaccine intended for global use must protect people against more than one local version of the bacterium. Encouragingly, Dr. Hawley and her colleagues have found that some outer membrane proteins appear to change little from strain to strain, making them promising potential vaccine targets. 

At the same time, a collaboration with clinical researchers in Colombia is providing specimens from people with active syphilis infections. Those samples allow the team to determine whether proposed vaccine targets are actually present during natural human infection—an essential piece of evidence before moving a candidate protein forward.

How AI Is Helping Advance Syphilis Vaccine Research

New computational tools are accelerating that work. Dr. Hawley’s team is using bioinformatics and artificial intelligence tools to predict the three-dimensional structures and possible functions of these critical proteins. “These modeling algorithms have the ability to compute a lot of things that an individual couldn’t do previously, and they are allowing us to learn a great deal more about how T. pallidum successfully infects humans,” she said. 

How Early Research Funding Leads to Greater Opportunities

In 2023, Dr. Hawley received a research grant from Connecticut Children’s Connection. It was that early seed funding that helped give her project the momentum it needed to successfully compete for funding from the Gates Foundation and Coefficient Giving. “It used to be the holy grail to have only NIH dollars,” she said. “Today, the reality is that NIH grants are so competitive. If you don’t have some preliminary data, you’re much less likely to get funded.” 

Philanthropy gives researchers the early support they need to generate data, as well as the flexibility to pursue promising avenues of inquiry quickly. Time matters when you’re studying a pathogen as wily as T. pallidum—and an infection as devastating to babies as syphilis. “I’m not sure who’s more persistent, the bacteria or me,” Dr. Hawley said. “But I have every intention of winning this fight.