Development of a Chimeric Syphilis Vaccine Candidate to Combat Local, Disseminated and Congenital Syphilis Infection

PROJECT SUMMARY
In several high-income nations, including the United States, infectious syphilis has been resurgent for
over two decades now, while syphilis is still endemic in low- and middle-income countries. Syphilis is therefore
still a public global health concern, particularly because it can lead to neurological sequelae such as dementia
and stroke-like syndromes, as well as cardiovascular manifestations potentially leading to death. Furthermore,
about half a million pregnancies are adversely affected by congenital transmission of the pathogen every year.
The partial success of recent syphilis control campaigns promoted by the CDC and WHO clearly highlights the
necessity of devising novel ways to control this serious infection.
The availability of an effective syphilis vaccine could make a significant difference in the global effort to
control the spread of this serious infection. Over the last decade, our research programs have had the focus of
identifying vaccine candidates among the surface-exposed antigens of the syphilis agent, Treponema pallidum
subsp. pallidum (T. pallidum). These studies have led to the discovery that the T. pallidum repeat (Tpr) protein
family and the Tp0751 vascular adhesin are critical proteins in the processes of chancre development/immune
evasion and systemic dissemination, respectively. When tested in immunization/challenge experiments in the
rabbit model of syphilis, these antigens were shown to provide significant protection against infection.
Furthermore, within these antigens, we have been able to pinpoint the epitopes necessary to generate a
protective host response.
To reduce the complexity and production costs of our vaccine candidates, we have developed a
chimeric protein platform where the non-functional loops of the Tp0751 protein are exchanged with conserved
epitopes from the Tpr proteins. This approach provides a single construct that retains the critical Tp0751
epitopes while allowing presentation of protective epitopes from other antigens in a stable and soluble scaffold.
This proposal encompasses the next phase of this research endeavor consisting of Investigational New Drug
(IND)-enabling pre-clinical studies. To this end, we will create future generations of the chimera vaccine
candidate to assess the level of induced immunoreactivity and protection, after which the vaccine delivery
formulation will be optimized with the lead candidate by performing in vivo immunization/challenge
experiments, toxicity and stability tests, and studies investigating compatibility with scale-up production.
Collectively these studies are anticipated to provide us with an efficacious syphilis vaccine candidate
that is ready for clinical studies.

Grant Number: 5U01AI182035-02
NIH Institute/Center: NIH
Principal Investigator: CAROLINE CAMERON