Current status of syphilis vaccine development: Need, challenges, prospects

Abstract

Syphilis is a multistage disease caused by the invasive spirochete Treponema pallidum subsp. pallidum. Despite inexpensive and effective antibiotic therapy, syphilis remains a prevalent disease in developing countries and has re-emerged as a public health threat in developed nations. In addition to the medical burden imparted by infectious syphilis, congenital syphilis is considered the most significant infectious disease affecting fetuses and newborns worldwide, and individuals afflicted with syphilis have an enhanced risk for HIV transmission and acquisition. The global disease burden of syphilis and failure of decades of public health efforts to stem the incidence of disease highlight the need for an effective syphilis vaccine. Although challenges associated with T. pallidum research have impeded understanding of this pathogen, the existence of a relevant animal model has enabled insight into the correlates of disease protection. Complete protection against infection has been achieved in the animal model using an extended immunization regimen of γ-irradiated T. pallidum, demonstrating the importance of treponemal surface components in generation of protective immunity and the feasibility of syphilis vaccine development. Syphilis is a prime candidate for development of a successful vaccine due to the (1) research community’s accumulated knowledge of immune correlates of protection; (2) existence of a relevant animal model that enables effective pre-clinical analyses; (3) universal penicillin susceptibility of T. pallidum which enhances the attractiveness of clinical vaccine trials; and (4) significant public health benefit a vaccine would have on reduction of infectious/congenital syphilis and HIV rates. Critical personnel, research and market gaps need to be addressed before the goal of a syphilis vaccine can be realized, including recruitment of additional researchers to the T. pallidum research field with a proportional increase in research funding, attainment of a definitive understanding of correlates of protection in humans, and engagement of industry/funding partnerships for syphilis vaccine production.

Transcription of TP0126, Treponema pallidum Putative OmpW Homolog, Is Regulated by the Length of a Homopolymeric Guanosine Repeat

“…The well-documented role of phase variation in controlling expression of surface-exposed proteins involved in the hostpathogen interaction promoted us to investigate whether TP0126 might also be a putative T. pallidum OMP not previously identified (52,53). As reported here, in silico analysis and CD spectrum data indicate that TP0126 exhibits structural characteristics consistent with a ␤-barrel OMP, supporting our hypothesis that TP0126 is a putative surface antigen.…”

Bipartite Topology of Treponema pallidum Repeat Proteins C/D and I

“…The proteins that assemble into the syphilis spirochete's outer membrane (OM) 2 determine the bacterium's ability to obtain nutrients, negotiate its way through tissue and endothelial barriers, fend off host defenses, and accomplish the many other facets of its complex and enigmatic infectivity program (7,8,11). Unfortunately, the dearth of information concerning its repertoire of outer membrane proteins (OMPs) has long been a major stumbling block to basic syphilis research and vaccine development (12,13). It is well established that the physical properties, composition, and molecular architecture of the T. pallidum OM differ considerably from those of Gram-negative bacteria (11).…”

A Homology Model Reveals Novel Structural Features and an Immunodominant Surface Loop/Opsonic Target in the Treponema pallidum BamA Ortholog TP_0326

“…The collective paucity of surfaceexposed pathogen-associated molecular patterns (PAMPs) and OM-spanning proteins is believed to be the ultrastructural basis for the syphilis spirochete's impressive capacity to evade innate and adaptive host defenses, a parasitic strategy designated "stealth pathogenicity" (26). Not surprisingly, molecular characterization of the spirochete's OMP repertoire has long been regarded as critical for unraveling the many enigmas of syphilis as well as being the key to the development of an effective vaccine (22,27). Rare OMPs presumably fulfill virulence-related and physiological functions in T. pallidum, an extreme auxotroph (28), analogous to those of their extensively characterized, nonorthologous Gramnegative counterparts (29).…”

“…Rare OMPs presumably fulfill virulence-related and physiological functions in T. pallidum, an extreme auxotroph (28), analogous to those of their extensively characterized, nonorthologous Gramnegative counterparts (29). Moreover, epitopes on the spirochetal surface represent potential targets for immune responses that contribute to containment of the pathogen during natural infection and/or confer protection following artificial immunization (26,27). It is also conceivable that sequence diversity in rare OMPs among circulating T. pallidum strains (30, 31) is a major contributory factor to the dynamics of disease transmission and reinfection in at-risk populations (32,33).…”