A defined syphilis vaccine candidate inhibits dissemination of Treponema pallidum subspecies pallidum

Abstract

Syphilis is a prominent disease in low- and middle-income countries, and a re-emerging public health threat in high-income countries. Syphilis elimination will require development of an effective vaccine that has thus far remained elusive. Here we assess the vaccine potential of Tp0751, a vascular adhesin from the causative agent of syphilis, Treponema pallidum subsp. pallidum. Tp0751-immunized animals exhibit a significantly reduced bacterial organ burden upon T. pallidum challenge compared with unimmunized animals. Introduction of lymph nodes from Tp0751-immunized, T. pallidum-challenged animals to naive animals fails to induce infection, confirming sterile protection. These findings provide evidence that Tp0751 is a promising syphilis vaccine candidate.

Syphilis

“…However, research on virulence determinants of T. pallidum , and our understanding of protective immunity against it, have been hindered by our inability to culture the bacteria in vitro. To overcome this limitation, genome sequencing of T. pallidum directly from clinical samples is now possible 92,238 This advance should enable understanding of strain variation on a global scale, and help to identify outer membrane proteins and other surface antigens as possible vaccine candidates 81 . A recent study showed that immunization of rabbits with the lipoprotein TP071 prevented dissemination of T. pallidum and, hence, has become a promising vaccine candidate 81 .…”

“…To overcome this limitation, genome sequencing of T. pallidum directly from clinical samples is now possible 92,238 This advance should enable understanding of strain variation on a global scale, and help to identify outer membrane proteins and other surface antigens as possible vaccine candidates 81 . A recent study showed that immunization of rabbits with the lipoprotein TP071 prevented dissemination of T. pallidum and, hence, has become a promising vaccine candidate 81 . Integration of potential vaccine targets with diagnostic targets in discovery programmes also hold promise in accelerating progress towards improved tools for control, prevention and ultimately the elimination of this disease.…”

“…For example, TP0751 (also known as pallilysin) is a laminin-binding lipoprotein and zinc-dependent metalloproteinase capable of degrading clots and extracellular matrix 76–78 . Although expressed by T. pallidum in minute quantities, surface exposure of TP0751 has been demonstrated by knock-in experiments in Borrelia burgdorferi (the spirochete that causes Lyme borreliosis 79 ), and the cultivatable commensal treponeme T. phagedenis 80 , opsonophagocytosis assays in T. pallidum 77 and, most recently, protection of immunized rabbits against dissemination of spirochetes following intradermal challenge 81 . The X-ray structure of TP0751, demonstrating an unusual lipocalin fold, should inform efforts to clarify its multi-functionality 79 .…”

“…Shown in the outer membrane are TP0751 (as known as pallilysin) 79,81 and Tpp17 (also known as TP0435) 82,241 — two surface-exposed lipoproteins; TP0453, a lipoprotein attached to the inner leaflet of the outer membrane 83 ; BamA (also known as TP0326) 84,94 ; a full-length T. pallidum repeat (Tpr) attached by its N-terminal portion to the peptidoglycan 93,94 ; and a generic β-barrel that represents other non-Tpr outer-membrane proteins identified by computational mining of the T. pallidum genome 112 . Substrates and nutrients present in high concentration in the extracellular milieu (such as, glucose) traverse the outer membrane through porins, such as TprC.…”

PCR detection for syphilis diagnosis: Status and prospects

“…In fact, it has also been used in the vaccine and bacterial resistance fields. For example, Lithgow Karen et al utilized real‐time PCR to detect the quantity of T. pallidum in New Zealand rabbits, and this method provided the precise immune effect of recombinational proteins Tp0751 and FlaB3. Although T. pallidum has been sensitive to penicillin since it first appeared, we should continue to be vigilant at drug‐resistant strains because of antibiotic abuse and gene mutations.…”