# Outer Membrance Protein vaccinogens of Treponema pallium

> **NIH NIH U19** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2022 · $528,617

## Abstract

Syphilis, a sexually transmitted infection caused by the Treponema pallidum subsp. pallidum (TPA), has
undergone a dramatic resurgence in the United States since the late 1990s. Syphilis also poses a major threat
globally with an estimated 5.6 million new cases annually and 350,000 adverse pregnancy outcomes due to
mother-to-child transmission. There is a growing sense of urgency about the need for a syphilis vaccine as a
cornerstone of a strategy for global containment. Our quest to develop a syphilis vaccine began with the
recognition that the outer membrane (OM) of TPA differs fundamentally from those of prototypical Gram-
negative bacteria, such as E. coli. We hypothesized that TPA's `unorthodox' OM is the basis for its impressive
capacity for immune evasion and that identification of TPA's repertoire of rare OM-spanning proteins (OMPs)
holds the key to vaccine development.
 The ability of all previously tested antigens to confer at best only limited protection suggests that a syphilis
vaccine will require multiple components and, consequently, the need for a pipeline of candidate vaccinogens to
identify the combination that provides the greatest breadth and degree of local and systemic protection. Despite
the availability of genomic sequences, until recently, syphilologists were unable to catalog the spirochete's
`OMPeome'. The breakthrough came by using bioinformatics, computational, and structural algorithms to mine
the TPA genome for proteins predicted to form an amphiphilic b-barrel, the structural hallmark of OM-spanning
proteins. With this approach, we identified 20 candidate OMPs in TPA, which fall into two `classes': Tprs and a
group of unrelated (`non-Tpr') b-barrel-forming proteins. For several (TP0326/BamA and members of Tpr
subfamily I), b-barrel formation and OM localization in TPA has been validated by rigorous experimentation,
and their ability to elicit potent opsonic activity also has been demonstrated. Our proposal takes the notion of
`opsonic target as protective antigen' in an unbiased and novel direction: leading candidate OMP vaccinogens
are selected based on genomic sequences, bioinformatics, biophysical analysis, and structural modeling, rather
than whether they are recognized by immune sera generated during infection. Our pipeline consists of OMPs
from four `groups': BamA, subfamily I and II Tprs, and the FadLs. In Aim 1, we will refine our topological and
structural models for leading candidates in the Tpr subfamilies and FadL groups. In Aim 2, we will assess whether
high titer antisera against one or more candidate OMPs promote opsonophagocytosis of TPA (an ex vivo
correlate of protection) using rabbit and mouse macrophages. In Aim 3, we will determine in rabbits, and in
exploratory studies with mice, if immunization with one or more OMPs provides broad as well as strong
protection following challenge with diverse strains of TPA.

## Key facts

- **NIH application ID:** 10399446
- **Project number:** 5U19AI144177-04
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Justin D Radolf
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $528,617
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399446

## Citation

> US National Institutes of Health, RePORTER application 10399446, Outer Membrance Protein vaccinogens of Treponema pallium (5U19AI144177-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10399446. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*