Immunization with a tri-antigen syphilis vaccine significantly attenuates chancre development, reduces bacterial load, and inhibits dissemination of Treponema pallidum

Lukehart, Sheila A.; Molini, Barbara J.; Gomez, Alloysius; Godornes, Charmie; Hof, Rebecca; Fernandez, Mark C.; Pitner, Ragan A; Gray, Sean A.; Carter, Darrick; Giacani, Lorenzo; Cameron, Caroline E.

doi:10.1016/j.vaccine.2022.11.002

Cited by 16 publications

(12 citation statements)

References 56 publications

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“…It is also essential to considerer immune evasion strategies developed by TPA, such as functional redundancy and phase variation. In this sense, targeting several proteins with two or more functions, such as transport and adhesion, could increase vaccine efficacy, as it was previously observed (218,219).…”

Section: Discussionmentioning

confidence: 59%

Syphilis vaccine: challenges, controversies and opportunities

et al. 2023

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Syphilis is a sexually or vertically (mother to fetus) transmitted disease caused by the infection of Treponema pallidum subspecie pallidum (TPA). The incidence of syphilis has increased over the past years despite the fact that this bacterium is an obligate human pathogen, the infection route is well known, and the disease can be successfully treated with penicillin. As complementary measures to preventive campaigns and early treatment of infected individuals, development of a syphilis vaccine may be crucial for controlling disease spread and/or severity, particularly in countries where the effectiveness of the aforementioned measures is limited. In the last century, several vaccine prototypes have been tested in preclinical studies, mainly in rabbits. While none of them provided protection against infection, some prototypes prevented bacteria from disseminating to distal organs, attenuated lesion development, and accelerated their healing. In spite of these promising results, there is still some controversy regarding the identification of vaccine candidates and the characteristics of a syphilis-protective immune response. In this review, we describe what is known about TPA immune response, and the main mechanisms used by this pathogen to evade it. Moreover, we emphasize the importance of integrating this knowledge, in conjunction with the characterization of outer membrane proteins (OMPs), to expedite the development of a syphilis vaccine that can protect against TPA infection.

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Section: Discussionmentioning

confidence: 59%

Syphilis vaccine: challenges, controversies and opportunities

et al. 2023

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“…It may be that an optimal protective immune response in humans must target multiple proteins. In 2022, Lukehart et al [31 ▪▪ ] demonstrated that immunization with a tri-antigen syphilis vaccine containing TprK, TprC, and Tp0571 peptides successfully protected animals from developing progressive lesions and significantly inhibited dissemination of organisms in rabbits. In this way, systematic study of the proteins that could potentially be targeted for vaccine candidates will make a significant impact on public health.…”

Section: Steps Towards a Syphilis Vaccinementioning

confidence: 99%

Update on syphilis in pregnancy: marrying basic science advances and clinical perseverance to solve an ancient public health problem

Adhikari

2024

Current Opinion in Obstetrics &Amp; Gynecology

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Purpose of review While the clinical disease of syphilis, its consequences in pregnancy, and its sensitivity to penicillin treatment have remained relatively unchanged for a century or more, new technologies and basic discoveries in syphilis research have translated into tangible advances in clinical diagnosis, treatment, and prevention. The purpose of this review is to help the reader understand some of the recent relevant scientific publications on syphilis and its causative organism in a clinical obstetric context. Recent findings Rates of adult and congenital syphilis have risen dramatically in the last decade despite public health efforts. Penicillin shortages and lack of screening or adequate treatment have all contributed to global disease burden. Advances in genomic and microbiological characterization of this spirochete have led to new developments in serologic and molecular diagnosis as well as evaluation of potential vaccine candidates. Until a syphilis vaccine is available, substance use disorders and lack of screening in pregnancy are associated with increased congenital syphilis, and these challenges will require novel solutions to fully address this public health crisis. Summary Addressing the burden of congenital syphilis demands that obstetricians stay well informed of new tools and resources for diagnosis, treatment, and prevention of syphilis now and in the future.

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“…Examples of vaccine candidates that were identified and tested thanks to the application of bioinformatics analyses to find putative surface-exposed antigens include conserved regions of the T. pallidum repeat antigen K (TprK; encoded by the tp0897 gene), the conserved amino-terminal portion of the TprC-I antigens (encoded by the tp0117, tp0131, tp0316, and tp0620 genes), and the Tp0751 adhesin. Immunization with Tpr-based peptides was shown to attenuate early lesion development and reduce the treponemal burden at injection sites following challenge (29)(30)(31) , while Tp0751-immunized animals had significantly reduced T. pallidum dissemination to distant organs after infection (31,32) . Vaccine formulations based on Tpr and Tp0751 antigens constitute the hub of a twopronged approach to vaccine development that exploits the ability of these antigens to attenuate early manifestations (hence reducing the chances of transmission) and inhibit dissemination, which is associated with the most serious manifestations of the infection (31) .…”

Section: Genetic Diversity Of T Pallidum and Vaccine Developmentmentioning

confidence: 99%

“…Immunization with Tpr-based peptides was shown to attenuate early lesion development and reduce the treponemal burden at injection sites following challenge (29)(30)(31) , while Tp0751-immunized animals had significantly reduced T. pallidum dissemination to distant organs after infection (31,32) . Vaccine formulations based on Tpr and Tp0751 antigens constitute the hub of a twopronged approach to vaccine development that exploits the ability of these antigens to attenuate early manifestations (hence reducing the chances of transmission) and inhibit dissemination, which is associated with the most serious manifestations of the infection (31) . At the same time, these early works highlighted the importance of sequencing genomes of syphilis strains to define the overall degree of genetic diversity in these genes.…”

Section: Genetic Diversity Of T Pallidum and Vaccine Developmentmentioning

confidence: 99%

Strategies for syphilis vaccine development

Giacani

2022

J Bras Doenças Sex Transm

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Research to identify a syphilis vaccine began shortly after the isolation of the first Treponema pallidum subspecies pallidum (T. pallidum) strain in 1912 by Nichols and Hough and the identification of several possible animal models for the infection, with the rabbit being the best one. During the century following T. pallidum isolation, none of the numerous immunization/challenge experiments performed with preparations ranging from whole-inactivated T. pallidum cells to recombinant proteins yielded an effective vaccine, and the search for a vaccine languished. Recently, however, scientific communities have experienced a resurgence in interest in developing a syphilis vaccine due to 1. the awareness that syphilis constitutes a tremendous burden for maternal health, particularly in low- and middle-income nations; 2. the improved understanding of the immunological processes leading to pathogen clearance during natural infection and of the mechanisms this pathogen developed to persist in the host; 3. the availability of a near-complete list of T. pallidum genes encoding putative surface-exposed antigens, which represent the most likely vaccine candidates; and, last but not least, 4. the effort made to expand the knowledge on the genetic and antigenic diversity of these vaccine candidates in strains circulating worldwide. Thus far, the most recent vaccine designs based on a subset of the pathogen’s surface-exposed antigens have provided immunized rabbits with a significant but incomplete protection upon infectious challenge. Nonetheless, the outcomes of these experiments help investigators refine strategies to achieve a formulation with the highest chances of moving from preclinical experimental settings to clinical trials. This editorial focuses on a subset of the strategies currently believed to be essential for vaccine development, namely, the improvement of our still limited understanding of the genomic diversity in T. pallidum strains from diverse geographical locations through the collection and isolation of modern syphilis strains and the identification of protective epitopes in potential vaccine targets by evaluating the ability of monoclonal antibodies to bind the target antigen and facilitate pathogen clearance. The use of genetic engineering of the syphilis spirochete to identify target surface proteins with an essential or near-essential role in T. pallidum biology to target in immunization/challenge experiments is also discussed.

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Immunization with a tri-antigen syphilis vaccine significantly attenuates chancre development, reduces bacterial load, and inhibits dissemination of Treponema pallidum

Cited by 16 publications

References 56 publications

Syphilis vaccine: challenges, controversies and opportunities

Syphilis vaccine: challenges, controversies and opportunities

Update on syphilis in pregnancy: marrying basic science advances and clinical perseverance to solve an ancient public health problem

Strategies for syphilis vaccine development

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