Innovative approaches to syphilis vaccine design

梅毒疫苗设计的创新方法

• 批准号: 9318448
• 负责人: CAROLINE E CAMERON
• 金额: $ 53万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-19 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9318448
• 关键词: Adjuvant; Adult; Affect; Africa; Antibodies; Antigens; Appearance; Attenuated; Basic Science; Biopsy; Blood; Canada; Cellular Immunity; Child; China; Clinical; Collection; Country; Custom; Development; Disease; Distant; Dose; Ensure; Epitopes; Europe; Evaluation; Fetal Death; Focal Infection; Formulation; Genomics; Goals; HIV; Human; Humoral Immunities; Immune response; Immunity; Immunization; Immunize; Immunologics; Incidence; Infant; Infection; Infection prevention; Interferon-alpha; Intravenous; Investigation; Knowledge; Laboratories; Latin America; Lead; Lesion; Life; Low Birth Weight Infant; Measures; Membrane Proteins; Methodology; Methods; Modeling; Molecular; Molecular Conformation; Morbidity - disease rate; N-terminal; National Institute of Allergy and Infectious Disease; Neonatal; Newborn Infant; Oryctolagus cuniculus; Penicillins; Peptide Hydrolases; Peptides; Persons; Population; Pregnant Women; Prevalence; Production; Proteins; Public Health; Recombinant Proteins; Recombinants; Recording of previous events; Regimen; Reporting; Risk; Sampling; Savings; Site; Surface Antigens; Syphilis; Syphilitic chancre; Systemic disease; Testing; Time; Treponema pallidum; Ulcer; United States; Vaccine Antigen; Vaccine Design; Vaccines; Vertical Disease Transmission; Viral Tumor Antigens; Virulent; Vulnerable Populations; Work; adverse pregnancy outcome; cell motility; cytokine; design; effective therapy; efficacy testing; innovation; knowledge base; mortality; novel vaccines; premature; prevent; programs; public health relevance; stillbirth; syphilis vaccine; transmission process; vaccine candidate; vaccine development

 DESCRIPTION (provided by applicant): Syphilis is the only bacterial STI for which proof of concept for vaccine development has been achieved, yet the complete protection reported by Dr. James N. Miller in 1973 was achieved only by 60 intravenous doses of motile γ-irradiated Treponema pallidum over 37 weeks. Although obviously impractical, this study emphasized the importance of surface antigens of T. pallidum and their native conformation. Our proposal embraces those critical concepts and unites the independent vaccine-related studies of two laboratory groups, providing a two- pronged approach to development of an effective syphilis vaccine that will (1) prevent development of the infectious ulcerative lesions to abolish transmission of T. pallidum and (2) inhibit treponemal dissemination through the host to prevent systemic disease and sequelae. Importantly, this proposal includes the evaluation of two human-track adjuvants designed to induce the Th1 immune responses required for protection. Through our respective basic research programs, we have identified two separate groups of highly conserved treponemal peptides that, when used as immunogens, inhibit (a) chancre development or ulceration (the N-terminal portions of TprK and Tpr subfamily I) and (b) treponemal dissemination in the host (Tp0751 [pallilysin]). This proposal builds on a two decade history of work to define protective antigens of T. pallidum, including optimized methods for recombinant antigen production (soluble pallilysin and refolded TprK and Tpr subfamily I); structural analyses to establish that recombinant proteins are in a close-to-native conformation; genomics-based knowledge of epitopes conserved among strains of T. pallidum; careful adjuvant selection to ensure use of a human-approved formulation that generates the required humoral and cellular immunity; and identification of possible correlates of protection. To accomplish our long-term goal of developing an effective vaccine for syphilis, we propose to (1) determine the combined immunoprotective capacity of the tri-antigen vaccine candidate cocktail in rabbits, using carefully refolded recombinant conserved N-terminal portions of TprK plus Tpr Subfamily I and soluble recombinant pallilysin, with two optimized human-track custom adjuvants; (2) determine the correlates of protection against syphilis, including cytokine production and multiple antibody functions; (3) determine the duration of immunity afforded by the vaccine cocktail prepared in the optimal custom adjuvant; and (4) determine the capacity of the tri-antigen cocktail to protect against infection by four additional strains of T. pallidum. Th successful accomplishment of these aims will lead the way toward development of an effective and broadly protective vaccine to prevent an infection that currently affects nearly 11 million adults, children, and infants each year.

 描述（由申请人提供）：梅毒是唯一一种已实现疫苗开发概念验证的细菌性传播感染，但 James N. Miller 博士于 1973 年报告的完全保护作用仅通过在 37 周内静脉注射 60 剂活动的 γ 射线照射的梅毒螺旋体来实现。尽管显然不切实际，但这项研究强调了梅毒螺旋体表面抗原及其天然构象的重要性。我们的提案涵盖了这些关键概念，并结合了两个实验室小组独立的疫苗相关研究，提供了一种双管齐下的方法来开发有效的梅毒疫苗，该疫苗将（1）防止感染性溃疡病变的发展，从而消除梅毒螺旋体的传播；（2）抑制密螺旋体通过宿主传播，以预防全身性疾病和后遗症。重要的是，该提案包括对两种人类轨迹佐剂的评估，这些佐剂旨在诱导保护所需的 Th1 免疫反应。通过我们各自的基础研​​究项目，我们已经确定了两组独立的高度保守的密螺旋体肽，当它们用作免疫原时，可抑制 (a) 下疳发展或溃疡（TprK 和 Tpr 亚家族 I 的 N 末端部分）和 (b) 宿主中的密螺旋体传播 (Tp0751 [palilysin])。该提案建立在定义梅毒螺旋体保护性抗原的二十年工作历史的基础上，包括重组抗原生产的优化方法（可溶性苍白球菌素和重折叠的 TprK 和 Tpr 亚家族 I）；结构分析以确定重组蛋白处于接近天然的构象；基于基因组学的梅毒螺旋体菌株中保守表位的知识；仔细选择佐剂，以确保使用经人类批准的配方，能够产生所需的体液和细胞免疫；并确定保护的可能相关性。为了实现我们开发有效的梅毒疫苗的长期目标，我们建议（1）使用仔细重折叠的TprK重组保守N端部分加上Tpr亚家族I和可溶性重组苍蝇素，以及两种优化的人轨定制佐剂，确定三抗原候选疫苗混合物对兔的联合免疫保护能力； (2)确定预防梅毒的相关性，包括细胞因子的产生和多种抗体功能； (3) 确定在最佳定制佐剂中制备的疫苗混合物所提供的免疫持续时间； (4)确定三抗原混合物防止四种另外的梅毒螺旋体菌株感染的能力。这些目标的成功实现将为开发一种有效且具有广泛保护性的疫苗来预防目前每年影响近 1100 万成人、儿童和婴儿的感染奠定基础。