The global spread of multidrug-resistant strains of Neisseria gonorrhoeae constitutes a public health emergency. With limited antibiotic treatment options, there is an urgent need for development of a safe and effective vaccine against gonorrhea. Previously, we constructed a prototype vaccine candidate comprising a peptide mimic (mimitope) of a glycan epitope on gonococcal lipooligosaccharide (LOS), recognized by monoclonal antibody 2C7. The 2C7 epitope is (i) broadly expressed as a gonococcal antigenic target in human infection, (ii) a critical requirement for gonococcal colonization in the experimental setting, and (iii) a virulence determinant that is maintained and expressed by gonococci. Here, we have synthesized to >95% purity through a relatively facile and economical process a tetrapeptide derivative of the mimitope that was cyclized through a nonreducible thioether bond, thereby rendering the compound homogeneous and stable. This vaccine candidate, called TMCP2, when administered at 0, 3, and 6 weeks to BALB/c mice at either 50, 100 or 200 μg/dose in combination with glucopyranosyl lipid A-stable oil-in-water nanoemulsion (GLA-SE; a Toll-like receptor 4 and TH1-promoting adjuvant), elicited bactericidal IgG and reduced colonization levels of gonococci in experimentally infected mice while accelerating clearance by each of two different gonococcal strains. Similarly, a 3-dose biweekly schedule (50 μg TMCP2/dose) was also effective in mice. We have developed a gonococcal vaccine candidate that can be scaled up and produced economically to a high degree of purity. The candidate elicits bactericidal antibodies and is efficacious in a preclinical experimental infection model.IMPORTANCE Neisseria gonorrhoeae has become resistant to most antibiotics. The incidence of gonorrhea is also sharply increasing. A safe and effective antigonococcal vaccine is urgently needed. Lipooligosaccharide (LOS), the most abundant outer membrane molecule, is indispensable for gonococcal pathogenesis. A glycan epitope on LOS that is recognized by monoclonal antibody (MAb) 2C7 (called the 2C7 epitope) is expressed almost universally by gonococci in vivo Previously, we identified a peptide mimic (mimitope) of the 2C7 epitope, which when configured as an octamer and used as an immunogen, attenuated colonization of mice by gonococci. Here, a homogenous, stable tetrameric derivative of the mimitope, when combined with a TH1-promoting adjuvant and used as an immunogen, also effectively attenuates gonococcal colonization of mice. This candidate peptide vaccine can be produced economically, an important consideration for gonorrhea, which affects socioeconomically underprivileged populations disproportionately, and represents an important advance in the development of a gonorrhea vaccine.

中文翻译：

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脂寡糖肽模拟候选淋球菌疫苗的临床前功效。

淋病奈瑟氏球菌的多药耐药性菌株在全球范围内传播构成了突发公共卫生事件。由于抗生素治疗选择有限，因此迫切需要开发安全有效的淋病疫苗。以前，我们构建了原型疫苗候选物，其中包含由单克隆抗体2C7识别的淋球菌脂联低聚糖（LOS）上的聚糖表位的肽模拟物（拟肽）。2C7表位在人类感染中广泛表达为淋球菌抗原靶标，（ii）在实验环境中对淋球菌定殖的关键要求，以及（iii）由淋球菌维持和表达的毒力决定簇。在这里，我们合成了> 通过相对容易且经济的方法，纯度达到95％的拟肽的四肽衍生物通过不可还原的硫醚键环化，从而使该化合物均匀且稳定。当以0、3、5和6周的剂量分别以50、100或200μg/剂的剂量与葡萄糖吡喃糖基脂质A稳定的水包油纳米乳剂（GLA-SE）组合施用给BALB / c小鼠时，称为TMCP2的这种候选疫苗； Toll样受体4和促TH1的佐剂）在实验感染的小鼠中引起了IgG杀菌并降低了淋球菌的定殖水平，同时加速了两种不同淋病球菌菌株的清除。同样，每两周一次3剂（50μgTMCP2 /剂量）对小鼠也有效。我们已经开发出一种淋球菌候选疫苗，可以按比例放大并经济地生产高纯度的疫苗。该候选物可产生杀菌抗体，并在临床前实验感染模型中有效。重要淋病奈瑟氏球菌已对大多数抗生素产生抗药性。淋病的发病率也急剧增加。迫切需要安全有效的抗淋球菌疫苗。脂寡糖（LOS）是最丰富的外膜分子，对于淋球菌的发病机理是必不可少的。单克隆抗体（MAb）2C7识别的LOS聚糖表位（称为2C7表位）在体内由淋球菌几乎普遍表达。先前，我们鉴定了2C7表位的肽模拟物（拟表位），将其配置为八聚体时并用作免疫原 减缓了淋球菌对小鼠的定植。在此，当与促进TH1的佐剂结合并用作免疫原时，mimitope的均质，稳定的四聚体衍生物还可以有效减轻小鼠的淋球菌定植。这种候选肽疫苗可以经济地生产，这是淋病的重要考虑因素，它对社会经济上处于贫困地位的人群造成了不成比例的影响，代表了淋病疫苗开发的重要进展。