Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine
Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine
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DOI：
10.1128/mbio.02552-19
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发表时间：
2019-11-01
期刊：
影响因子：
6.4
通讯作者：
Rice, Peter A.
中科院分区：
文献类型：
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作者：
Gulati, Sunita;Pennington, Michael W.;Rice, Peter A.
淋病奈瑟菌多重耐药菌株的全球传播构成突发公共卫生事件。由于抗生素治疗选择有限，迫切需要开发一种安全有效的淋病疫苗。此前，我们构建了一种原型候选疫苗，该疫苗包含淋球菌脂寡糖（LOS）上聚糖表位的肽模拟物（mimitope），可被单克隆抗体2C7识别。2C7表位(i)在人类感染中作为淋球菌抗原靶点广泛表达，（ii）在实验环境中淋球菌定植的关键要求，以及（iii）淋球菌维持和表达的毒力决定因子。在这里，我们已经通过一个相对简单和经济的过程合成了一个四肽衍生物，纯度为>95%，通过一个不可还原的硫醚键环化，从而使化合物均匀和稳定。这种被称为TMCP2的候选疫苗，在BALB/c小鼠0、3和6周时，分别以50、100或200 μ g/剂量与glucopyranosyl脂质a -稳定水浸油纳米乳（GLA-SE；一种toll样受体4和T(H)1促进佐剂）联合使用，可诱导杀菌IgG，降低实验感染小鼠中淋球菌的定植水平，同时加速两种不同淋球菌菌株的清除。同样，两周给药3次（50 μ g TMCP2/剂量）对小鼠也有效。我们已经开发出一种淋球菌候选疫苗，可以扩大规模并经济地生产到高纯度。该候选药物引起杀菌抗体，并在临床前实验感染模型中有效。淋病奈瑟菌已对大多数抗生素产生耐药性。淋病的发病率也在急剧上升。迫切需要一种安全有效的抗淋球菌疫苗。低脂寡糖（LOS）是淋球菌最丰富的外膜分子，在淋球菌的发病过程中是不可或缺的。淋球菌在体内几乎普遍表达一种能被单克隆抗体（MAb） 2C7识别的LOS上的聚糖表位（称为2C7表位）。先前，我们鉴定了2C7表位的肽模拟物（mimitope），当其配置为八聚体并用作免疫原时，可以减少淋球菌在小鼠中的定植。在这里，一种均匀的、稳定的四聚体衍生物，当与促进T(H)1的佐剂结合并作为免疫原使用时，也能有效地减少淋球菌在小鼠中的定植。这种候选肽疫苗可以经济地生产，这是淋病的一个重要考虑因素，淋病对社会经济条件较差的人群影响较大，并且代表了淋病疫苗开发方面的重要进展。
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 mu g/dose in combination with glucopyranosyl lipid A-stable oil-in-water nanoemulsion (GLA-SE; a Toll-like receptor 4 and T(H)1-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 mu g 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 T(H)1-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.