Recombinant polymorphic membrane protein D in combination with a novel, second-generation lipid adjuvant protects against intra-vaginal Chlamydia trachomatis infection in mice.
Recombinant polymorphic membrane protein D in combination with a novel, second-generation lipid adjuvant protects against intra-vaginal Chlamydia trachomatis infection in mice.
复制标题
重组多态性膜蛋白 D 与新型第二代脂质佐剂相结合，可防止小鼠阴道内沙眼衣原体感染。
DOI：
10.1016/j.vaccine.2016.06.081
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发表时间：
2016
期刊：
影响因子：
5.5
通讯作者：
Lacey,CharlesJN
中科院分区：
文献类型：
--
作者：
Paes,Wayne;Brown,Naj;Brzozowski,AndrzejM;Coler,Rhea;Reed,Steve;Carter,Darrick;Bland,Martin;Kaye,PaulM;Lacey,CharlesJN
开发一种能增强粘膜保护性免疫的衣原体疫苗对防治性传播沙眼衣原体（Ct）感染的全球传播至关重要。虽然衣原体抗原的鉴定和优先顺序是有效疫苗设计的关键先决条件，但新佐剂的开发和选择也可能在临床前Ct疫苗的转化潜力中发挥关键作用。虽然免疫调节组分的分子性质是最重要的，但佐剂制剂和递送系统也可控制疫苗功效和效力。我们的研究提供了重组Ctpolymorphic膜蛋白D（rPmpD）与三种不同配方的新型第二代脂质佐剂（SLA）组合的第一个临床前评价。SLA是通过修饰吡喃葡萄糖基脂质佐剂（GLA）（一种目前处于II期临床开发的TLR 4激动剂前体分子）在计算机上合理设计的。我们证明了对小鼠阴道内Ct攻击的强大保护作用，证明了对感染的抵抗力显著增强和平均细菌负荷减少。引人注目的是，保护被发现与强大的抗-rPmpD血清和宫颈阴道IgG滴度的存在相关，即使在不存在由每种SLA制剂引起的澄清剂诱导的Th 1型细胞免疫应答的情况下，我们进一步表明，抗-rPmpD抗体识别CtEB。这些发现强调了SLA的实用性和临床前Ct疫苗开发中佐剂的合理分子设计，但也表明抗rPmpD抗体在预防泌尿生殖道Ct感染中的重要作用。
The development of a chlamydial vaccine that elicits protective mucosal immunity is of paramount importance in combatting the global spread of sexually transmittedChlamydia trachomatis(Ct) infections. While the identification and prioritization of chlamydial antigens is a crucial prerequisite for efficacious vaccine design, it is likely that novel adjuvant development and selection will also play a pivotal role in the translational potential of preclinicalCtvaccines. Although the molecular nature of the immuno-modulatory component is of primary importance, adjuvant formulation and delivery systems may also govern vaccine efficacy and potency. Our study provides the first preclinical evaluation of recombinantCtpolymorphic membrane protein D (rPmpD) in combination with three different formulations of a novel second-generation lipid adjuvant (SLA). SLA was rationally designedin silicoby modification of glucopyranosyl lipid adjuvant (GLA), a TLR4 agonistic precursor molecule currently in Phase II clinical development. We demonstrate robust protection against intra-vaginalCtchallenge in mice, evidenced by significantly enhanced resistance to infection and reduction in mean bacterial load. Strikingly, protection was found to correlate with the presence of robust anti-rPmpD serum and cervico-vaginal IgG titres, even in the absence of adjuvant-induced Th1-type cellular immune responses elicited by each SLA formulation, and we further show that anti-rPmpD antibodies recognizeCtEBs. These findings highlight the utility of SLA and rational molecular design of adjuvants in preclinicalCtvaccine development, but also suggest an important role for anti-rPmpD antibodies in protection against urogenitalCtinfection.