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首页> 外文期刊>Vaccine >Low doses of flagellin-L2 multimer vaccines protect against challenge with diverse papillomavirus genotypes.
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Low doses of flagellin-L2 multimer vaccines protect against challenge with diverse papillomavirus genotypes.

机译：低剂量的鞭毛蛋白-L2多聚体疫苗可抵抗各种乳头瘤病毒基因型的攻击。

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摘要

Genetically modified bacterial flagellin (Fla), a Toll-like receptor-5 (TLR5) ligand, was evaluated as a fusion partner for human papillomavirus (HPV) L2-based immunogens in two animal challenge models; either cutaneous inoculation of rabbits with HPV 'quasivirions' containing cottontail rabbit papillomavirus (CRPV) genomes that induce warts, or intra-vaginal inoculation of mice with HPV 'pseudovirions' encapsidating a luciferase reporter plasmid and measurement of bioluminescence to determine infectivity. An Escherichia coli production system was developed for flagellin-L2 (Fla-L2) fusions containing either monomeric HPV-16 L2 a.a. 11(*11-200) or oligomeric L2 comprising a fusion of the a.a. 11-88 peptides of five (Fla-5*11-88) or eight (Fla-8*11-88) genital HPV types. Immunogenicity and bioactivity of Fla-L2 constructs were assessed using an in vitro neutralization and cell-based TLR-5 binding assay, respectively. Efficacy was evaluated following active immunization of rabbits or mice administered 3 intramuscular doses of Fla-L2 recombinants without exogenous adjuvant, followed by challenge. In addition, passive immunization studies of naive rabbits with serial dilutions of pooled immune sera were used to determine End-Point Protection Titers (EPPT) for each formulation against a broader spectrum of HPV quasivirions. Efficacy was assessed for up to 10 weeks on the basis of wart volume induced following challenge and results compared to licensed L1-VLP vaccines (Gardasil and Cervarix). Following active immunization at doses as low as 1 g, Fla-L2 fusions afforded complete protection against infection (mice) and disease (rabbits) following either homologous or heterologous HPV challenge. Passive immunization with anti-L2 immune sera discriminated between the different vaccine candidates under evaluation, demonstrated the protective role of antibody and suggested the superiority of this oligomeric L2-TLR5 agonist fusion approach compared to L1-based vaccines in its ability to cross-protect against non-vaccine HPV types.
机译：转基因细菌鞭毛蛋白（Fla），一种Toll样受体5（TLR5）配体，在两种动物攻击模型中被评估为基于人乳头瘤病毒（HPV）L2免疫原的融合伴侣。可以对兔子进行皮肤接种含有可诱发疣的棉尾兔乳头瘤病毒（CRPV）基因组的HPV'拟病毒体'，或对小鼠进行阴道内接种带有萤光素酶报告质粒的HPV'pseudovirions'并进行生物发光测定以确定感染性。开发了一种大肠杆菌生产系统，用于含有单体HPV-16 L2 a.a的鞭毛蛋白-L2（Fla-L2）融合蛋白。 11（* 11-200）或包含a.a.五个（Fla-5 * 11-88）或八个（Fla-8 * 11-88）生殖器HPV类型的11-88肽。分别使用体外中和法和基于细胞的TLR-5结合测定法评估Fla-L2构建体的免疫原性和生物活性。在对兔子或小鼠进行3次肌肉内剂量的Fla-L2重组体（不含外源佐剂）的主动免疫后，进行免疫接种，然后进行攻击，评估疗效。此外，对幼兔进行连续免疫血清稀释后的被动免疫研究用于确定每种制剂针对更广谱的HPV拟病毒体的终点保护滴度（EPPT）。与授权的L1-VLP疫苗（Gardasil和Cervarix）相比，根据攻击后诱导的疣体积和结果评估了长达10周的功效。在以低至1 g的剂量进行主动免疫后，Fla-L2融合蛋白可完全保护其免受同源或异源HPV攻击后的感染（小鼠）和疾病（兔子）侵害。在评估中的不同候选疫苗之间使用抗L2免疫血清进行被动免疫，证明了抗体的保护作用，并表明这种低聚L2-TLR5激动剂融合方法与基于L1的疫苗相比具有交叉防御能力非疫苗HPV类型。

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