Low doses of flagellin-L2 multimer vaccines protect against challenge with diverse papillomavirus genotypes.
Low doses of flagellin-L2 multimer vaccines protect against challenge with diverse papillomavirus genotypes.
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DOI：
10.1016/j.vaccine.2014.04.032
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发表时间：
2014-06-12
期刊：
影响因子：
5.5
通讯作者：
Kleanthous, Harold
中科院分区：
文献类型：
--
作者：
Kalnin, Kirin;Tibbitts, Timothy;Yan, Yanhua;Stegalkina, Svetlana;Shen, Lihua;Costa, Victor;Sabharwal, Robert;Anderson, Stephen F.;Day, Patricia M.;Christensen, Neil;Schiller, John T.;Jagu, Subhashini;Roden, Richard B. S.;Almond, Jeffrey;Kleanthous, Harold
关键词：
转基因细菌鞭毛蛋白 (Fla) 是一种 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 的免疫原的融合伴侣；要么对兔子进行皮肤接种，其中含有诱发疣的棉尾兔乳头瘤病毒 (CRPV) 基因组的 HPV“准病毒体”，要么对小鼠进行阴道内接种，用包裹荧光素酶报告质粒的 HPV“假病毒体”并测量生物发光以确定感染性。开发了一种大肠杆菌生产系统，用于包含单体 HPV-16 L2 a.a. 和 HPV-16 L2 的鞭毛蛋白-L2 (Fla-L2) 融合体。 11(× 11–200) 或包含 a.a. 融合体的寡聚 L2。 5 个 (Fla~5 × 11–88) 或 8 个 (Fla~8 × 11–88) 生殖器 HPV 类型的 11–88 肽。分别使用体外中和和基于细胞的 TLR-5 结合测定来评估 Fla-L2 构建体的免疫原性和生物活性。给兔子或小鼠主动免疫3次肌肉注射剂量的Fla-L2重组体（不含外源佐剂），然后进行攻击，然后评估功效。此外，使用连续稀释的混合免疫血清对初次接种的兔子进行被动免疫研究，以确定每种制剂针对更广泛的 HPV 准病毒颗粒的终点保护滴度 (EPPT)。根据攻击后诱导的疣体积以及与许可的 L1-VLP 疫苗（Gardasil 和 Cervarix）相比的结果，评估疗效长达 10 周。在以低至 1 μg 的剂量进行主动免疫后，Fla-L2 融合体在同源或异源 HPV 攻击后可提供针对感染（小鼠）和疾病（兔子）的完全保护。使用抗 L2 免疫血清的被动免疫区分了正在评估的不同候选疫苗，证明了抗体的保护作用，并表明与基于 L1 的疫苗相比，这种寡聚 L2-TLR5 激动剂融合方法在交叉保护非疫苗 HPV 类型的能力方面具有优越性。
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 naïve 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 μg, 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.
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影响因子：
56.9
作者：
Blander, JM;Medzhitov, R
通讯作者：
Medzhitov, R
影响因子：
--
作者：
Day, Patricia M.;Pang, Yuk-Ying S.;Schiller, John T.
通讯作者：
Schiller, John T.
影响因子：
5.4
作者：
Mejia, Andres F.;Culp, Timothy D.;Christensen, Neil D.
通讯作者：
Christensen, Neil D.
与HPV 16/18疫苗接种相关的英格兰年轻女性的生殖器疣下降：一项生态研究。
DOI：
10.1093/infdis/jit361
发表时间：
2013-11-01
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Howell-Jones R;Soldan K;Wetten S;Mesher D;Williams T;Gill ON;Hughes G
通讯作者：
Hughes G
影响因子：
5.4
作者：
Barr, Tom A;Brown, Sheila;Ryan, Gemma;Zhao, Jiexin;Gray, David
通讯作者：
Gray, David