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首页> 外文期刊>Vaccine >A rationally designed flagellin-L2 fusion protein induced serum and mucosal neutralizing antibodies against multiple HPV types
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A rationally designed flagellin-L2 fusion protein induced serum and mucosal neutralizing antibodies against multiple HPV types

机译：理性设计的鞭毛蛋白-L2融合蛋白诱导血清和粘膜中和抗体对多种HPV类型的抗体

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摘要

The amino terminus of human papillomavirus (HPV) minor capsid protein L2 harbors several conserved neutralizing epitopes, including aa.17-36 (RG-1 epitope) and aa.65-85 consensus epitope (cL2 epitope), which are considered to be promising for the construction of cost-effective pan-HPV vaccine candidates. However, the immunogenicity of L2 epitope/peptide is rather weak, and the neutralizing spectrum induced by single type of L2 antigen is suboptimal. In this study, we constructed L2 concatemer with HPV18/33/58/59 RG-1 epitopes and 16L2 aa.11-88 peptide, and fused it with flagellin, a strong systemic and mucosal adjuvant, by hypervariable region replacement. A copy of cL2 epitope was also introduced to the C-terminus of the recombinant protein. The resultant Fla-5PcL2 protein can be produced in E. coli expression system with high yield and good stability. We assessed the immunogenicity of Fla-5PcL2 in mouse model via systemic and mucosal route, and found that subcutaneous immunization with Fla-5PcL2 induced robust serum neutralizing antibodies against divergent HPV types, while intranasal immunization with Fla-5PcL2 induced remarkable L2-specific IgA and cross-neutralizing antibodies in mucosal secretions, and medium titers of cross-neutralizing antibodies in sera. Moreover, Fla-5PcL2 induced full protection against vaginal HPV challenges. As mucosal antibodies provide the first-line defense at infection sites, and needle-free immunizations may increase vaccine compliance and require less public health resources, our results demonstrate that Fla-5PcL2 is a promising vaccine candidate which possibly meet the need in low-resource regions. (C) 2019 Elsevier Ltd. All rights reserved.
机译：人乳头瘤病毒（HPV）的氨基末端（HPV）次胶囊蛋白L2近几种保守中和表位，包括AA.17-36（RG-1表位）和AA.65-85共识表位（CL2表位），其被认为是有前途的用于建造具有成本效益的PAN-HPV疫苗候选者。然而，L 2表位/肽的免疫原性相当弱，并且单一型L2抗原诱导的中和光谱是次优。在这项研究中，我们用HPV18 / 33/58/59 RG-1表位和16L2 AA.11-88肽构建了L2调节剂，并用鞭毛素，强大的全身和粘膜佐剂融合，通过高变区域更换。还将Cl2表位的副本引入重组蛋白的C-末端。得到的FLA-5PCL2蛋白质可以在大肠杆菌表达系统中产生高产率和良好的稳定性。我们通过全身和粘膜途径评估了小鼠模型中FLA-5PCL2的免疫原性，发现用FLA-5PCL2诱导的稳健血清中和抗体免受发散HPV类型的稳健血清，而用FLA-5PCL2诱导显着的L2特异性IgA和鼻内免疫交叉中和粘膜分泌中的抗体，血清中的交叉中和抗体的中等滴度。此外，FLA-5PCL2诱导了对阴道HPV挑战的全面保护。由于粘膜抗体提供了感染部位的一线防御，无针免疫免疫可能会增加疫苗依从性并需要较少的公共卫生资源，我们的结果表明FLA-5PCL2是可能符合低资源需求的有希望的疫苗候选者地区。 （c）2019 Elsevier Ltd.保留所有权利。

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