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Alum 与 TLR7 激动剂联合使用，同时结合内源性 TLR4 和 5 激动剂，可协同增强针对 HPV RG1 表位的免疫应答。

Alum and a TLR7 agonist combined with built-in TLR4 and 5 agonists synergistically enhance immune responses against HPV RG1 epitope.

机构信息

Department of Microbiology, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.

Department of Hepatitis, AIDS and Blood borne Diseases, Pasteur Institute of Iran, Tehran, Iran.

出版信息

Sci Rep. 2023 Oct 5;13(1):16801. doi: 10.1038/s41598-023-43965-3.

DOI:10.1038/s41598-023-43965-3
PMID:37798448
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10556035/
Abstract

To relieve the limitations of the human papillomavirus (HPV) vaccines based on L1 capsid protein, vaccine formulations based on RG1 epitope of HPV L2 using various built-in adjuvants are under study. Herein, we describe design and construction of a rejoined peptide (RP) harboring HPV16 RG1 epitope fused to TLR4/5 agonists and a tetanus toxoid epitope, which were linked by the (GGGS) linker in tandem. In silico analyses indicated the proper physicochemical, immunogenic and safety profile of the RP. Docking analyses on predicted 3D model suggested the effective interaction of TLR4/5 agonists within RP with their corresponding TLRs. Expressing the 1206 bp RP-coding DNA in E. coli produced a 46 kDa protein, and immunization of mice by natively-purified RP in different adjuvant formulations indicated the crucial role of the built-in adjuvants for induction of anti-RG1 responses that could be further enhanced by combination of TLR7 agonist/alum adjuvants. While the TLR4/5 agonists contributed in the elicitation of the Th2-polarized immune responses, combination with TLR7 agonist changed the polarization to the balanced Th1/Th2 immune responses. Indeed, RP + TLR7 agonist/alum adjuvants induced the strongest immune responses that could efficiently neutralize the HPV pseudoviruses, and thus might be a promising formulation for an inexpensive and cross-reactive HPV vaccine.

摘要

为了缓解基于人乳头瘤病毒 (HPV) L1 衣壳蛋白的疫苗的局限性，研究人员正在研究基于 HPV L2 RG1 表位的疫苗制剂，并使用各种内置佐剂。在此，我们描述了一种含有 HPV16 RG1 表位的重新连接肽 (RP) 的设计和构建，该表位融合了 TLR4/5 激动剂和破伤风类毒素表位，由 (GGGS) 接头串联连接。计算机分析表明，RP 具有适当的物理化学、免疫原性和安全性特征。对预测的 3D 模型进行对接分析表明，TLR4/5 激动剂在 RP 内与其相应的 TLR 之间具有有效的相互作用。在大肠杆菌中表达 1206 bp 的 RP 编码 DNA 可产生 46 kDa 的蛋白质，用不同佐剂制剂中天然纯化的 RP 对小鼠进行免疫接种表明，内置佐剂在诱导抗 RG1 反应中起关键作用，而 TLR7 激动剂/明矾佐剂的组合可以进一步增强这种反应。虽然 TLR4/5 激动剂有助于引发 Th2 极化的免疫反应，但与 TLR7 激动剂结合会将其极化转变为平衡的 Th1/Th2 免疫反应。事实上，RP+TLR7 激动剂/明矾佐剂诱导的免疫反应最强，能够有效地中和 HPV 假病毒，因此可能是一种有前途的廉价且具有交叉反应性的 HPV 疫苗制剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9d2/10556035/5f1597b9d0cf/41598_2023_43965_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9d2/10556035/d39c165bcf27/41598_2023_43965_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9d2/10556035/02366487b8b2/41598_2023_43965_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9d2/10556035/e1243b2831b3/41598_2023_43965_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9d2/10556035/447acbc0dcc1/41598_2023_43965_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9d2/10556035/8c1fb66c8ecc/41598_2023_43965_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9d2/10556035/6eca8c076dc3/41598_2023_43965_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9d2/10556035/5f1597b9d0cf/41598_2023_43965_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9d2/10556035/d39c165bcf27/41598_2023_43965_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9d2/10556035/02366487b8b2/41598_2023_43965_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9d2/10556035/e1243b2831b3/41598_2023_43965_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9d2/10556035/447acbc0dcc1/41598_2023_43965_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9d2/10556035/8c1fb66c8ecc/41598_2023_43965_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9d2/10556035/6eca8c076dc3/41598_2023_43965_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9d2/10556035/5f1597b9d0cf/41598_2023_43965_Fig7_HTML.jpg

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