Department of Surgery, The University of Chicago, Chicago, IL 60637, USA.
Department of Surgery, The University of Chicago, Chicago, IL 60637, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
J Control Release. 2018 Jul 28;282:120-130. doi: 10.1016/j.jconrel.2018.04.031. Epub 2018 Apr 17.
Influenza vaccines that can be administered intranasally or by other needle-free delivery routes have potential advantages over injected formulations in terms of patient compliance, cost, and ease of global distribution. Supramolecular peptide nanofibers have been investigated previously as platforms for vaccines and immunotherapies and have been shown to raise immune responses in the absence of exogenous adjuvants and without measurable inflammation. However, at present it has not been tested whether the immunogenicity of these materials extends to the intranasal route. Here we investigated the extent to which self-assembled peptide nanofibers bearing an influenza peptide epitope elicit antigen-specific CD8 T cell responses when delivered intranasally, and we compared these responses with those elicited by subcutaneous immunization. Peptides containing an epitope from influenza acid polymerase (PA) and the Q11 self-assembly domain formed nanofibers that were avidly taken up by dendritic cells in lung-draining mediastinal lymph nodes after intranasal immunization. Intranasally delivered nanofibers generated greater antigen-specific CD8 T cell responses in the lung-draining lymph nodes than subcutaneous immunizations while retaining the non-inflammatory character of the materials observed in other delivery sites. The CD8 T cells elicited systemically were functional as assessed by their ability to produce IFN-γ ex vivo, lyse epitope-pulsed target cells in vivo, and diminish viral loads in infected mice. Compared to subcutaneously delivered nanofibers, intranasally delivered peptide nanofibers significantly increased the number of persisting antigen-specific tissue resident memory CD8 T cells in the lung, allowing for a more rapid response to infection at 6 weeks post-vaccination. These results indicate that intranasally delivered self-assembled peptide nanofibers are immunogenic when delivering CD8 epitopes without adjuvant or CD4 epitopes, are non-inflammatory, and promote more lung-resident memory CD8 T cells compared to subcutaneous immunization.
流感疫苗可通过鼻内或其他无针输送途径给药，与注射制剂相比，在患者依从性、成本和全球分发的便利性方面具有潜在优势。超分子肽纳米纤维以前曾被研究作为疫苗和免疫疗法的平台，并且已被证明在没有外源性佐剂和无明显炎症的情况下可提高免疫反应。然而，目前尚未测试这些材料的免疫原性是否扩展到鼻内途径。在这里，我们研究了携带流感肽表位的自组装肽纳米纤维在鼻内给药时引起抗原特异性 CD8 T 细胞反应的程度，并将这些反应与皮下免疫引起的反应进行了比较。含有流感酸聚合酶（PA）表位和 Q11 自组装结构域的肽形成纳米纤维，在鼻内免疫后，被肺部引流的纵隔淋巴结中的树突状细胞强烈摄取。与皮下免疫相比，鼻内给药的纳米纤维在肺部引流的淋巴结中产生了更大的抗原特异性 CD8 T 细胞反应，同时保留了在其他给药部位观察到的材料的非炎症特征。通过其体外产生 IFN-γ 的能力、体内裂解表位脉冲靶细胞的能力以及减少感染小鼠中的病毒载量来评估，系统中产生的 CD8 T 细胞是功能性的。与皮下给药的纳米纤维相比，鼻内给药的肽纳米纤维显著增加了肺部中持续存在的抗原特异性组织驻留记忆 CD8 T 细胞的数量，使疫苗接种后 6 周对感染的反应更快。这些结果表明，鼻内给药的自组装肽纳米纤维在不添加佐剂或 CD4 表位的情况下传递 CD8 表位时具有免疫原性，无炎症，并与皮下免疫相比，促进了更多的肺部驻留记忆 CD8 T 细胞。
