Evaluation of the nasal adjuvant activity of angiotensin peptide Ang-(1-7)

血管紧张素肽Ang-(1-7)的鼻佐剂活性评价

• 批准号: 8245668
• 负责人: Herman F Staats
• 金额: $ 19.63万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245668
• 关键词: Address; Adjuvant; Adverse effects; Angiotensins; Anthrax disease; Antigens; Attenuated Vaccines; Binding; Biological Assay; CD8B1 gene; Cholera Toxin; Data; Developing Countries; Development; Emergency Situation; Environment; Epitopes; Evaluation; Foundations; General Population; Gold; HIV-1; Health Personnel; Human; IgE; Immune response; Immune system; Immunity; Immunization; Immunoglobulin A; Immunoglobulin G; Infectious Agent; Inflammatory; Injection of therapeutic agent; Learning; Life; Lymphoid Tissue; Methods; Monitor; Nasal cavity; Needles; Nose; Peptides; Population; Proteins; Public Health; Publishing; Recombinants; Route; Safety; Serum; Signal Transduction; Smallpox Vaccine; Staging; Subunit Vaccines; Testing; Toxic effect; Training; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccine Design; Vaccines; Virus; Work; angiotensin I (1-7); anthrax protective factor; cell mediated immune response; enzyme linked immunospot assay; experience; immunogenicity; mouse model; mucosal vaccine; novel; preclinical study; receptor; response; tool; vaccine delivery; vaccine development; vaccine efficacy

DESCRIPTION (provided by applicant): Studies proposed in this application will evaluate the adjuvant activity of a natural peptide product when delivered using the needle-free method of intranasal mucosal immunization. We will build upon previous published studies from our group and utilize anthrax recombinant protective antigen (rPA) and a peptide immunogen to evaluate the natural peptide angiotensin-(1-7) (Ang-(1-7)) for its ability to provide nasal adjuvant activity for the induction of serum and mucosal antigen-specific humoral and cell- mediate immune responses to include serum IgG, mucosal IgA as well as systemic and mucosal epitope-specific CD8 responses. We will also initiate studies to better define the mechanism of action of this natural peptide adjuvant. Our specific aims are listed below and will utilize a mouse model of nasal immunization to perform early-stage preclinical studies to determine the safety and efficacy of Ang-(1-7) as a nasal vaccine adjuvant when compared to the gold-standard mucosal adjuvant cholera toxin (cholera toxin is not suitable for use in humans due to numerous toxicities). Information learned by the completion of the studies proposed in this application will provide a foundation for the development of a novel, natural peptide for use as an adjuvant for needle-free mucosal vaccines. Our specific aims are: Aim 1. Evaluate the nasal adjuvant activity of Ang-(1-7) when nasally delivered with protein or peptide immunogens. Studies performed in this aim will evaluate the adjuvant activity of Ang-(1-7) when nasally delivered with a protein antigen (anthrax protective antigen) or a peptide immunogen (C4-V3 HIV-1 peptide). When using the protein antigen, we will monitor vaccine-induced antigen-specific serum IgG, IgA and IgE responses as well as mucosal IgA. When using the peptide antigen, we will monitor the induction of epitope-specific CD8 responses using IFN3 ELISPOT and tetramer assays. The adjuvant activity of Ang-(1-7) will be compared to control adjuvants cholera toxin and CpG. Aim 2. Perform studies to evaluate the mechanism of action of Ang-(1-7) and its safety when used as a nasal vaccine adjuvant. Ang-(1-7) is known to signal via the MAS receptor. Studies performed in this aim will utilize the MAS antagonist A-779 to determine if the MAS receptor is required for the adjuvant activity of Ang-(1-7) and to determine if the use of Ang-(1-7) influences the cellular composition of the nasal cavity lymphoid tissue after nasal vaccination. Additional studies will evaluate the safety of Ang-(1-7) when used as a nasal vaccine adjuvant. PUBLIC HEALTH RELEVANCE: Studies proposed in this application will evaluate the angiotensin peptide Ang-(1-7) for its ability to be used as a vaccine adjuvant and enhance the immunogenicity of vaccines delivered by the nasal route. These vaccines are designed to be delivered intranasally and may someday replace vaccines injected with a needle. The identification and development of safe and effective nasal vaccine adjuvants is needed to make progress in the development of nasally-administered vaccines.

描述（由申请人提供）：本申请中提出的研究将评估使用无针鼻腔内粘膜免疫方法传递天然肽产物的佐剂活性。我们将基于我们小组的先前发表的研究，并利用炭疽重组保护性抗原（RPA）和肽免疫原来评估天然肽血管紧张素 - （1-7）（ANG-（1-7）），以便为其提供血清和粘膜的鼻辅助剂提供鼻腔和粘膜的辅助性，以提供血清和粘膜的抗原性抗药性，并具有伴随性的抗原性抗原性抗原性粘膜和细胞性均匀的效果 - 粘膜IgA以及全身和粘膜表位特异性CD8响应。我们还将开始研究以更好地定义这种天然肽辅助的作用机理。我们的具体目的在下面列出，并将利用鼻腔免疫的小鼠模型进行早期临床前研究，以确定Ang-（1-7）作为鼻疫苗佐剂的安全性和功效，与金标准粘膜粘膜辅助糖毒素毒素相比（霍乱毒素毒素不适合使用荷马毒性毒性）。通过完成本申请中提出的研究所学的信息将为开发一种新颖的天然肽的发展提供基础，以用作无针头粘膜疫苗的辅助。我们的具体目的是：目标1。当用蛋白质或肽免疫原子递送鼻腔时，评估Ang-（1-7）的鼻辅助活性。当用蛋白质抗原（炭疽保护抗原）或肽免疫原（C4-V3 HIV-1肽）鼻塞递送时，以此目标进行的研究将评估Ang-（1-7）的辅助活性。使用蛋白质抗原时，我们将监测疫苗诱导的抗原特异性血清IgG，IgA和IgA反应以及粘膜IGA。使用肽抗原时，我们将使用IFN3 ELISPOT和四聚体测定法监测表位特异性CD8响应的诱导。将Ang-（1-7）的佐剂活性与对照佐剂霍乱毒素和CpG进行比较。 AIM 2。进行研究，以评估Ang-（1-7）的作用机理及其在用作鼻疫苗辅助时的安全性。已知Ang-（1-7）通过MAS受体发出信号。在此目标中进行的研究将利用MAS拮抗剂A-779来确定Ang-（1-7）辅助活性是否需要MAS受体，并确定使用ANG-（1-7）是否影响鼻腔疫苗后鼻腔淋巴样组织的细胞组成。当用作鼻疫苗佐剂时，其他研究将评估Ang-（1-7）的安全性。 公共卫生相关性：本应用中提出的研究将评估血管紧张素肽ANG-（1-7）的能力，其能力用作疫苗佐剂并增强鼻途径传递的疫苗的免疫原性。这些疫苗被设计为鼻内输送，有一天可能会取代注入针头的疫苗。需要确定和开发安全有效的鼻疫苗佐剂，以在开发鼻水疫苗方面取得进展。