An Adjuvant-Independent Dual-Targeted (Multi-Function) Mucosal Vaccine Platform

不依赖佐剂的双靶点（多功能）粘膜疫苗平台

• 批准号: 8911997
• 负责人: Edmund J Gosselin
• 金额: $ 21.88万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911997
• 关键词: Activities of Daily Living; Adjuvant; Antibody Response; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Attenuated; B-Lymphocytes; Binding; Cell Maturation; Cells; Chimeric Proteins; Clinical; Communicable Diseases; Complex; Data; Dendritic Cells; Development; Dose; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Foundations; Francisella tularensis; Future; Generations; Human; IL2RA gene; Immune; Immune response; Immunity; Immunization; In Vitro; Infection; Inflammatory; Licensing; Life; Lung; Lymphoid Tissue; M cell; Measures; Mediating; Modeling; Mono-S; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Nose; Perception; Peripheral; Predisposition; Production; Protein Binding; Proteins; Publishing; Recombinants; Risk; Route; Serum Albumin; Staging; Streptococcus pneumoniae; System; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Technology; Testing; Toxic effect; Transgenic Mice; Vaccination; Vaccine Antigen; Vaccine Research; Vaccines; Variant; Viral; Work; base; biodefense; crosslink; cytokine; enzyme linked immunospot assay; immunogenic; immunogenicity; improved; in vitro Model; in vitro testing; infectious disease model; innovation; monolayer; mouse model; mucosal site; mucosal vaccine; neonatal Fc receptor; novel; novel vaccines; pathogen; pneumococcal surface protein A; prevent; protective efficacy; protein function; prototype; public health relevance; response; success; targeted sequencing; trafficking; vaccine development

 DESCRIPTION (provided by applicant): Most human pathogens enter via mucosal routes. Yet, there are very few licensed mucosal vaccines. Thus, there is a need for new vaccine technologies or adjuvants that stimulate protective immunity at mucosal sites. However, current mucosal adjuvants have significant limitations, including toxicity. We propose to develop/establish a novel recombinant, adjuvant-free, mucosal vaccine platform. The potential for an adjuvant-free mucosal vaccine platform is demonstrated using a mono [human FcγRI (hFcγRI)]-specific prototype fusion protein (FP) consisting of pneumococcal surface protein A (PspA) antigen (Ag) targeted to hFcγRI. Specifically, this prototype FP enhances immunogenicity and protection against a mucosal S. pneumoniae (Sp) challenge when administered intranasally (i.n.) to hFcγRI transgenic mice, in the absence of adjuvant. We now propose creating a dual-targeted (multi-functional) FP which: 1) Enhances delivery of vaccine Ag to hFcγRI-expressing Ag presenting cells (APCs) within the nasal-associated lymphoid tissue (NALT), via FcRn mediated transepithelial transport of FP. 2) Further enhances Ag internalization, dendritic cell (DC) maturation, and Ag presentation/T cell activation, via increased hFcγRI crosslinking on APCs within the NALT. Importantly, with the current focus of vaccine research primarily on adjuvant discovery, maximizing the potency of this adjuvant-free vaccine platform will be crucial to changing perceptions regarding the need for adjuvant. To achieve this, we will: Aim 1) Add an FcRn targeting sequence to the prototype (mono-targeted) PspA containing FP, as well as convert the bivalent FP to a trivalent FP. This novel multi-functional FP will then be tested in vitro for its ability to sequentially enhance transepithelial transport of Ag, Ag internalization, DC maturation, and Ag presentation/T cell activation. Aim 2: Optimize FP platform immunogenicity and protective efficacy utilizing the Sp PspA Ag mucosal vaccine model and hFcRn/hFcγRI-expressing mice. Specifically, we will compare bivalent vs. trivalent hFcRI-targeted FP (plus and minus the FcRn targeting component) i.n. The most protective FP will then be selected for further development and will also be tested for immunity and protection against multiple Sp strains versus a licensed Sp vaccine. Aim 3: Utilize an in vitro transwell model of the human nasal tract consisting of a human epithelial cell layer in the top well (representing the nasal lumen) and human immune cells in the lower well (representing the NALT). The ability of the optimized FP to transport Ag from the upper well to the lower well and subsequently enhance human T and B cell responses in the lower well will be examined. Ag-specific antibody responses will be measured by ELISA/ELISPOT. T cell activation will be measured via increased CD25 expression, T cell proliferation, and cytokine production. The proposed studies will be crucial to establishing this novel and innovative (dual-targeted/multi-functional) vaccine platform as a viable adjuvant-free approach for mucosal immunization. Furthermore, its success will fundamentally transform the paradigm for vaccine generation/administration against a wide array of infectious disease agents.

 描述（由申请人证明）：大多数人的病原体通过粘膜途径进入了新的疫苗技术或粘膜保护性的佐剂。平台。在没有佐剂的情况下，当鼻内（I.N.）对HFCγRI转基因小鼠施用时，我们提出创建（多功能）FP，这会增强疫苗促进AG呈现的细胞（APC）（APC） NALT，通过FCRN介导的FP的transepithitherelialialialialialialsport。为了实现佐剂，我们将在佐剂上添加FCRN的靶向序列（单靶）PSPA containg fp，并转换这个新型的多功能FP Enhance Transepithithialialialialialialialialialialialialialialialialialialialialialialialialialialialialialialialialialialia Transport of AG, AG Internalization, DC MATURATION, AG PRESENTATION/ T Cell Activation. 2: Optimize FP Platform IMMUNOGENICTIVE EFFICACYING THE SPA AG AG AG MUCCINE MODEL AND γRi-expressing Mice. Specifically, We Will Compare Bivalent vs. Trivalent HFCRI-目标FP组件）I.N。最具保护性的FP将进一步开发，并且还将测试Fornity和Protection agaltip le菌株与许可的SP SP疫苗3：使用体外 在顶部井中的人类上皮细胞层的Transwell模型较低（压抑NALT）。 ELISA/ELISPOT的红色将通过CD25表达，T细胞增殖和细胞因子的产生来测量/针对多种传染病药物的管理。