Novel Nanoparticle Respiratory Tract Mucosal Vaccine

新型纳米颗粒呼吸道粘膜疫苗

• 批准号: 10599198
• 负责人: FREDERICK D QUINN
• 金额: $ 47.96万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599198
• 关键词: Acceleration; Adjuvant; Adsorption; Aerosols; Animal Model; Animals; Antibodies; Antigen Targeting; Antigen-Presenting Cells; Antigens; Antimycobacterial Agents; BCG Live; Bacille Calmette-Guerin vaccination; Bacillus; Bacteria; Bacterial Adhesins; Blood Circulation; Blood Screening; Bronchoalveolar Lavage; C57BL/6 Mouse; CD4 Positive T Lymphocytes; CD8B1 gene; COVID-19; Cause of Death; Cavia; Cells; Child; Chimeric Proteins; Combined Vaccines; Dangerousness; Data; Development; Diffuse; Disease; Dose; Epithelial Cells; Fluorescence Microscopy; Future; Genes; Glycolates; Goals; Granzyme; Histopathology; Human; IL17 gene; Immune; Immune response; Immune system; Immunity; Immunoglobulin A; Immunoglobulin G; Immunologic Stimulation; Immunologics; Immunotherapy; Incubated; Infection; Infectious Agent; Inhalation; Innate Immune Response; Interferons; Link; Lung; Lymphatic; Membrane Microdomains; Microbe; Microscopic; Mucosal Immune Responses; Mucosal Immune System; Mucous Membrane; Mucous body substance; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Organ; Pathology; Pattern recognition receptor; Phase; Predisposition; Preparation; Production; Protein Secretion; Proteins; Residual state; Respiratory Mucosa; Respiratory System; Route; Safety; Signal Transduction; Spleen; Surface; Temperature; Testing; Th1 Cells; Toxic effect; Tuberculosis; Tuberculosis Vaccines; VDAC1 gene; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Viral; Waxes; adaptive immune response; airway epithelium; alveolar epithelium; biophysical properties; booster vaccine; cytokine; cytotoxic; cytotoxic CD8 T cells; delivery vehicle; efficacy evaluation; granulysin; guinea pig model; heparin-binding hemagglutinin; improved; microbial; mucosa-associated lymphoid tissue; mucosal vaccine; mutant; nanoparticle; nanoparticle delivery; nonhuman primate; novel; pathogen; perforin; prevent; protective efficacy; protein complex; recruit; respiratory pathogen; response; safety study; screening; sensor; subcutaneous; trafficking; transmission process; uptake; vaccine safety

Summary Bacterial and viral respiratory pathogens interact closely with mucosal surfaces. Specialized innate and adaptive mucosal immune systems protect these surfaces and are the first line of defense for the body. One of the more important reasons for the development of mucosal vaccines is the increasing evidence that stimulating and preparing local mucosal immune responses is important for protection against infectious against diseases, such as tuberculosis. Although the entire immune response repertoire needed for protection against Mycobacterium tuberculosis (Mtb) infection is not known, recent data in animal models suggest that vaccine-induced CD4+ cells of the T helper 17 (Th17) cell subtype, which naturally traffic to the airways, can accelerate the recruitment of protective Th1 cells and production of IFN, IL-17 and other cytokines. Cytotoxic CD8+ and CD4+ T cells also are important and can be assessed via levels of antigen-specific induction of perforin, granzyme B, and granulysin. In addition, IgA and IgG mucosal antibodies have been shown to interfere with the progression towards disease with other respiratory pathogens and may act similarly against Mtb. The respiratory epithelial cell is a primary target for mucosal vaccines. A major portion of the mucosa is comprised of cells that can provide a barrier function and serve as sensors to detect dangerous microbial components through pattern-recognition receptors and transmit signals to underlying mucosal cells to trigger innate and promote adaptive immune responses. Studies involving several Mtb secreted proteins including HBHA, Rv3351c and ESAT6 have identified links between the initial interaction of the inhaled pathogen with alveolar epithelial cells and the subsequent dissemination of the microbes from the lung. These Mtb proteins also have been shown to generate important immune responses in mice given subcutaneous or intranasal doses. Nanoparticles (NPs) are attractive mucosal vaccine/immunotherapy delivery vehicles due to the enhanced uptake by antigen-presenting cells, the preferential draining of NPs to lymphatics rather than to the bloodstream, and depending on size and composition, the ability of NPs to diffuse through mucus and cross mucosal barriers. Delivery of NP-based vaccines to the respiratory tract may be a means of enhancing innate immune responses and will be the emphasis of this study. By combining all three of these epithelial cell-targeting Mtb proteins on a NP vehicle combined with VacSIM® immune- stimulating matrix plus adjuvant, and deploying as a mucosal booster vaccine to the subcutaneous BCG prime, we expect protective cellular and humoral responses in animal lungs and significantly-elevated protection from Mtb infection compared to that conferred by BCG vaccination alone. In Aims 1 and 2, we will evaluate the efficacy and immune responses for multiple vaccine preparations and identify the two most protective which will be assessed in Aim 3 for safety, stability, and then protective efficacy will be confirmed in guinea pigs. Our hypothesis is that by stimulating humoral and cellular immune responses with our Mtb multi-antigen mucosal nanoparticle matrix vaccine, subsequent Mtb aerosol exposure will result in reduced bacterial replication in the lungs and augment systemic immune responses generated by the BCG-priming vaccine to more-effectively clear residual bacteria and decrease or prevent dissemination. We are confident this approach will be successful against Mtb in two different animal models, and thus, lay the groundwork for subsequent non-human primate trials.

概括 细菌和病毒呼吸道病原体与粘膜表面密切相互作用。 免疫系统保护这些表面，是身体的第一道防线。 粘膜疫苗的开发是越来越多的证据表明刺激和准备局部粘膜免疫 虽然整个免疫系统对预防传染病（例如结核病）的反应非常重要。 预防结核分枝杆菌 (Mtb) 感染所需的反应库尚不清楚，最近的数据 动物模型表明，疫苗诱导的 T 辅助细胞 17 (Th17) 细胞亚型的 CD4+ 细胞会自然地运输到 气道中，可以加速保护性 Th1 细胞的募集以及 IFN-、IL-17 和其他细胞因子的产生。 细胞毒性 CD8+ 和 CD4+ T 细胞也很重要，可以通过穿孔素的抗原特异性诱导水平进行评估， 此外，IgA 和 IgG 粘膜抗体已被证明可以干扰进展。 呼吸道上皮细胞是一种与其他呼吸道病原体相同的疾病，并且可能对结核分枝杆菌有类似的作用。 粘膜疫苗的主要目标 粘膜的主要部分由可以提供屏障功能的细胞组成。 并作为传感器通过模式识别受体检测危险的微生物成分并传输信号 作用于底层粘膜细胞，触发先天性和促进适应性免疫反应。 包括 HBHA、Rv3351c 和 ESAT6 在内的分泌蛋白已经确定了吸入物质的初始相互作用之间的联系。 病原体与肺泡上皮细胞结合，随后微生物从肺部传播。 也已被证明可以在给予皮下或鼻内剂量的小鼠中产生重要的免疫反应。 纳米颗粒 (NP) 是有吸引力的粘膜疫苗/免疫治疗递送载体，因为它增强了 抗原呈递细胞，纳米颗粒优先排至淋巴管而不是血液，并且取决于 大小和组成，纳米颗粒通过粘液扩散和穿过粘膜屏障的能力。 呼吸道可能是增强先天免疫反应的一种方法，也是本研究的重点。 将所有三种上皮细胞靶向 Mtb 蛋白结合在 NP 载体上，并与 VacSIM® 免疫结合 我们预计，刺激基质加佐剂，并作为皮下 BCG Prime 的粘膜加强疫苗部署 动物肺部的保护性细胞和体液反应，并显着提高对结核分枝杆菌感染的保护 与单独接种 BCG 疫苗相比，在目标 1 和 2 中，我们将评估功效和免疫反应。 多种疫苗制剂，并确定两种最具保护性的疫苗，将在目标 3 中评估其安全性、稳定性、 然后，保护功效将在豚鼠中得到证实，我们的假设是通过刺激体液和细胞。 使用我们的 Mtb 多抗原粘膜纳米颗粒基质疫苗产生免疫反应，随后的 Mtb 气溶胶暴露将 导致肺部细菌复制减少，并增强 BCG 引发产生的全身免疫反应 我们对这种方法充满信心，可以更有效地清除残留细菌并减少或防止传播。 将在两种不同的动物模型中成功对抗 Mtb，从而为后续的非人类研究奠定基础 灵长类动物试验。