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紧密相互作用。专门的先天和自适应粘膜 免疫系统保护这些表面，是身体的第一道防线。更重要的原因之一 粘膜疫苗的发展是越来越多的证据表明刺激和准备局部粘膜免疫 反应对于防止感染性疾病（例如结核病）很重要。虽然整个免疫力 防止结核分枝杆菌（MTB）感染所需的反应曲目尚不清楚 动物模型表明，疫苗诱导的T辅助器17（Th17）细胞亚型的CD4+细胞自然地流动到 气道可以加速受保护的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，可以通过抗原特异性诱导穿孔蛋白的水平来评估， 颗粒酶B和颗粒状。另外，IgA和IgG粘膜抗体已显示出干扰进展 患有其他呼吸道病原体的疾病，可能对MTB采取类似的作用。呼吸上皮细胞是 粘膜疫苗的主要靶标。粘膜的主要部分是可以提供屏障功能的细胞 并用作传感器，通过模式识别受体检测危险的微生物组件并发射信号 潜在的粘膜细胞引发先天并促进适应性免疫反应。涉及多个MTB的研究 包括HBHA，RV3351C和ESAT6在内的分泌蛋白质已经确定了继承的初始相互作用之间的联系 病原体具有肺泡上皮细胞，随后从肺部传播微生物。这些MTB蛋白 还显示出在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/免疫疗法递送车，由于增强的吸收率 抗原呈递细胞，NP的首选淋巴处理，而不是淋巴机，而不是血液，并取决于 大小和组成，NP通过粘液和跨粘膜屏障扩散的能力。基于NP的疫苗的输送 呼吸道可能是增强先天免疫反应的一种手段，将是本研究的重点。经过 将所有这三个上皮细胞靶向MTB蛋白结合在NP车辆上 刺激矩阵加上可调节的矩阵，并将其作为粘膜增强疫苗部署到皮下BCG Prime，我们期望 动物肺中的保护性细胞和体液反应，并明显地保护MTB感染 与仅BCG疫苗接种所征收的相比。在目标1和2中，我们将评估效率和免疫回报 对于多种疫苗制剂，并确定将在AIM 3中评估的两个最受保护的疫苗，以确保安全，稳定性， 然后将在豚鼠中确认受保护的效率。我们的假设是通过刺激体液和细胞 我们的MTB多抗原粘膜纳米颗粒基质疫苗的免疫反应，随后的MTB气溶胶暴露将 导致肺部细菌复制减少，并增强BCG酸化产生的全身免疫反应 疫苗以更有效地清除残留细菌并减少或防止传播。我们相信这种方法 将在两个不同的动物模型中成功针对MTB，因此为随后的非人类奠定了基础 灵长类动物试验。