Novel Nanoparticle Respiratory Tract Mucosal Vaccine

新型纳米颗粒呼吸道粘膜疫苗

• 批准号: 10442173
• 负责人: FREDERICK D QUINN
• 金额: $ 48.5万
• 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/10442173
• 关键词: Adjuvant; Aerosols; Animal Model; Animals; Antibodies; Antigen Targeting; Antigen-Presenting Cells; Antigens; BCG Live; BCG Vaccine; 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; Helper-Inducer T-Lymphocyte; Histopathology; Human; Immune; Immune response; Immune system; Immunity; Immunoglobulin A; Immunoglobulin G; Immunologics; Immunotherapy; Infection; Infectious Agent; Inhalation; Innate Immune Response; Interferons; Interleukin-17; 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; Preparation; Production; 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; base; 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; mycobacterial; nanoparticle; nanoparticle delivery; nonhuman primate; novel; pathogen; perforin; prevent; protective efficacy; protein complex; recruit; respiratory pathogen; response; safety study; screening; sensor; subcutaneous; trafficking; 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.

总结 细菌和病毒性呼吸道病原体与粘膜表面密切相互作用。专门的先天性和适应性粘膜 免疫系统保护这些表面，是身体的第一道防线。其中一个更重要的原因 粘膜疫苗的发展越来越多地证明，刺激和制备局部粘膜免疫 应对措施对于预防结核病等传染病十分重要。尽管整个免疫系统 保护免受结核分枝杆菌（Mtb）感染所需的反应谱尚不清楚， 动物模型表明，疫苗诱导的辅助性T细胞17（Th 17）亚型的CD 4+细胞，其自然地运输到 呼吸道，可以加速保护性Th 1细胞的募集和IFN γ、IL-17和其他细胞因子的产生。 细胞毒性CD 8+和CD 4 + T细胞也是重要的，并且可以通过穿孔素的抗原特异性诱导水平来评估， 颗粒酶B和颗粒溶素。此外，伊加和IgG粘膜抗体已被证明会干扰进展 对其他呼吸道病原体的疾病，并可能采取类似的行动，对结核分枝杆菌。呼吸道上皮细胞是一种 粘膜疫苗的主要目标。粘膜的主要部分由可提供屏障功能的细胞组成 作为传感器，通过模式识别受体检测危险的微生物成分， 以触发先天性和促进适应性免疫反应。涉及几种结核分枝杆菌的研究 分泌的蛋白质包括HBHA、Rv 3351 c和ESAT 6已经确定了吸入的微生物制剂的初始相互作用之间的联系。 病原体与肺泡上皮细胞和随后的传播的微生物从肺。这些Mtb蛋白 也已显示在给予皮下或鼻内剂量的小鼠中产生重要的免疫应答。 纳米颗粒（NPs）是有吸引力的粘膜疫苗/免疫疗法递送载体，这是由于纳米颗粒（NPs）增强的吸收。 抗原呈递细胞，优先排出的纳米粒子的血管，而不是血液，并取决于 大小和组成，NP通过粘液和穿过粘膜屏障扩散的能力。基于NP的疫苗的递送 可能是增强先天性免疫反应的一种手段，将是本研究的重点。通过 将所有这三种靶向上皮细胞的Mtb蛋白组合在NP载体上，所述NP载体与VacSIM®免疫- 刺激基质加佐剂，并作为粘膜加强疫苗部署到皮下卡介苗初免，我们预计， 动物肺中的保护性细胞和体液应答以及显著提高的抗Mtb感染保护 与单独接种BCG相比，在目标1和2中，我们将评估疗效和免疫应答 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， 然后在豚鼠中确认保护效力。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的免疫应答，随后的Mtb气溶胶暴露将 导致肺部细菌复制减少，并增强由BCG引发产生的全身免疫应答 疫苗，以更有效地清除残留的细菌，减少或防止传播。我们相信这种方法 将在两种不同的动物模型中成功对抗Mtb，从而为随后的非人类研究奠定基础。 灵长类动物试验