不同铝佐剂配比HJY-ATRQβ-001疫苗制剂的免疫效应及安全性研究  

The immunological effects and safety of HJY-ATRQβ-001 vaccine preparations with different proportions of aluminum adjuvant

作　　者：胡夏君 刘倩倩 徐冬梅 杨红涛 廖玉华[1,2,3,4] 廖梦阳 邱志华 HU Xiajun;LIU Qianqian;XU Dongmei;YANG Hongtao;LIAO Yuhua;LIAO Mengyang;QIU Zhihua(Department of Cardiology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430022,China;Hubei Key Laboratory of Biological Targeted Therapy;Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases;Wuhan Huajiyuan Biotechnology Development Co.,Ltd)

机构地区：[1]华中科技大学同济医学院附属协和医院心内科,武汉430022 [2]生物靶向治疗研究湖北省重点实验室 [3]心血管疾病免疫诊疗湖北省工程研究中心 [4]武汉华纪元生物技术开发有限公司

出　　处：《临床心血管病杂志》2024年第5期394-401,共8页Journal of Clinical Cardiology

基　　金：国家自然科学基金项目(No:31370931)。

摘　　要：目的:具有生物靶向效应的治疗性疫苗在心血管疾病治疗中极具前景。针对血管紧张素Ⅱ受体1型(AT1R)的病毒样颗粒疫苗ATRQβ-001已在多种高血压动物模型中显示出良好的降压效果及靶器官保护效应。为进一步提高疫苗免疫效率,氢氧化铝佐剂被用于疫苗制备中。本研究旨在评价不同铝佐剂配比HJYATRQβ-001疫苗制剂的免疫效应和安全性,以指导铝佐剂的合理应用。方法:将ATRQβ-001分别与不同浓度氢氧化铝混合制成HJY-ATRQβ-001疫苗制剂1(含1mg/mL氢氧化铝)和疫苗制剂2(含2mg/mL氢氧化铝),皮下免疫后通过免疫荧光、流式细胞检测、酶联免疫吸附试验及酶联免疫斑点试验等方法评价疫苗制剂诱导的差异性免疫反应。结果:经皮免疫后,HJY-ATRQβ-001疫苗进入引流淋巴结的包膜下区域,并逐步转移并沉积于滤泡树突状细胞(FDCs)表面,为滤泡B细胞提供持续的抗原刺激。同时,两种疫苗制剂均能有效诱导抗原提呈细胞(DCs)成熟,并辅助2型辅助性T细胞(Th2)和滤泡辅助性T细胞(Tfh)主导的T细胞活化。值得注意的是,含高浓度佐剂的疫苗制剂2同时一过性激活了Th17细胞、细胞毒性T细胞(CTLs)和调节性T细胞(Treg),展示出更强的T细胞刺激性。疫苗在FDCs上的沉积和辅助性T细胞活化共同促进针对AT1R短肽的高效体液免疫应答,表现为特异性抗体分泌细胞、特异性抗体以及B细胞记忆形成,但含不同浓度铝佐剂的两组疫苗制剂在体液免疫激活效应上没有显著性差异。结论:氢氧化铝佐剂在HJY-ATRQβ-001疫苗免疫中表现出良好的免疫辅助效应,提高铝佐剂浓度在增加免疫刺激性的同时,未能显著提升体液免疫效果。为平衡免疫效果和安全性,在疫苗制备过程中应仔细考虑佐剂的添加和合适的剂量。Objective:Therapeutic vaccines with biological targeting effects have great potential in the cardiovascular diseases therapy.The viral like particle-based vaccine ATRQp-o01 targeting angiotensin II receptor type l(ATiR)has shown effective anti-hypertensive and target organ protective effects in various hypertension animal models.To further improve the immune efficiency,aluminum hydroxide adjuvant is used in vaccine preparation.The purpose of this study is to evaluate the immunological responses and safety of HJY-ATRQβ-001 vaccine preparations with different concentrations of aluminum hydroxide,aiming to guide the proper application of the adjuvant.Methods:HJY-ATRQβ-001 was mixed with different concentrations of aluminum hydroxide to produce vac-cine preparation 1(containing 1 mg/mL aluminum hydroxide)and vaccine preparation 2(containing 2 mg/ml aluminum hydroxide).Differential immune responses induced by the vaccine preparations were evaluated through immunofluorescence,flow cytometry,enzyme-linked immunosorbent assay and enzyme-linked immunospot assay.Results:Following subcutaneous immunization,HJY-ATRQβ-001 entered the subcapsular area of the draining lymph nodes and gradually deposited on the surface of follicular dendritic cells(FDCs),providing continuous antigen stimulation to follicular B cells.Meanwhile,both vaccine preparations effectively induced the maturation of antigen presenting cells(DCs)and T cell activation dominated by T helper 2 cells(Th2)and follicular helper T cells(Tfh).Notably,vaccine preparation 2 simultaneously activated Th17,cytotoxic T cells(CTLs)and regulatory T cells(Treg),showing stronger T cell stimulation,although these T cells activation was not sustained.Vaccine deposition and helper T cells activation promoted efficient humoral immune responses,manifested as specific antibody secreting cells,specific antibodies,and B cell memory formation against ATiR peptide segment.However,there was no significant differences in humoral immunity activation between the two groups of vaccine p

关 键 词：高血压 治疗性疫苗 铝佐剂 T细胞免疫 B细胞免疫 免疫安全性 

分 类 号：R544.1[医药卫生—心血管疾病]