Hendrix Emily K, Sha Jian, Kilgore Paul B, Neil Blake H, Verma Atul K, Chopra Ashok K
Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA.
Vaccines (Basel). 2024 Dec 1;12(12):1361. doi: 10.3390/vaccines12121361.
Plague, caused by , poses a public health threat not only due to sporadic outbreaks across the globe but also due to its potential as a biothreat agent. Ironically, among the seven deadliest pandemics in global history, three were caused by . Pneumonic plague, the more contagious and severe form of the disease, is difficult to contain, requiring either prophylactic antibiotic treatment or vaccination. However, no vaccine (live attenuated or subunit) is currently approved by the Food and Drug Administration, requiring rigorous preclinical studies in different animal models, thus forming the basis of this study. : The aim of this study was to evaluate the efficacy and immune responses of two live attenuated vaccines (LAVs), LMA and LMP, either alone or in combination with a trivalent adenoviral vector-based vaccine (Ad5-YFV), in IL-17A-depleted and IgG control mice by using an anti-IL-17A monoclonal antibody (mAb) or its matched isotype IgG, respectively. : IL-17A mAb or IgG isotype control was administered to mice twice per week to their respective groups during the course of immunization. Serum, spleens, and broncho-alveolar lavage fluid (BALF) were collected for assessing immunological responses, and another cohort of mice was intranasally challenged with a lethal dose of parental CO92. : Robust humoral and cellular immune responses followed by complete protection were observed in all vaccinated animals against highly lethal intranasal challenge doses of parental CO92. Serum IgG titers to YscF and overall mucosal IgA titers to all three antigens of the Ad5-YFV vaccine were significantly lower, with slightly reduced serum LcrV-neutralizing antibodies when IL-17A was depleted compared to IgG control animals during the course of immunization. A remarkable reduction in Th1 (IFNγ or IL-2) and Th17 cell populations was observed in IL-17A-depleted mice compared to IgG controls in response to vaccination. On the other hand, B cell activities in germinal centers, overall activated antigen-specific T cells, and memory B and T cells remained at comparable levels in both vaccinated IL-17A-depleted and IgG control mice. : These data demonstrated the effectiveness of our vaccines even under the reduced levels of both Th1 and Th17 responses and thus should be suitable for those individuals associated with certain immune deficiencies.
由鼠疫耶尔森菌引起的鼠疫不仅因全球范围内的零星爆发，还因其作为生物威胁因子的潜在性而对公共卫生构成威胁。具有讽刺意味的是，在全球历史上最致命的七次大流行中，有三次是由鼠疫耶尔森菌引起的。肺鼠疫是该疾病传染性更强、更严重的形式，难以控制，需要进行预防性抗生素治疗或接种疫苗。然而，目前美国食品药品监督管理局尚未批准任何疫苗（减毒活疫苗或亚单位疫苗），这就需要在不同动物模型中进行严格的临床前研究，本研究即基于此展开。研究目的：本研究旨在通过分别使用抗白细胞介素 -17A 单克隆抗体（mAb）或其匹配的同型 IgG，评估两种减毒活疫苗（LMA 和 LMP）单独使用或与三价腺病毒载体疫苗（Ad5 - YFV）联合使用时，在白细胞介素 -17A 缺失小鼠和 IgG 对照小鼠中的疗效和免疫反应。方法：在免疫过程中，每周给各小鼠组两次注射白细胞介素 -17A mAb 或 IgG 同型对照。收集血清、脾脏和支气管肺泡灌洗液（BALF）以评估免疫反应，另一组小鼠经鼻给予致死剂量的亲本鼠疫耶尔森菌 CO92。结果：在所有接种疫苗的动物中，针对亲本鼠疫耶尔森菌 CO92 的高致死性鼻内攻击剂量，均观察到了强烈的体液和细胞免疫反应以及完全保护作用。与 IgG 对照动物相比，在免疫过程中，当白细胞介素 -17A 缺失时，针对 YscF 的血清 IgG 滴度以及针对 Ad5 - YFV 疫苗所有三种抗原的总体黏膜 IgA 滴度均显著降低，血清 LcrV 中和抗体略有减少。与 IgG 对照相比，在接种疫苗后白细胞介素 -17A 缺失的小鼠中，Th1（干扰素γ或白细胞介素 -2）和 Th17 细胞群体显著减少。另一方面，在接种疫苗的白细胞介素 -17A 缺失小鼠和 IgG 对照小鼠中，生发中心的 B 细胞活性、总体活化的抗原特异性 T 细胞以及记忆 B 和 T 细胞水平相当。结论：这些数据证明了即使在 Th1 和 Th17 反应水平降低的情况下，我们的疫苗仍然有效，因此应该适用于那些存在某些免疫缺陷的个体。
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