A nonhuman primate toxicology and immunogenicity study evaluating aerosol delivery of AERAS-402/Ad35 vaccine Evidence for transient t cell responses in peripheral blood and robust sustained responses in the lungs
A nonhuman primate toxicology and immunogenicity study evaluating aerosol delivery of AERAS-402/Ad35 vaccine Evidence for transient t cell responses in peripheral blood and robust sustained responses in the lungs
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DOI：
10.4161/hv.29108
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发表时间：
2014-01-01
影响因子：
4.8
通讯作者：
Sizemore, Donata
中科院分区：
文献类型：
--
作者：
Hokey, David A.;Wachholder, Robert;Sizemore, Donata
卡介苗（BCG）是唯一获得许可的预防结核病（TB）的疫苗，对某些形式的结核分枝杆菌（Mtb）感染仅提供有限的保护。虽然Mtb感染可以用抗生素治疗，但这种疗法昂贵，有毒，需要几个月的治疗。此外，抗药性菌株的出现限制了抗生素的影响，并强调了开发更有效的疫苗来控制这种疾病的重要性。鉴于肺结核是最常见的疾病形式，能够诱导肺驻留免疫的疫苗可能有利于对抗这种感染。肺部分娩的新进展使这种疫苗接种途径可行且负担得起。在这里，我们评估了一种雾化的基于Ad 35的疫苗AERAS-402的安全性和免疫原性，作为GLP急性和慢性毒理学和安全性研究的一部分，该疫苗被递送到非人灵长类动物的肺部。在本研究中，动物通过雾化器吸入三次高剂量（1 x 10（11）vp）AERAS-402，间隔1周。AERAS-402的气雾剂递送导致相对肺重量增加以及肺、纵隔淋巴结、支气管相关淋巴组织和鼻咽部的显微镜检查结果，这与急性期免疫应答的诱导一致。这些结果在慢性期消退，被认为是非不良反应。此外，我们在外周血中观察到短暂的疫苗特异性免疫应答，以及在接种疫苗的非人灵长类动物的支气管肺泡灌洗液中观察到持续的高水平多功能CD 4（+）和CD 8（+）T细胞应答。这些数据表明，肺部递送基于Ad 35的疫苗可以是安全的，并且可以诱导有效的肺部驻留免疫。
Bacille Calmette-Guerin (BCG), the only licensed vaccine for the prevention of tuberculosis (TB), provides only limited protection against certain forms of Mycobacterium tuberculosis (Mtb) infection. While infection with Mtb can be treated with antibiotics, the therapy is expensive, toxic, and requires several months for treatment. In addition, the emergence of drug resistant strains limits the impact of antibiotics and underlines the importance of developing a more effective vaccine to control this disease. Given that pulmonary TB is the most common form of the disease, a vaccine capable of inducing lung-resident immunity may be advantageous for combating this infection. New advances in pulmonary delivery make this route of vaccination feasible and affordable. Here, we evaluate the safety and immunogenicity of an aerosolized Ad35-based vaccine, AERAS-402, delivered to the lungs in nonhuman primates as part of a GLP acute and chronic toxicology and safety study. In this study, animals received three high doses (1 x 10(11) vp) of AERAS-402 by inhalation via a nebulizer at 1-week intervals. Aerosol delivery of AERAS-402 resulted in an increase in relative lung weights as well as microscopic findings in the lungs, mediastinal lymph nodes, bronchus-associated lymphatic tissue, and the naso-oropharynx that were consistent with the induction of an immune response during the acute phase. These findings resolved by the chronic phase and were considered to be non-adverse. Furthermore, we observed transient vaccine-specific immune responses in the peripheral blood as well as sustained high-level polyfunctional CD4(+) and CD8(+) T cell responses in the bronchoalveolar lavage fluid of vaccinated nonhuman primates. The data suggest that pulmonary delivery of Ad35-based vaccines can be safe and can induce potent lung-resident immunity.