Immunoevasive Mucosal Vaccines Against HIV-1

针对 HIV-1 的免疫逃避粘膜疫苗

• 批准号: 8849820
• 负责人: Michael A Barry
• 金额: $ 77.6万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8849820
• 关键词: Adenoviruses; Adverse effects; Antibody Response; Antigen Targeting; Antigens; CCR5 gene; Cells; Chemical Engineering; Clinic; Complement; Data; Developing Countries; Foundations; Future; Gene Expression; Generations; Genes; Genetic Engineering; Goals; HIV; HIV Antigens; HIV vaccine; HIV-1; Human; Immune response; Immune system; Immunity; Immunization; Infection; Infection prevention; Intramuscular; Macaca; Macaca mulatta; Mediating; Modeling; Mucosal Immune Responses; Mucous Membrane; Mus; Open Reading Frames; Oral; Primates; Reagent; Research; Rest; Route; SIV; Safety; Serotyping; Surface; T-Lymphocyte; Testing; Time; Translations; Vaccination; Vaccines; Vagina; Viral Load result; Viremia; Virus; Work; chemical genetics; expression vector; helper-dependent adenoviral vector; immunogenic; improved; mouse model; mucosal vaccination; mucosal vaccine; nonhuman primate; novel; oral vaccine; rectal; response; simian human immunodeficiency virus; technology development; vaccine development; vaccine efficacy; vaccine evaluation; vaccine safety; vaccine trial; vector; vector-induced

DESCRIPTION (provided by applicant): The vast majority of HIV-1 infections occur at mucosal surfaces in the body. There is therefore an immediate need for potent HIV vaccines that can provide barrier protection at mucosal surfaces. While there is this need, most HIV vaccines have been developed and tested for their ability to drive systemic immune responses and not for mucosal responses. Given that systemic immunization generally does not provoke potent mucosal protection, this project will the ability of adenoviral vaccines to mediate protection against mucosal SIV infectoin after systemic immunization and compare this to protection after mucosal immunization by the oral route. Current first generation adenoviral (FG-Ad) vaccines encode 17 adenoviral open reading frames that can be targeted by anti-vector T cells. In contrast, helper-dependent adenoviral (HD-Ad) vectors encode zero. HD-Ad vectors therefore have a safety advantage over current clinically-utilized FG-Ad vaccines. Helper-dependent vectors can also be serotype-switched to evade pre-existing and vector-induced immune responses allowing four or more rounds of immunization. Given this and the recent side effects observed in the HIV STEP vaccine trial, this project will develop HD-Ad vectors to evade pre-existing immunity in humans. This project will first compare the ability of serotype-switched HD-Ad vectors to drive anti-SIV immune responses and protect macaques from mucosal SIV challenge after intramuscular and oral immunization. The ability of the serotype-switched vectors to evade anti-vector immune responses will be compared to the stealth abilities of helper-dependent adenovirus that is shielded with PEG. These vaccine challenge studies will be complemented with aims geared to improve the functionality of both the HD-Ad vectors and PEG with the goal of better evading immune responses in humans. These improvements will be made by genetic and chemical engineering and will be tested for function in mouse models. Development of these technologies combined with comparisons made in the macaque-SIV mucosal challenge model will provide information and reagents relevant to translation of these vaccines into humans. This work will also generate adenoviral vaccines with improved safety and efficacy as compared to current adenoviral vaccines in the clinic.

描述（由申请人提供）：绝大多数HIV-1感染发生在体内的粘膜表面。因此，立即需要有效的HIV疫苗，可以在粘膜表面提供障碍物保护。尽管有这种需求，但大多数艾滋病毒疫苗已经开发并测试了它们的驱动全身免疫反应的能力，而不是粘膜反应。鉴于系统性免疫通常不会引起有效的粘膜保护，因此该项目将腺病毒疫苗在全身免疫后介导对粘膜SIV感染的保护，并将其与口腔途径进行粘膜免疫后的保护。 当前的第一代腺病毒（FG-AD）疫苗编码17个可以由抗媒介T细胞靶向的腺病毒开放式阅读框。相反，依赖辅助腺病毒（HD-AD）向量编码零。因此，HD-AD载体比当前临床上利用的FG-AD疫苗具有安全性。还可以将辅助载体依赖性向量进行血清型转换，以逃避预先存在的和载体诱导的免疫反应，从而允许四轮免疫。鉴于此和最近在HIV步骤疫苗试验中观察到的副作用，该项目将开发HD-AD向量，以逃避人类预先存在的免疫力。 该项目将首先比较血清型开关的HD-AD载体驱动抗SIV免疫反应并保护猕猴免受肌肉内和口服免疫后粘膜SIV挑战的能力。将血清型转换矢量逃避抗载体免疫反应的能力将与用钉子屏蔽的辅助依赖性腺病毒的隐身能力进行比较。这些疫苗挑战研究将以旨在提高HD-AD载体和PEG功能的目的进行补充，目的是更好地逃避人类的免疫反应。这些改进将通过遗传和化学工程进行，并将在小鼠模型中进行功能测试。 这些技术的开发以及在猕猴粘膜挑战模型中进行的比较将提供与这些疫苗转化为人类有关的信息和试剂。与诊所中当前的腺病毒疫苗相比，这项工作还将产生具有提高安全性和功效的腺病毒疫苗。