Immunoevasive Mucosal Vaccines Against HIV-1

针对 HIV-1 的免疫逃避粘膜疫苗

• 批准号: 8662690
• 负责人: Michael A Barry
• 金额: $ 78.24万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662690
• 关键词: Adenoviruses; Adverse effects; Antibody Formation; Antigen Targeting; Antigens; CCR5 gene; Cells; Chemical Engineering; Clinic; Complement; Data; Developing Countries; Drug Formulations; 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 efficacy; vaccine evaluation; vaccine safety; 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 感染发生在体内粘膜表面。因此，迫切需要能够在粘膜表面提供屏障保护的有效艾滋病毒疫苗。尽管存在这种需求，但大多数艾滋病毒疫苗的开发和测试都是为了驱动全身免疫反应，而不是粘膜反应。鉴于全身免疫通常不会引起有效的粘膜保护，本项目将研究腺病毒疫苗在全身免疫后介导针对粘膜SIV感染的保护的能力，并将其与口服途径粘膜免疫后的保护进行比较。 目前的第一代腺病毒 (FG-Ad) 疫苗编码 17 个腺病毒开放阅读框，可以被抗载体 T 细胞靶向。相反，辅助依赖性腺病毒（HD-Ad）载体编码零。因此，HD-Ad载体比目前临床使用的FG-Ad疫苗具有安全性优势。辅助依赖性载体还可以进行血清型转换，以逃避预先存在的和载体诱导的免疫反应，从而允许四轮或更多轮免疫。鉴于这一点以及最近在 HIV STEP 疫苗试验中观察到的副作用，该项目将开发 HD-Ad 载体来逃避人类预先存在的免疫力。 该项目将首先比较血清型转换的 HD-Ad 载体驱动抗 SIV 免疫反应并保护猕猴在肌肉注射和口服免疫后免受粘膜 SIV 攻击的能力。血清型转换载体逃避抗载体免疫反应的能力将与用 PEG 屏蔽的辅助依赖性腺病毒的隐形能力进行比较。这些疫苗挑战研究将与旨在改善 HD-Ad 载体和 PEG 功能的目标相补充，以更好地逃避人类的免疫反应。这些改进将通过基因和化学工程实现，并将在小鼠模型中测试其功能。 这些技术的开发与猕猴-SIV粘膜攻击模型中的比较相结合，将为将这些疫苗转化为人类提供相关的信息和试剂。与目前临床上的腺病毒疫苗相比，这项工作还将产生安全性和有效性更高的腺病毒疫苗。