Immunoevasive Mucosal Vaccines Against HIV-1

针对 HIV-1 的免疫逃避粘膜疫苗

• 批准号: 8489258
• 负责人: Michael A Barry
• 金额: $ 30.26万
• 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/8489258
• 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(申请人提供)：绝大多数HIV-1感染发生在身体的粘膜表面。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。虽然有这种需求，但大多数艾滋病毒疫苗的开发和测试是为了它们驱动全身免疫反应的能力，而不是粘膜反应。鉴于系统免疫一般不会引起强大的粘膜保护，本项目将研究腺病毒疫苗在系统免疫后介导对黏膜SIV感染的保护作用的能力，并将其与口服粘膜免疫后的保护作用进行比较。 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架，可以被抗载体T细胞靶向。相反，辅助者依赖腺病毒(HD-Ad)载体编码为零。因此，与目前临床使用的FG-Ad疫苗相比，HD-Ad载体具有更好的安全性。辅助者依赖载体也可以进行血清型转换，以逃避预先存在的和媒介诱导的免疫反应，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，以逃避人类先前存在的免疫。 本项目将首先比较血清类型转换的HD-Ad载体在肌肉内和口服免疫后驱动抗SIV免疫反应和保护猕猴免受粘膜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聚乙二醇包被的辅助子依赖型腺病毒的隐形能力进行比较。这些疫苗挑战研究将辅以旨在改善HD-Ad载体和聚乙二醇乙二醇酯功能的目标，目的是更好地逃避人类的免疫反应。这些改进将通过基因工程和化学工程进行，并将在小鼠模型上进行功能测试。 这些技术的发展，结合在猕猴-SIV黏膜挑战模型中进行的比较，将提供与将这些疫苗转化为人类相关的信息和试剂。这项工作还将产生比目前临床上使用的腺病毒疫苗更安全和更有效的腺病毒疫苗。