Immunoevasive Mucosal Vaccines Against HIV-1

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HIV疫苗。虽然存在这种需求，但大多数HIV疫苗已经开发并测试了它们驱动全身免疫应答的能力，而不是粘膜应答。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粘膜SIV感染保护的能力，并将其与口服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，其可以被抗载体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载体相对于目前临床使用的FG-Ad疫苗具有安全性优势。辅助者依赖性载体也可以被转型以逃避预先存在的和载体诱导的免疫应答，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，以逃避人类预先存在的免疫力。 本项目将首先比较转基因HD-Ad载体驱动抗SIV免疫应答的能力，并在肌内和口服免疫后保护猕猴免受粘膜SIV攻击。将比较转基因载体逃避抗载体免疫应答的能力与用PEG屏蔽的辅助依赖性腺病毒的隐形能力。这些疫苗攻毒研究将补充旨在改善HD-Ad载体和PEG的功能，以更好地逃避人体免疫反应。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。 这些技术的发展与猕猴-SIV粘膜攻击模型中的比较相结合，将提供与这些疫苗转化为人类相关的信息和试剂。这项工作也将产生腺病毒疫苗，与目前临床上的腺病毒疫苗相比，其安全性和有效性有所提高。

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.