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POLYNUCLEOTIDE VACCINES FOR SIV INFECTION AND DISEASE

用于 SIV 感染和疾病的多核苷酸疫苗

基本信息

批准号：
6169245
负责人：
Robert Wallace Malone
金额：
$ 5.4万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-08-01 至 2001-02-16
项目状态：
已结题

项目摘要

This application proposes independent investigator support for a candidate who has been active in the development of non-viral gene delivery since 1986, and has participated in a number of original and significant studies including studies resulting in the conception of polynucleotide vaccines. The scope specifically involves the provision of funds to support the training of the principal investigator over a five year period. The majority of the work is supported by an active ARMDC award which will cover all other costs of the investigation. Recently the candidate has founded and directs a small academic gene therapy program, which has developed methods for mucosal gene delivery and polynucleotide vaccines. This gene therapy program has been assembled at the University of California at Davis, where it has been able to exploit the substantial expertise of the UC Davis CFAR research community and the local primate research center (CRFRC). The candidate currently holds an adjunct appointment, and the requested support would provide for some stability in salary for the candidate, allowing further development as an independent academic investigator. The candidate intends to continue to focus on the development and testing of non-viral gene transfer technologies and the application of those technologies to appropriate clinical targets. The candidate believes that polynucleotide vaccines are ht most appropriate therapeutic application for current non-viral gene delivery technologies, and hence is focused on the development of such vaccines for prevention of lentiviral disease and acute viral pneumonia. Genetic immunization (DNA vaccination) and cytokine augmentation of antiviral immune responses are novel areas of vaccine research. Limited studies have demonstrated that plasmids expressing viral genes induce protective antiviral immune responses after direct injection, and that exogenously administered cytokines can also influence pre-existing or developing host immune responses. However, the efficacy of genetic vaccines (with or without cytokines and /or B7) directed against lentiviruses which cause fatal immunodeficiency in primates (including humans) has not been proven. In addition, wee have yet to clarify immune responses in vaccinated primates that do confer protection versus those that do not. This proposal is aimed at defining a "safe" genetic immunization protocol capable of inducing protective immunity to SIV infection and disease, and concurrently identifying the immune mechanisms responsible for this protective immunity. The identification of these mechanisms is expected to further open the way to effective post exposure immunotherapies for already infected individuals. This application will provide support for achieving the following specific aims; 1. Development of DNA vectors for enhanced expression of lentiviral proteins. 2. Generating and evaluating immune responses to lentiviral proteins after direct DNA injection using mouse and macaque models. 3. Generating and evaluating immune responses to lentiviral proteins after direct DNA injection of vectors expressing both lentiviral proteins and cytokines. 4. Evaluation of clinical course of macaques which have been vaccinated using DNA injection and challenged with pathogenic SIV.

此应用程序建议为候选人提供独立调查员支持世卫组织一直积极参与非病毒基因传递的发展。 1986年，参与了许多原创性和有意义的研究包括导致多核苷酸疫苗概念的研究。该范围具体涉及提供资金以支持对首席调查员进行为期五年的培训。这个大部分工作得到了一个积极的ARMDC奖项的支持，该奖项将包括调查的所有其他费用。最近，这位候选人成立了并指导了一个小型的学术基因治疗项目，该项目已经开发出粘膜基因传递和多核苷酸疫苗的方法。这个基因治疗计划已经在加州大学洛杉矶分校组装完成戴维斯，在那里它能够利用加州大学戴维斯分校CFAR研究社区和当地灵长类研究中心 (CRFRC)。候选人目前担任兼职，而所请求的支助将为以下人员提供一些稳定的薪金候选人，允许作为独立学者进一步发展调查员。候选人打算继续把重点放在非病毒基因转移技术的开发和测试以及将这些技术应用于适当的临床靶点。这个候选人认为多核苷酸疫苗是最合适的当前非病毒基因传递技术的治疗应用，因此专注于这种疫苗的开发，以预防慢病毒病和急性病毒性肺炎。基因免疫(DNA 疫苗接种)和细胞因子增强抗病毒免疫反应疫苗研究的新领域。有限的研究已经证明表达病毒基因的质粒诱导保护性抗病毒免疫直接注射和外源性注射后的反应细胞因子也可以影响预先存在的或正在形成的宿主免疫回应。然而，基因疫苗(有或没有)的效力细胞因子和/或B7)针对导致致命的慢病毒灵长类动物(包括人类)的免疫缺陷尚未得到证实。在……里面此外，我们还没有弄清接种疫苗的灵长类动物的免疫反应。提供保护的人与不提供保护的人相比。这项提议旨在在定义一种“安全”的基因免疫方案时对SIV感染和疾病的保护性免疫，并同时确定负责这种保护性免疫的免疫机制。这些机制的确定有望进一步开辟道路对已经感染的患者进行有效的暴露后免疫治疗个人。这个应用程序将为实现遵循特定的目标； 1.慢病毒DNA增强表达载体的研制蛋白质。 2.慢病毒蛋白免疫应答的产生和评价使用小鼠和猕猴模型直接注射DNA。 3.慢病毒蛋白免疫应答的产生和评价直接DNA注射表达慢病毒蛋白和细胞因子。 4.已接种疫苗猕猴的临床病程评价使用DNA注射，并用致病性SIV攻击。