Mucosal Helper-dependent Adenovirus Vaccines Against HIV-1

针对 HIV-1 的粘膜辅助依赖性腺病毒疫苗

• 批准号: 7086397
• 负责人: Michael A Barry
• 金额: $ 7.2万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2006-06-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7086397
• 关键词: AIDS vaccines; Adenoviridae; HIV infections; genetically modified animals; helper virus; human immunodeficiency virus 1; immune response; laboratory mouse; laboratory rabbit; mucosal immunity; neutralizing antibody; simian immunodeficiency virus; transfection /expression vector; vaccine development; vaccine evaluation; virus antigen

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 develop safer replication-defective helper-dependent adenoviral gene delivery vectors for mucosal vaccination. This project will pursue this goal in the following Aims: Specific Aim 1. Test Helper-dependent Adenoviral (HD-Ad) Vectors Expressing Codon-optimized SHIV Antigens for Their Ability to Drive Mucosal and Systemic Immune Responses. Specific Aim 2. Test Vector Immune Evasion Strategies to Enable Multiple Rounds of Priming and Boosting with HD-Ad Vectors. Specific Aim 3. Compare Routes of Administration and Enteric-coated Capsules to Maximize Mucosal T Cell and Neutralizing Antibody Responses. This project will generate HD-Ad vectors expressing HIV gag-pol, SIV gag-pol, and HIV-1 env. These HD-Ad vectors should prove safer than first generation vectors and will be packaged by four serotypes of adenovirus to test serotype switching as a means to evade neutralizing vector-specific immune responses and allow more effective vaccine boosting. Serotype-switching will be compared to polyethylene glycol (PEG) modification of the HD-Ad vectors for their abilities to evade vector neutralizing antibodies. These approaches should allow HD-Ad to be utilized for multiple rounds of immunization in the same host to take advantage of to robust supraphysiology transgene expression of Ad vectors. This project will package these adenoviral vaccines in enteric-coated capsules to develop a simple oral vaccine that delivers the vaccines more effectively to mucosal immune cells. These vectors will be tested in humanized HLA-A*0201 transgenic mice for T cell responses and will be tested in rabbits for neutralizing env antibody production. Successful pursuit of this project will enable more specific and less dangerous adenoviral vaccines for future testing in rhesus macaque SHIV challenge models and for future use in humans.

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，该项目将开发更安全的复制缺陷辅助依赖性腺病毒基因递送载体，用于粘膜疫苗接种。 该项目将通过以下目标来实现这一目标： 具体目标 1. 测试表达密码子优化的 SHIV 抗原的辅助依赖性腺病毒 (HD-Ad) 载体驱动粘膜和全身免疫反应的能力。 具体目标 2. 测试载体免疫逃避策略，以实现使用 HD-Ad 载体进行多轮启动和增强。 具体目标 3. 比较给药途径和肠溶胶囊以最大化粘膜 T 细胞和中和抗体反应。 该项目将生成表达 HIV gag-pol、SIV gag-pol 和 HIV-1 env 的 HD-Ad 载体。这些 HD-Ad 载体应该比第一代载体更安全，并将由四种血清型腺病毒包装，以测试血清型转换，作为逃避中和载体特异性免疫反应的手段，并允许更有效的疫苗加强。将比较血清型转换与 HD-Ad 载体的聚乙二醇 (PEG) 修饰，以了解其逃避载体中和抗体的能力。这些方法应该允许 HD-Ad 在同一宿主中用于多轮免疫，以利用 Ad 载体的强大的超生理学转基因表达。该项目将把这些腺病毒疫苗包装在肠溶胶囊中，开发一种简单的口服疫苗，将疫苗更有效地递送至粘膜免疫细胞。这些载体将在人源化 HLA-A*0201 转基因小鼠中测试 T 细胞反应，并在兔子中测试中和 env 抗体的产生。该项目的成功实施将为未来在恒河猴 SHIV 攻击模型中的测试以及未来在人类中的使用提供更特异且危险性更小的腺病毒疫苗。