Optimization of Salmonelle-HIV-1 DNA Vaccine Vectors

沙门氏菌-HIV-1 DNA 疫苗载体的优化

• 批准号: 7768199
• 负责人: David Michael Hone
• 金额: $ 25.04万
• 依托单位: BACILLIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7768199
• 关键词: Antibodies; Antibody Formation; Antigens; Apoptosis; B-Lymphocytes; Bacteriophages; Cell Nucleus; Cells; Cholera Toxin; Clinical; Cytolysis; Cytoplasm; DNA Vaccines; Development; Doctor of Philosophy; Dose; Drug Formulations; Endosomes; FUS-1 Protein; Generations; Genetic Transcription; Goals; HIV Envelope Protein gp120; HIV-1; HIV-1 vaccine; Human poliovirus; Immune; Immune response; Infection; Intramuscular Injections; Invaded; Life; Link; Lymphoid Tissue; Measures; Mediating; Memory; Messenger RNA; Modality; Modeling; Modification; Mus; Nuclear; Nuclear Localization Signal; Nucleic Acid Vaccines; Oral; Polioviruses; Principal Investigator; Proteins; Protocols documentation; Replicon; Research; Research Personnel; Salmonella; Secondary Immunization; Series; Serum; Testing; Tropism; Vaccinated; Vaccination; Vaccines; design; experience; improved; meetings; mucosal vaccine; neutralizing antibody; oral HIV; oral vaccine; plasmid DNA; research study; response; stem; vaccination strategy; vaccine delivery; vector; vector-induced

DESCRIPTION (provided by applicant): The goal of the research in this proposal is to identify a Salmonella HIV-1 DNA vaccine vector configuration that induces durable, high-titer neutralizing antibody responses to HIV-1 in the mucosal and systemic immune compartments. The capacity of Salmonella vectors to deliver DNA vaccines and induce immune responses in the mucosal and systemic compartments supports the idea to deploy this vector to deliver DNA vaccines that express conformationally constrained HIV-1 Env immunogens. Moreover, strong humoral responses to gp120 developed in mice primed with a Salmonella gp120 DNA vaccine vector following two parenteral booster vaccinations with gp120 protein; in contrast, no such responses occurred in mice primed with the control Salmonella construct and boosted twice with gp120 protein (Section 3.3). The significance of having identified an effective vaccination protocol for the induction of high-titer antibody responses to a model HIV-1 antigen following a mucosal prime will not be overlooked. However, the Principal Investigator (PI) proposes that the complete utilization of this inexpensive oral vaccine vector necessitates that such responses arise without a heterologous vaccine modality boosts. In this regard, the responses induced by a first-generation Salmonella Env/gp120 DNA vaccine vectors to HIV-1 were predominantly cell-mediated ((1); App. 1). Nonetheless, the afore mentioned humoral priming attribute suggests the occurrence of low-dose immunogen expression, which induced memory T helper and B cell responses (12-16). By extension, the central hypothesis of this proposal is that the magnitude of the antibody responses to HIV-1 following vaccination with a Salmonella HIV-1 DNA vaccine vector is directly linked to the efficiency DNA vaccine delivery and immunogen expression in host cells. To test this hypothesis the potency and duration of mucosal and systemic antibody responses will be measured in mice vaccinated with Salmonella vectors that carry modifications designed to optimize DNA vaccine delivery and immunogen expression. It is projected that this approach will provide fundamental information germane to the development of an inexpensive oral HIV-1 vaccine.

描述(由申请人提供)：这项研究的目标是确定一种沙门氏菌HIV-1 DNA疫苗载体配置，在粘膜和系统免疫隔间诱导持久的、高滴度的HIV-1中和抗体反应。沙门氏菌载体传递DNA疫苗并在粘膜和系统内诱导免疫反应的能力支持利用该载体传递表达构象受限的HIV-1Env免疫原的DNA疫苗的想法。此外，用沙门氏菌gp120 DNA疫苗载体启动的小鼠在用gp120蛋白进行两次非肠道强化免疫后，对gp120产生了强烈的体液反应；相反，在使用对照沙门氏菌构建物和两次gp120蛋白加强免疫的小鼠中，没有发生这种反应(第3.3节)。确定一种有效的疫苗接种方案，以在粘膜启动后诱导对模型HIV-1抗原的高滴度抗体反应，其重要性将不会被忽视。然而，首席调查员(PI)提出，要完全利用这种廉价的口服疫苗载体，就必须在没有异源疫苗增强的情况下产生这种反应。在这方面，第一代沙门氏菌Env/gp120 DNA疫苗载体对HIV-1诱导的应答主要是细胞介导的(1)；1)。尽管如此，上述体液启动属性表明存在低剂量免疫原表达，从而诱导记忆T辅助细胞和B细胞反应(12-16)。推而广之，这一建议的中心假设是，接种沙门氏菌HIV-1 DNA疫苗载体后对HIV-1的抗体反应的大小直接与DNA疫苗的交付效率和宿主细胞中免疫原的表达有关。为了验证这一假设，将在接种沙门氏菌载体的小鼠身上测量粘膜和系统抗体反应的效力和持续时间，沙门氏菌载体带有旨在优化DNA疫苗递送和免疫原表达的修改。据预测，这种方法将提供与开发廉价的HIV-1口服疫苗密切相关的基本信息。