Chimeric adenoviruses for an improved HIV vaccine

用于改进艾滋病毒疫苗的嵌合腺病毒

• 批准号: 8446338
• 负责人: Qiana L Matthews
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-08 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446338
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adenovirus Vector; Adenovirus hexon capsid protein; Adenoviruses; Agreement; Animal Model; Antibodies; Antibody Formation; Antigens; Avidity; B-Lymphocytes; Biological Models; CD4 Positive T Lymphocytes; Capsid; Capsid Proteins; Cavia; Cell Maturation; Cell physiology; Cells; Cessation of life; Clinical; Complementarity Determining Regions; Data; Development; Engineering; Epitopes; Future; Generations; Genes; Genetic Transduction; Goals; HIV; HIV Antibodies; HIV Infections; HIV vaccine; HIV-1; Helper-Inducer T-Lymphocyte; Human; Humoral Immunities; Immune response; Immunity; Immunoglobulin Class Switching; In Vitro; Individual; Infection; Kinetics; Lead; Life; Malaria; Modeling; Modification; Mutation; Predisposition; Process; Property; Proteins; Pseudomonas; Rodent Model; Role; Serotyping; Serum; Severe Acute Respiratory Syndrome; Signal Transduction; Solutions; Structure of germinal center of lymph node; System; TNFRSF5 gene; Testing; Transgenes; Translations; Vaccination; Vaccine Clinical Trial; Vaccines; Viral Vector; Virus; World Health; antigen processing; base; immunogenicity; improved; in vivo; neutralizing antibody; next generation; novel; pandemic disease; pre-clinical; public health relevance; response; transduction efficiency; vaccine development; vector

DESCRIPTION (provided by applicant): Our proposal will address the need for a safe and effective HIV vaccine using next generation adenovirus (Ad) - based vectors. A variety of viral vectors have been employed to accomplish gene-based vaccination. One particularly promising approach is based upon genetic transduction via replication-incompetent adenoviral vectors (Ad). This utility has predicated the application of Ad-based vectors for a wide range of vaccine approaches, including recent studies demonstrating utility for Malaria, Ebola, SARS, Pseudomonas, and HIV. However, the recent findings of the STEP HIV vaccine clinical trial failed to reproduce promising findings seen in animal model systems. In this regard, this trial, which used a Ad5-based vaccine, failed to protect Ad5-seronegative individuals against infection and may even have enhanced infection in vaccinees with prior immunity to adenoviruses. In the aggregate, the general agreement is that efforts to reduce vector immunogenicity with respect to pre-existing Ad5 immunity will be required to generate a safer and effective Ad- based vector as an HIV vaccine. Therefore, our proposal will address these key points by engineering multiple genetic alterations as follows: (1) To evade humoral responses to the Ad5 vector, the major capsid protein hexon will be exchanged for the hexon of Ad3, a less prevalent serotype. Human immune responses largely focus on epitopes present in the hypervariable regions (HVR) of the Ad capsid hexon; therefore, a chimeric Ad5H3 capsid will evade recognition by preimmune Abs to Ad5 hexon (2) To induce HIV specific immune responses we will employ HIV capsid incorporation of antigen. We hypothesize that these Ad vectors can circumvent Ad5 immunity and provide HIV-specific immunity. The full merit of the promising adenovirus-based approach for vaccination is currently limited by host related immunity toward the vector. Accomplishing the goals of this proposal will expand our current understanding of host-vector interactions that will be critical for advancing the Ad vector platform as a viable approach for developing effective HIV vaccines. .

描述（由申请人提供）：我们的建议将解决使用基于下一代腺病毒（AD）的载体安全有效的HIV疫苗的需求。已经采用了多种病毒载体来完成基于基因的疫苗接种。一种特别有前途的方法是基于通过不含复制的腺病毒载体（AD）的遗传转导。该效用已经预测了基于AD的载体在多种疫苗方法中的应用，包括最近的研究证明了疟疾，埃博拉病毒，SARS，假单胞菌和HIV的效用。 但是，艾滋病毒疫苗临床试验的最新发现未能再现动物模型系统中看到的有前途的发现。在这方面，使用基于AD5的疫苗的试验未能保护AD5副疗法个体免受感染的影响，甚至可能增强了对腺病毒先前免疫力的疫苗感染。在总体上，一般的共识是，要减少先前存在的AD5免疫的媒介物免疫原性的努力才能产生作为HIV疫苗的更安全，有效的AD载体。因此，我们的建议将通过工程进行多种遗传改变来解决这些关键点：（1）为了逃避对AD5载体的体液反应，主要的CAPSID蛋白hexon将用于AD3的Hexon（一种较不普遍的血清型）。人的免疫反应主要集中在AD Capsid Hexon的高变量区域（HVR）中的表位；因此，嵌合AD5H3衣壳将通过免疫前ABS避免识别AD5己酮（2），以诱导HIV特异性免疫反应，我们将采用HIV Capsid掺入抗原。 我们假设这些AD载体可以规避AD5的免疫力并提供HIV特异性的免疫力。目前，基于腺病毒的有前途的基于腺病毒的方法的全部优点受宿主与载体相关的免疫力的限制。实现这一建议的目标将扩大我们对宿主向量互动的当前理解，这对于推进AD向量平台作为开发有效的HIV疫苗的可行方法至关重要。 。