Preclinical Studies and T cell Responses

临床前研究和 T 细胞反应

• 批准号: 8821575
• 负责人: Rama Rao Amara
• 金额: $ 67.16万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821575
• 关键词: AIDS Vaccines; AIDS/HIV problem; ALVAC; Adjuvant; Antibodies; Antibody Response; Antigens; Antiviral Agents; Avidity; B-Lymphocytes; Binding; Cellular Immunity; Clinical; DNA; DNA Vaccines; Data; Dendritic Cells; Development; Dose; Genes; Genetic; Goals; HIV; HIV vaccine; HIV-1; Human; Humoral Immunities; Immune; Immunity; Infection; Infection prevention; Instruction; Life; Macaca; Macaca mulatta; Mediating; Phase I Clinical Trials; Proteins; Regimen; Relative (related person); Role; SIV; Safety; Specificity; Surface; T cell response; TNFSF5 gene; Testing; Universities; Vaccination; Vaccines; Virus; efficacy testing; immunogenicity; improved; novel; novel vaccines; poxvirus vectors; preclinical study; programs; protective efficacy; research study; safety testing; simian human immunodeficiency virus; vaccination strategy; vaccine efficacy; vector; vector vaccine

The overall goal of this project is to develop novel vaccination approaches that not only enhance the magnitude but also enhance the functional quality of anti-HIV cellular and humoral immunity. Specifically, we propose to combine two new vaccination approaches developed recently at Emory University that showed great promise in rhesus macaques. The first approach uses CD40L, a co-stimulatory molecule for dendritic cells (DC) and B cells, expressed on the surface of HIV VLPs as a genetic adjuvant for enhancing the magnitude and functional quality of HIV-specific cellular and humoral immunity leading to enhanced protection from acquisition of SIV infection. Adjuvanting the DNA prime with CD40L of a DNA/MVA S1V239 vaccine significantly enhanced the functional quality of anti-SIV cellular and humoral immunity, and efficacy against a heterologous mucosal SlV challenge. The second approach uses a new MVA that lacks 4 immune modulatory genes (MVAA4) as a vaccine vector that showed a significant increase in the magnitude of HIV-specific cellular and humoral immunity in rhesus macaques. In this project, we combine these two new complementary approaches to develop a novel vaccination strategy against HIV. Project 2 has two specific aims: Aim 1 will test the relative immunogenicity and efficacy of MVA and MVAA4 boosts for enhancing protective antibody responses primed by the CD40L-adjuvanted DNA vaccine. Results from this Aim will direct the clinical use of MVAA4 as a boost for our DNA vaccines in a heterologous primeboost vaccination regimen against HIV. Aim 2 will test the safety, immunogenicity, and protective efficacy of MVA/CD40L.co-delivered with the MVA/HIV vaccine. Results from this Aim will direct the clinical use of MVA/CD40L as an adjuvant for a homologous prime-boost MVA vaccination regimen against HIV. These macaque studies will use HIV clade C immunogens and SHIV challenge. The Envs in the immunogen and the proposed challenge virus shares only 76% identity and thus will allow the opportunity to test protection against a heterologous tier-2 clade C Env.

该项目的总体目标是开发新型的疫苗接种方法，不仅可以增强 大小，但还提高了抗HIV细胞和体液免疫的功能质量。具体来说，我们 建议结合最近在埃默里大学开发的两种新的疫苗接种方法 猕猴的巨大希望。第一种方法使用CD40L，这是一种用于树突状的共刺激分子 细胞（DC）和B细胞，在HIV VLP的表面表达为遗传佐剂，以增强 HIV特异性细胞和体液免疫的大小和功能质量导致增强 保护免于获得SIV感染。用DNA/MVA S1V239的CD40L佐剂DNA Prime 疫苗显着提高了抗Siv细胞和体液免疫的功能质量，并有效性 反对异源粘膜SLV挑战。第二种方法使用了缺乏4个免疫力的新MVA 调节基因（MVAA4）作为疫苗载体，显示出HIV特异性的大小显着增加 恒河猕猴中的细胞和体液免疫。在这个项目中，我们结合了这两个新的 互补的方法来制定针对艾滋病毒的新型疫苗接种策略。 项目2具有两个具体的目标：AIM 1将测试MVA和MVAA4的相对免疫原性和功效 增强CD40L辅助DNA疫苗启动的保护性抗体反应的增强。结果 从此目的将MVAA4的临床用途指导为我们的DNA疫苗在异源PrimeBoost中的提升 针对艾滋病毒的疫苗接种方案。 AIM 2将测试安全性，免疫原性和保护性的功效 MVA/CD40L.co用MVA/HIV疫苗交付。该目标的结果将指导 MVA/CD40L作为抗HIV的同源原始MVA疫苗接种方案的佐剂。这些 猕猴的研究将使用HIV进化枝C免疫原和SHIV挑战。 env在免疫原和 拟议的挑战病毒只有76％的身份，因此将有机会测试保护 反对异源层2进化枝环境。