CD40L-Adjuvanted Vaccines for HIV/AIDS

CD40L 佐剂 HIV/AIDS 疫苗

基本信息

批准号：
7904446
负责人：
Rama Rao Amara
金额：
$ 67.65万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7904446
关键词：
Acquired Immunodeficiency Syndrome Adenoviruses Adherence Adjuvant Animal Model Antigens Antiviral Agents Avidity B-Cell Activation B-Lymphocytes Binding CCR5 gene CD4 Positive T Lymphocytes CD8B1 gene Cause of Death Cell physiology Cells Country Cytotoxic T-Lymphocytes DNA DNA Vaccines Dendritic Cells Developed Countries Development Dose Electroporation Failure Frequencies Gagging Generations Goals HIV HIV Envelope Protein gp120 HIV vaccine HIV-1 HIV-1 vaccine HIV/SIV vaccine Human Humoral Immunities Immunosuppressive Agents In Vitro Individual Infection Infection Control Interleukin-12 Laboratories Lead Life Longevity Lymphocytic choriomeningitis virus Macaca Macaca mulatta Memory Memory B-Lymphocyte Modified Vaccinia Virus Ankara Needles Pathway interactions Pharmaceutical Preparations Phase Phenotype Play Production Proteins Role SIV SIV Vaccines Safety Sirolimus Solutions Structure of germinal center of lymph node Surface T cell response T memory cell T-Cell Development T-Lymphocyte TNFRSF5 gene TNFSF5 gene Testing Time Toxic effect Treatment Protocols United States Vaccination Vaccine Antigen Vaccines Viral Viral Vector Virus Virus Diseases Virus-like particle base cost crosslink design drug resistant virus immunogenicity improved functioning in vivo mTOR protein novel novel vaccines prototype receptor response safety testing simian human immunodeficiency virus

项目摘要

The failure of Ad5 based HIV-1 vaccine in humans that is designed to elicit primarily antiviral T cells strongly suggests the need to develop novel vaccine approaches that generate high levels of anti-viral T cells with improved function as well as protective Ab. The goal of this project is to adjuvant the cellular and humoral immunity elicited by our DNA/MVA vaccine that has just entered phase II testing in humans in US. Specifically, we propose to target the CD40 pathway on dendritic cells (DC) and B cells using CD40L. Stimulation of CD40 on DC results in production of IFNg and IL-12 that are critical for generation of highly functional antiviral CDS response. Activation of B cells through CD40 is necessary for germinal center formation where affinitv maturation of B cells occurs leading to generation of high avidity Ab. Here, we will express CD40L on the surface of a SIV virus-like particle (CD40L-VLP). These CD40L-VLPs are potent activators of DC and B cells in vitro. In addition, they can be targeted to DC (through interaction between gpl20 on VLP and CD4 on DC) and allow presentation of Env in its native form that is critical for eliciting broadly cross-reactive neutralizing Ab. In specific aim 1. we will test the potential of CD40L-adiuvanted DNA/MVA SIV vaccine to enhance control of a pathogenic SIV challenge. In addition, we will test whether delivering DNA by electroporation enhances the immunogenicity of the adluvanted and non-adiuvanted DN/VMVA vaccines. Recent studies from Dr. Rafi Ahmed's lab (PI of project 2) demonstrated that mTOR regulates memory T cell development and inhibition of this pathway following infection or vaccination using rapamycin enhances the magnitude and functional quality of antigen-specific CDS T cells. Rapamycin has also been shown to down regulate expression of CCR5 on CD4 T cells that results in marked reduction of HIV replication. This could be an added advantage for HIV vaccines, because the vaccine-elicited CCR5' virus-specific CD4 T cells may not be infected by the virus. Essentially we may be reducing the freguency of potential virus target cells while preserving the much-needed CD4 T cell helD following infection. In specific aim 2, we will test the synergy between inhibiting mTOR and activating CD40 pathways for adjuvanting the immunogenicity and efficacy of DNA/MVA vaccines.

基于 Ad5 的 HIV-1 疫苗在人类中的失败，该疫苗旨在强烈激发主要抗病毒 T 细胞表明需要开发新的疫苗方法来产生高水平的抗病毒 T 细胞改善功能以及保护性抗体。该项目的目标是辅助细胞和体液我们的 DNA/MVA 疫苗刚刚在美国进入人体 II 期测试，从而产生了免疫力。具体来说，我们建议使用 CD40L 将 CD40 通路靶向树突状细胞 (DC) 和 B 细胞。 CD40的刺激 DC 导致 IFNg 和 IL-12 的产生，这对于生成高功能抗病毒 CDS 至关重要回复。通过 CD40 激活 B 细胞对于生发中心的形成是必要的，其中亲和力 B 细胞的成熟导致高亲合力抗体的产生。在这里，我们将CD40L表达在 SIV病毒样颗粒（CD40L-VLP）的表面。这些 CD40L-VLP 是 DC 和 B 细胞的有效激活剂体外。此外，它们可以靶向 DC（通过 VLP 上的 gpl20 和 DC 上的 CD4 之间的相互作用）允许以天然形式呈现 Env，这对于引发广泛的交叉反应中和抗体至关重要。在具体目标 1. 我们将测试 CD40L 增强型 DNA/MVA SIV 疫苗增强控制病毒的潜力致病性SIV挑战。此外，我们将测试通过电穿孔传递 DNA 是否可以增强增强型和非增强型 DN/VMVA 疫苗的免疫原性。拉菲博士的最新研究 Ahmed 的实验室（项目 2 的 PI）证明 mTOR 调节记忆 T 细胞的发育并抑制使用雷帕霉素感染或接种疫苗后，该途径增强了强度和功能质量抗原特异性 CDS T 细胞。雷帕霉素还被证明可以下调 CCR5 的表达 CD4 T 细胞导致 HIV 复制显着减少。这可能是艾滋病毒的一个额外优势疫苗，因为疫苗引发的 CCR5' 病毒特异性 CD4 T 细胞可能不会被病毒感染。本质上，我们可能会降低潜在病毒靶细胞的频率，同时保留急需的细胞 CD4 T 细胞在感染后保留。在具体目标 2 中，我们将测试抑制 mTOR 和激活 CD40 途径以辅助 DNA/MVA 疫苗的免疫原性和功效。