Immune Correlates for GM-CSF Mediated Enhancement of Vaccine Efficacy

GM-CSF 介导的疫苗功效增强的免疫相关性

基本信息

批准号：
8198163
负责人：
Rama Rao Amara
金额：
$ 51.78万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-07 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8198163
关键词：
ALVAC Acquired Immunodeficiency Syndrome Adjuvant Affect Africa Antibodies Antigen-Presenting Cells Antigens Avidity B-Lymphocytes Binding Blood CD4 Positive T Lymphocytes CD8B1 gene Cause of Death Cellular biology Collaborations Colorectal Complement Cytotoxic T-Lymphocytes DNA DNA Vaccines DNA/MVA vaccine Encapsulated Event Gagging Gene Expression Generations Genes Goals Granulocyte-Macrophage Colony-Stimulating Factor HIV HIV Envelope Protein gp120 HIV vaccine HIV-1 Helper-Inducer T-Lymphocyte Homing Human Immune Immune response Immunity Immunoglobulin A Immunoglobulin G Immunologic Memory Individual Infection Life Ligands Macaca Macaca mulatta Measurement Mediating Modified Vaccinia Virus Ankara Mucous Membrane Phase III Clinical Trials Poxviridae Proteins Role SIV SIV Vaccines Serum Site T cell response Testing Tissues Toll-like receptors Vaccinated Vaccination Vaccines Viral Virus Virus-like particle acquired immunodeficiency aluminum sulfate efficacy testing efficacy trial nanoparticle neutrophil poxvirus vectors protective efficacy rectal response simian human immunodeficiency virus vaccine efficacy

项目摘要

The acquired immunodeficiency syndrome caused by HIV-1 is the leading cause of death in Africa and the fourth leading cause of death woridwide. The recent RV144 phase-3 trial (Thai trial) testing the efficacy of an AIDS vaccine consisting of a poxvirus vector (ALVAC) prime and protein boost demonstrated a modest efficacy where 25% ofthe vaccinated individuals were protected from HIV-1 infection. These results are highly encouraging, however the immune correlates for this protection are yet to be identified but suggest a role for non-neutralizing Ab in protection. Furthermore, the protection in the Thai trial appeared to be short lived (for the first six months) and there is a need for developing approaches that sustain immunological memory of vaccineelicited responses. Our ongoing studies in rhesus macaques demonstrated a similar protection from heterologous repetitive mucosal SIV challenges by a DNA prime and poxvirus (modified vaccinia Ankara) boost vaccine (DNA/MVA). In addition, co-delivery of granulocyte and macrophage colony stimulating factor (GM-CSF) DNA with our vaccine DNA significantly enhanced the protection mediated by the DNA/MVA vaccine from 25% to 70%. GM-CSF did not adjuvant the anti-viral CD8 T cell responses but enhanced the avidity of binding Ab specific to the Env and promoted generation of anti-viral IgA in rectal secretions. Importantly, the avidity of binding Ab against the challenge virus Env strongly correlated with enhanced protection against acquisition of SIV infection. These and results from other studies highlight an important role for other non-neutralizing activities of antibody in protection. The overall goals of this project are to identify the mechanisms of GM-CSF-mediated enhancement of protection against a mucosal SIV challenge and to test the effect of a protein boost for enhancing this protection against acquisition of heterologous repetitive intravaginal SIV challenges in rhesus macaques. In our specific aim 1, we will investigate the immune correlates for GM-CSF mediated enhanced protection. Here we will test the hypothesis that GM-CSF enhances the breadth, avidity, cytolytic activity and mucosal homing of anti-Env binding Ab in serum and mucosal secretions by modulating function of antigen presenting cells and T helper responses. In our specific aim 2, we will test whether addition of a protein boost, adjuvated with either alum or a combination of toll-like receptor ligands encapsulated in nanoparticles, to the GM-CSF-adjuvanted DNA/MVA vaccine will further enhance the longevitiy of protective immunity against acquisition of heterologous repetitive intravaginal SIV challenge.

HIV-1 引起的获得性免疫缺陷综合症是非洲的主要原因也是全球第四大死亡原因。最近的RV144 3期试验（泰国试验）测试疗效由痘病毒载体 (ALVAC) 引发剂和蛋白加强剂组成的艾滋病疫苗的研究显示，其效果适中 25% 的接种疫苗者免受 HIV-1 感染。这些结果非常令人鼓舞的是，然而，这种保护的免疫相关性尚未确定，但表明了免疫相关性的作用保护中的非中和抗体。此外，泰国审判中的保护似乎是短暂的（对于前六个月），并且需要开发维持疫苗引发的免疫记忆的方法回应。我们正在进行的恒河猴研究表明，对异源重复性具有类似的保护作用 DNA 引发疫苗和痘病毒（改良安卡拉牛痘）加强疫苗 (DNA/MVA) 刺激粘膜 SIV。在此外，粒细胞和巨噬细胞集落刺激因子 (GM-CSF) DNA 与我们的疫苗共同传递 DNA 将 DNA/MVA 疫苗介导的保护作用从 25% 显着增强至 70%。 GM-CSF 做到了不辅助抗病毒 CD8 T 细胞反应，但增强对 Env 和特异性抗体的结合亲和力促进直肠分泌物中抗病毒 IgA 的产生。重要的是，结合抗体的亲和力挑战病毒Env与增强对SIV感染的保护密切相关。这些和其他研究的结果强调了抗体的其他非中和活性在保护中的重要作用。该项目的总体目标是确定 GM-CSF 介导的增强的机制针对粘膜 SIV 攻击的保护作用，并测试蛋白质增强剂对增强这种保护作用的效果对抗恒河猴获得异源重复性阴道内 SIV 挑战。在我们的具体目标中 1，我们将研究 GM-CSF 介导的增强保护的免疫相关性。在这里我们将测试 GM-CSF 增强抗 Env 结合的广度、亲合力、细胞溶解活性和粘膜归巢的假设血清和粘膜分泌物中的抗体通过调节抗原呈递细胞的功能和 T 辅助反应。在我们的具体目标 2 中，我们将测试是否添加蛋白质增强剂、明矾或组合佐剂将 Toll 样受体配体封装在纳米颗粒中，将其添加到 GM-CSF 佐剂的 DNA/MVA 疫苗中进一步增强保护性免疫力的寿命，防止获得异源重复性阴道内感染 SIV 挑战。