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

• 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
• 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

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.

由HIV-1引起的获得的免疫缺陷综合征是非洲死亡的主要原因 以及死亡的第四个主要原因。最近的RV144第3期试验（泰语试验）测试了功效 由毒病毒载体（ALVAC）和蛋白质增强的艾滋病疫苗的疫苗表现出适中 有25％的疫苗接种个体受到HIV-1感染的疗效。这些结果很高 令人鼓舞的，但是这种保护的免疫相关性尚未确定，但提出了 在保护方面非中和AB。此外，泰国审判中的保护似乎很短（对于 前六个月），需要开发方法来维持对疫苗的免疫记忆 回答。 我们正在进行的在恒河猕猴中的研究表现出了类似的保护侵害异源重复性的 DNA Prime和Poxvirus（修饰的vacinia ankara）粘膜SIV挑战促进疫苗（DNA/MVA）。在 加上粒细胞和巨噬细胞刺激因子（GM-CSF）DNA的共同传递与我们的疫苗 DNA显着增强了由DNA/MVA疫苗介导的保护，从25％降低到70％。 GM-CSF做到了 不是辅助抗病毒CD8 T细胞反应，而是增强 在直肠分泌物中促进了抗病毒IgA的产生。重要的是，将AB与 挑战病毒ENV与增强免受SIV感染的保护密切相关。这些和 其他研究的结果突出了抗体在保护中的其他非中和活性的重要作用。 该项目的总体目标是确定GM-CSF介导的增强的机制 防止粘膜SIV挑战的保护并测试蛋白质增强蛋白质的影响 反对获取恒河猕猴中异源重复静脉内SIV挑战。在我们的特定目标中 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的假设可以增强抗ENV结合的宽度，亲切性，细胞溶作用和粘膜归巢 通过调节抗原呈递细胞和T助手反应的功能，血清和粘膜分泌物中的AB。 在我们的特定目标2中，我们将测试是否添加蛋白质增强，均为明矾或组合 封装在纳米颗粒中的Toll样受体配体，将其与GM-CSF-Adjuvant的DNA/MVA疫苗相关 进一步增强了防护免疫力的寿命 SIV挑战。