Defining the protective efficacy of antibodies against the EBV gH/gL glycoprotein complex

定义针对 EBV gH/gL 糖蛋白复合物的抗体的保护功效

• 批准号: 10199986
• 负责人: Andrew McGuire
• 金额: $ 43.28万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-09 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199986
• 关键词: Acquired Immunodeficiency Syndrome; Africa; Africa South of the Sahara; Age; Animal Model; Animals; Antibodies; Antibody Response; Antibody-mediated protection; Area; B-Cell Lymphomas; B-Lymphocytes; Binding; Blocking Antibodies; Cell surface; Cells; Central Nervous System Lymphoma; Cessation of life; Clinical; Complement 3d Receptors; Complement Receptor; Complex; Data; Development; Epithelial Cells; Epitopes; Epstein-Barr Virus Infections; Epstein-Barr Virus-Related Malignant Neoplasm; Glycoproteins; Goals; HIV; HIV-1; Hodgkin Disease; Human; Human Herpesvirus 4; Immune; Immune response; Immunocompromised Host; In Vitro; Incidence; Individual; Infant; Infection; Infectious Mononucleosis; Large-Cell Immunoblastic Lymphoma; Lead; Life; Link; Lymphocryptovirus; Lymphoma; Lymphomagenesis; Macaca; Macaca mulatta; Malignant Neoplasms; Mediating; Membrane; Membrane Fusion; Modeling; Monoclonal Antibodies; Mus; Nasopharynx; Non-Hodgkin' s Lymphoma; Oral; Orthologous Gene; Pathology; Patients; Persons; Play; Primary Infection; Recombinants; Relative Risks; Research; Resources; Rhesus; Risk; Role; Site; Source; Specificity; Subunit Vaccines; Target Populations; Testing; Vaccine Design; Vaccines; Viral; Viral Antigens; Viral Load result; Virion; Virus; Virus Latency; Work; base; cell type; cross reactivity; design; experimental study; human model; humanized mouse; immunogenicity; improved; insight; large cell Diffuse non-Hodgkin' s lymphoma; member; mouse model; neutralizing antibody; next generation; novel vaccines; overexpression; pathogen; phase II trial; prevent; primary effusion lymphoma; protective efficacy; receptor; scaffold; tumor; vaccine development; vaccine trial; viral transmission

PROJECT SUMMARY/ABSTRACT Epstein-Barr virus (EBV) is a nearly ubiquitous orally-transmitted pathogen for which there is no vaccine. Following primary infection, most individuals carry the virus asymptomatically; however, unchecked infection in immunocompromised individuals, such as those living with HIV-1/AIDS, can lead to the development of lymphomas. These include Non-Hodgkin's Lymphomas such as plasmablastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma and diffuse large B-cell lymphoma, as well as classic Hodgkin's lymphoma. Overall, HIV-infected individuals have a 60–200-fold higher relative risk to develop Non- Hodgkin's Lymphomas and an 8–10-fold higher relative risk to develop Hodgkin's Lymphoma compared to uninfected individuals. Thus, a safe and effective vaccine that prevents EBV infection and/or eliminates the EBV- associated component of risk could have a significant clinical benefit, particularly in resource-poor areas where HIV-1 is endemic. Successful vaccines are usually protective because they elicit neutralizing antibodies. At present it is not currently known whether pre-existing neutralizing antibodies can block EBV transmission. Since both B cells and epithelial cells are present in the nasopharynx, a preventative EBV vaccine would likely need to elicit antibodies that can block infection of both cell types. To date, subunit vaccine efforts focused on the gp350 glycoprotein which binds to complement receptors 1 and 2 and promotes attachment and internalization of virions by B cells without mediating membrane fusion. A phase II trial of a gp350 vaccine reduced the incidence of infectious mononucleosis but failed to protect against infection. Antibodies against gp350 can inhibit EBV infection of B cells, but most epithelial cells do not express complement receptors. Thus, the inability of gp350 vaccines to protect against EBV infection may be due to their inability to elicit antibodies that neutralize EBV infection of epithelial cells. We recently isolated a monoclonal antibody, AMMO1 that binds to the EBV gH/gL glycoprotein complex, which is an important regulator of fusion between the host cell and viral membranes. AMMO1 binds to gH/gL in a manner that disrupts membrane fusion and neutralizes EBV infection of both B and epithelial cells demonstrating, in principle, that vaccine elicited gH/gL antibodies could be more efficacious than those against gp350. The goal of this proposal is to define the protective capacity of AMMO1 and other anti-EBV monoclonal antibodies against EBV infection in complementary animal models: humanized mice that harbor human B cells and in infant rhesus macaques, which can be orally infected with the rhesus ortholog of EBV. We will also evaluate the ability of several gH/gL-based vaccines to elicit neutralizing antibodies and compare these gp350-based vaccines in relevant animal challenge models. These studies will delineate the role that antibodies play in preventing EBV infection and inform vaccine development. Moreover, the proposed challenge studies in infant macaques are highly relevant to the target-population in Sub-Sharan Africa where EBV infection normally occurs in the first 3 years of life.

项目摘要/摘要 爱泼斯坦 - 巴尔病毒（EBV）是一种几乎普遍存在的口服传播病原体，没有疫苗。 原发性感染后，大多数人不对称地携带病毒。但是，未检查的感染 免疫功能低下的个体，例如患有HIV-1/艾滋病的人，可以导致发展 淋巴瘤。其中包括非霍奇金的淋巴瘤，例如浆膜淋巴瘤，主要中心 神经系统淋巴瘤，一级积液淋巴瘤和弥漫性大B细胞淋巴瘤以及经典 霍奇金的淋巴瘤。总体而言，艾滋病毒感染者的相对风险高60-200倍，以发展非 - 霍奇金的淋巴瘤和与霍奇金淋巴瘤发展的相对风险高8-10倍 未感染的人。这是一种安全有效的疫苗，可防止EBV感染和/或消除EBV- 相关的风险组成部分可能具有巨大的临床利益，尤其是在资源贫乏的地区 HIV-1是内在的。成功的疫苗通常受到保护，因为它们会引起中和抗体。在 目前，目前尚不知道预先存在的中和抗体是否可以阻止EBV传播。自从 B细胞和上皮细胞都存在于鼻咽内，预防性EBV疫苗可能需要 引起可以阻止两种细胞类型的感染的抗体。迄今为止，亚基疫苗的工作重点是GP350 糖蛋白与补体受体1和2结合并促进病毒的附着和内在化 通过B细胞不介导膜融合。 GP350疫苗的II期试验可减少 传染性单核细胞增多症，但未能防止感染。针对GP350的抗体可以抑制EBV B细胞的感染，但大多数上皮细胞不表达补体受体。那，GP350的无能为力 防止EBV感染的疫苗可能是由于它们无法引起中和EBV的抗体 上皮细胞的感染。我们最近分离了一种与EBV GH/GL结合的单克隆抗体AMMO1 糖蛋白复合物是宿主细胞和病毒膜之间融合的重要调节剂。 AMMO1以破坏膜融合并中和B和EBV感染的方式与GH/GL结合 原则上表明疫苗引起的GH/GL抗体的上皮细胞可能比 那些反对GP350。该提议的目的是定义AMMO1和其他反EBV的保护能力 完整动物模型中针对EBV感染的单克隆抗体：藏有的人源化小鼠 人类B细胞和婴儿恒河猕猴，可以口服EBV的恒河类直系同源物。我们 还将评估几种基于GH/GL的疫苗引起中和抗体的能力，并将其比较 相关动物挑战模型中的基于GP350的疫苗。这些研究将描述抗体的作用 发挥防止EBV感染并为疫苗开发提供信息。此外，拟议的挑战研究 婴儿猕猴与ebv感染的亚牛兰非洲的目标人口高度相关 发生在生命的头三年。