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: 10669738
• 负责人: Andrew McGuire
• 金额: $ 76.38万
• 依托单位: FRED HUTCHINSON CANCER 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669738
• 关键词: Acquired Immunodeficiency Syndrome; Africa; Africa South of the Sahara; Age; Animal Model; Animals; Antibodies; Antibody Response; Antibody-mediated protection; 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; Cross Reactions; Data; Development; Epithelial Cells; Epithelium; 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; Infiltration; Large-Cell Immunoblastic Lymphoma; 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; Predisposition; Primary Infection; Recombinants; Relative Risks; Research; Resource-limited setting; 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; 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; transmission process; 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.

项目概要/摘要 EB 病毒 (EBV) 是一种几乎普遍存在的口腔传播病原体，目前尚无疫苗。 初次感染后，大多数人都没有症状地携带病毒，但也有未经控制的感染； 免疫功能低下的个体，例如 HIV-1/艾滋病感染者，可能会导致以下疾病的发生： 这些包括非霍奇金淋巴瘤，例如浆母细胞淋巴瘤、原发性中枢性淋巴瘤。 神经系统淋巴瘤、原发性渗出性淋巴瘤和弥漫性大 B 细胞淋巴瘤，以及经典的 总体而言，HIV 感染者患非霍奇金淋巴瘤的相对风险高出 60-200 倍。 与霍奇金淋巴瘤相比，患霍奇金淋巴瘤的相对风险高出 8-10 倍 因此，一种安全有效的疫苗可以预防 EBV 感染和/或消除 EBV- 风险的相关组成部分可能具有显着的临床益处，特别是在资源贫乏的地区 HIV-1 是地方性的，成功的疫苗通常具有保护作用，因为它们会产生中和抗体。 目前尚不清楚预先存在的中和抗体是否可以阻止 EBV 传播。 B 细胞和上皮细胞都存在于鼻咽部，预防性 EBV 疫苗可能需要 迄今为止，亚单位疫苗的研究重点是 gp350。 与补体受体 1 和 2 结合并促进病毒粒子附着和内化的糖蛋白 gp350 疫苗的 II 期试验降低了 B 细胞的发生率。 传染性单核细胞增多症，但无法预防感染。针对 gp350 的抗体可以抑制 EBV。 B细胞感染，但大多数上皮细胞不表达补体受体，因此，gp350无能力。 预防 EBV 感染的疫苗可能是因为它们无法引发中和 EBV 的抗体 我们最近分离出一种与 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融合的重要调节因子。 AMMO1 与 gH/gL 结合，破坏膜融合并中和 B 型和 原则上，上皮细胞证明疫苗引发的 gH/gL 抗体可能比疫苗更有效 该提案的目标是定义 AMMO1 和其他抗 EBV 的保护能力。 互补动物模型中针对 EBV 感染的单克隆抗体：携带病毒的人源化小鼠 人类 B 细胞和幼年恒河猴，它们可以通过口服感染 EB 病毒的恒河猴直系同源物。 还将评估几种基于 gH/gL 的疫苗引发中和抗体的能力，并比较这些疫苗 这些研究将阐明基于 gp350 的疫苗在相关动物攻击模型中的作用。 此外，拟议的挑战研究也有助于预防 EBV 感染并为疫苗开发提供信息。 猕猴幼崽与沙兰以南非洲的目标人群高度相关，那里的 EBV 感染通常 发生在生命的前 3 年。

项目成果

Epstein-Barr Virus Glycoprotein Antibody Titers and Risk of Nasopharyngeal Carcinoma.

EB 病毒糖蛋白抗体滴度和鼻咽癌的风险。

• 发表时间: 2022-12
• 影响因子: 4.2
• 作者: Coghill, Anna E;McGuire, Andrew;Sinha, Sweta;Homad, Leah;Sinha, Irika;Sholukh, Anton;Koh, Woon;Yuan, Jian Min
• 通讯作者: Yuan, Jian Min

Maternal Epstein-Barr Virus-Specific Antibodies and Risk of Infection in Ugandan Infants.

乌干达婴儿母亲 Epstein-Barr 病毒特异性抗体和感染风险。

• 发表时间: 2021
• 作者: Minab, Rana;Bu, Wei;Nguyen, Hanh;Wall, Abigail;Sholukh, Anton M;Huang, Meei;Ortego, Michael;Krantz, Elizabeth M;Irvine, Michael;Casper, Corey;Orem, Jackson;McGuire, Andrew T;Cohen, Jeffrey I;Gantt, Soren
• 通讯作者: Gantt, Soren