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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

基本信息

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
项目类别：
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&apos 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&apos 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

项目摘要

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.

项目总结/文摘