A multivalent prophylactic and therapeutic vaccine against EBV infection and EBV-associated malignancies

针对 EBV 感染和 EBV 相关恶性肿瘤的多价预防性和治疗性疫苗

• 批准号: 10247243
• 负责人: Javier Gordon Ogembo
• 金额: $ 85.86万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-08 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247243
• 关键词: Acute; Adolescent; Adult; Animal Model; Animals; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Autoimmunity; B-Lymphocytes; Blood; Cells; Childhood; Chronic Disease; Clinical Trials; Complex; Development; Disease; Dose; EBV-associated disease; Ensure; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Epstein-Barr Virus Infections; Epstein-Barr Virus-Related Malignant Neoplasm; Exhibits; Gardasil; Glycoproteins; Goals; HIV; Human; Human Herpesvirus 4; Human Papillomavirus; Iatrogenesis; Immune; Immune response; Immunization; Immunize; Immunocompetent; Immunocompromised Host; Immunoglobulin G; Immunosuppression; In Vitro; Individual; Infant; Infection; Infection prevention; Infectious Mononucleosis; Investigational New Drug Application; Knowledge; Lymphocryptovirus; Lymphoma; Lymphoproliferative Disorders; Macaca mulatta; Malignant Neoplasms; Measures; Mediating; Modeling; Modified Vaccinia Virus Ankara; Morbidity - disease rate; Mus; Myeloid Cells; Oncogenic; Oncogenic Viruses; Oral; Orthologous Gene; Oryctolagus cuniculus; Peripheral Blood Mononuclear Cell; Phase I/II Clinical Trial; Population; Preventive; Preventive vaccine; Primary Infection; Property; Regimen; Research; Rhesus; Risk; SIV; Saliva; Splenocyte; Structure; Subunit Vaccines; T-Lymphocyte; Testing; Time; Vaccines; Viral; Viral Antigens; Viral Genome; Viral Proteins; Virus; Virus Diseases; Virus Shedding; Virus-like particle; Wild Type Mouse; acute symptom; base; cell type; chronic infection; clinically relevant; co-infection; design; germ free condition; global health; human model; humanized mouse; immunogenic; immunogenicity; in vivo; innovation; lymph nodes; mortality; mouse model; neutralizing antibody; novel strategies; persistent EBV infection; post-transplant; pre-clinical; preclinical trial; prevent; prophylactic; response; success; therapeutic vaccine; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine trial; vector; viral DNA

ABSTRACT: Epstein-Barr virus (EBV) represents a major global health problem, as it is associated with infectious mononucleosis in adolescents and >200,000 pediatric and adult cancer cases worldwide each year. Despite the high morbidity and mortality associated with EBV infection, there is no licensed prophylactic EBV vaccine. Thus, a safe and effective EBV prophylactic vaccine is urgently needed. To date, no vaccine candidate has elicited neutralizing antibodies (nAbs) to completely block EBV infection in vivo. Approaches to EBV vaccine development have been limited in part by the oncogenic potential of the viral genome and a lack of animal models to test vaccine candidates. This proposed project will use a novel strategy to develop a safe and effective vaccine candidate that incorporates up to five EBV glycoproteins into a single Epstein-Barr virus- like particle (EBV-LP). The EBV glycoproteins gp350, gB, gp42, and gH/gL complex, which are essential for EBV attachment, fusion, and entry into host cells, are attractive targets for provoking a humoral/antibody- mediated response. Our group and others have shown that antibodies to these glycoproteins neutralize viral infection in vitro and in vivo. Thus, their inclusion is critical for developing an effective prophylactic vaccine that protects against viral infection. To our knowledge, this combination of EBV antigens has not been tested in pre- clinical or clinical trials. We will generate EBV-LPs containing combinations of up to five glycoproteins using modified vaccinia Ankara virus. We will determine the efficacy of the EBV-LPs to generate nAb responses in wild-type mice, then test the ability of these antibodies to neutralize >90% of EBV infection of human epithelial and B cells in vitro and to prevent infection of human B cells in vivo in a humanized mouse model (Aim 1). Because EBV is human-tropic, we will use the EBV-homologous rhesus lymphocryptovirus (rhLCV) as a surrogate virus to study vaccine efficacy in vivo in rhesus macaques (RM), considered the most relevant animal model that recapitulates key features of human EBV infection. Importantly, RM orally inoculated with rhLCV exhibit acute symptoms and viral shedding similar to EBV+ humans, as well as development of lymphoma after persistent infection under immunosuppression. We will evaluate the ability of our EBV-LP- based or analogous rhLCV-LP-based vaccines to elicit nAbs that can prevent or limit infection, with no/low EBV DNA in blood, splenocytes, or lymph nodes, and absence of EBV+ cancer in immunocompetent and immunocompromised RM, compared to well-characterized EBV gp350-based vaccines (Aim 2). Our central hypothesis is that EBV-LPs/rhLCV-LPs will generate protective anti-EBV/rhLCV glycoprotein nAb responses to prevent EBV/rhLCV infection in vitro and in vivo. We expect our approach to provide a path to an investigational new drug application for a prophylactic EBV vaccine. We will also define, for the first time, the minimum EBV/rhLCV glycoproteins required to elicit sterilizing nAbs in vitro and in vivo. This will advance our long-term goal of developing vaccines that prevent EBV infection and EBV-associated diseases and cancers.

摘要： EB 病毒（EBV）是一个重大的全球健康问题，因为它与 每年全世界有超过 200,000 例青少年传染性单核细胞增多症和儿童和成人癌症病例。 尽管 EBV 感染相关的发病率和死亡率很高，但目前还没有获得许可的预防性 EBV 药物 疫苗。因此，迫切需要一种安全有效的EBV预防疫苗。迄今为止，还没有疫苗 候选者已引发中和抗体（nAb）以完全阻断体内 EBV 感染。接近 EB 病毒疫苗的开发部分受到病毒基因组致癌潜力和缺乏 用于测试候选疫苗的动物模型。该拟议项目将使用一种新颖的策略来开发安全的 以及将多达 5 种 EBV 糖蛋白整合到单一 Epstein-Barr 病毒中的有效候选疫苗 类似颗粒（EBV-LP）。 EBV 糖蛋白 gp350、gB、gp42 和 gH/gL 复合物，对于 EBV 附着、融合和进入宿主细胞是激发体液/抗体的有吸引力的目标 介导的反应。我们的小组和其他人已经证明，这些糖蛋白的抗体可以中和病毒 体外和体内感染。因此，将它们纳入其中对于开发有效的预防性疫苗至关重要 防止病毒感染。据我们所知，这种 EBV 抗原组合尚未经过预测试。 临床或临床试验。我们将使用以下方法生成包含最多五种糖蛋白组合的 EBV-LP 改良痘苗安卡拉病毒。我们将确定 EBV-LP 产生 nAb 反应的功效 野生型小鼠，然后测试这些抗体中和 > 90% 的人类上皮细胞 EBV 感染的能力 和 B 细胞在体外，并在人源化小鼠模型中预防体内人类 B 细胞的感染（目标 1）。 由于 EBV 是人类嗜性病毒，我们将使用 EBV 同源恒河猴淋巴隐病毒 (rhLCV) 作为 替代病毒在恒河猴（RM）体内研究疫苗功效，被认为是最相关的 概括人类 EBV 感染主要特征的动物模型。重要的是，RM口服接种 rhLCV 表现出与 EBV+ 人类类似的急性症状和病毒脱落，以及发展为 免疫抑制下持续感染后的淋巴瘤。我们将评估我们的 EBV-LP 的能力- 基于或类似的基于 rhLCV-LP 的疫苗，可引发可预防或限制感染的 nAb，且无/低 EBV 血液、脾细胞或淋巴结中存在 DNA，且免疫功能正常且不存在 EBV+ 癌症 与充分表征的基于 gp350 的 EBV 疫苗相比，免疫功能低下的 RM（目标 2）。我们的中央 假设 EBV-LPs/rhLCV-LPs 将产生保护性抗 EBV/rhLCV 糖蛋白 nAb 反应 预防 EBV/rhLCV 体外和体内感染。我们希望我们的方法能够提供一条通往 预防性 EBV 疫苗的研究性新药申请。我们还将首次定义 体外和体内引发灭菌 nAb 所需的最低 EBV/rhLCV 糖蛋白。这将推进我们的 开发预防 EBV 感染以及 EBV 相关疾病和癌症的疫苗的长期目标。