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：爱泼斯坦 - 巴尔病毒（EBV）代表了一个主要的全球健康问题，因为它与 每年在全球范围内，青少年的传染性单核细胞增多症以及> 200,000个儿科和成人癌症病例。 尽管与EBV感染有关的发病率和死亡率很高，但没有许可的预防性EBV 疫苗。因此，迫切需要一种安全有效的EBV预防疫苗。迄今为止，没有疫苗 候选者引起中和抗体（NABS），以完全阻断体内EBV感染。方法 EBV疫苗发育受到病毒基因组的致癌潜力的一部分限制，缺乏 动物模型测试疫苗的候选物。这个拟议的项目将使用新颖的策略来制定安全 以及有效的疫苗候选者，将多达五种EBV糖蛋白纳入单个Epstein-Barr病毒 - 像粒子（EBV-LP）。 EBV糖蛋白GP350，GB，GP42和GH/GL复合物，这对于 EBV附着，融合和进入宿主细胞是引起体液/抗体 - 介导的反应。我们的小组和其他人表明，对这些糖蛋白的抗体中和病毒 体外和体内感染。因此，它们的包容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，EBV抗原的这种组合尚未在预审中进行测试 临床或临床试验。我们将生成含有多达五种糖蛋白组合的EBV-LPS 修改后的牛acta ankara病毒。我们将确定EBV-LPS在 野生型小鼠，然后测试这些抗体中和> 90％的EBV感染的能力 在体外和B细胞中，以防止人性化小鼠模型中人体内的人体B细胞感染（AIM 1）。 因为EBV是人类热带的，所以我们将使用EBV同源性恒星淋巴结病毒（RHLCV）作为一个 替代病毒在恒河猕猴（RM）中研究体内疫苗疗效，认为最相关 概括人EBV感染的关键特征的动物模型。重要的是，RM口服接种 RHLCV表现出急性症状和类似于EBV+人类的病毒脱落，以及 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RHLCV-LP疫苗可引起可以预防或限制感染的NAB，而无/低EBV 血液，脾细胞或淋巴结中的DNA，免疫能力和不存在EBV+癌症 与特征良好的基于​​EBV GP350的疫苗相比，免疫功能低下的RM（AIM 2）。我们的中心 假设是EBV-LPS/RHLCV-LPS将产生保护性抗EBV/RHLCV糖蛋白NAB反应 为了防止EBV/RHLCV感染体外和体内。我们希望我们的方法为通往 预防性EBV疫苗的研究新药应用。我们还将第一次定义 在体外和体内引起对NABS进行灭菌所需的最低EBV/RHLCV糖蛋白。这将推动我们的 开发可预防EBV感染和EBV相关疾病和癌症的疫苗的长期目标。