A novel VLP vaccine to prevent EBV infection and EBV - associated malignancies

一种预防 EBV 感染和 EBV 相关恶性肿瘤的新型 VLP 疫苗

• 批准号: 9302981
• 负责人: Javier Gordon Ogembo
• 金额: $ 23.5万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302981
• 关键词: Adult; Africa; Africa South of the Sahara; African; Age; Animal Model; Antibodies; Antibody Response; Antigens; Antiviral Response; B-Lymphocytes; Burkitt Lymphoma; CD8-Positive T-Lymphocytes; Cells; Cellular Immunity; Child; Chinese Hamster Ovary Cell; Cities; Clinical; Clinical Research; Clinical Trials; Complex; Diagnosis; Disease; EBV-associated disease; EBV-associated malignancy; Epstein-Barr Virus Infections; Epstein-Barr Virus Nuclear Antigens; Glycoproteins; Goals; Growth; Human; Human Herpesvirus 4; Immune system; Immunize; In Vitro; Inbred BALB C Mice; Incidence; Individual; Left; Legal patent; Life; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Mediating; Membrane Glycoproteins; Membrane Proteins; Mus; Nuclear Antigens; Oncogenic; Participant; Patients; Pediatric Neoplasm; Peripheral Blood Mononuclear Cell; Phase; Physiologic pulse; Polyvalent Vaccine; Population; Preventive vaccine; Primary Infection; Production; Property; Proteins; Public Health; Recurrent disease; Research; Safety; Second Primary Cancers; Subunit Vaccines; Surface; Survivors; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; United States Food and Drug Administration; United States National Institutes of Health; Vaccine Antigen; Vaccines; Viral; Viral Antigens; Viral Genome; Viral Proteins; Viral Structural Proteins; Virus; Virus Diseases; Virus-like particle; Wild Type Mouse; arm; base; cell immortalization; cell mediated immune response; chemotherapy; humanized mouse; immortalized cell; immunogenic; immunogenicity; immunological status; in vitro Model; in vivo; meetings; mouse model; neutralizing antibody; novel virus; pre-clinical; preclinical study; prevent; prophylactic; protective efficacy; protein complex; success; therapeutic vaccine; treatment response; tumor; vaccine candidate; vaccine development; vaccine evaluation; virus envelope

PROJECT SUMMARY Burkitt lymphoma (BL) is the most common childhood cancer in sub-Saharan Africa, outnumbering all other forms of pediatric tumors combined. BL is lethal if left untreated; however, the current treatment (intensive chemotherapy) is only 50% effective and difficult to implement in sub-Saharan Africa. To date, the vast majority of African cases of BL are associated with Epstein-Barr virus (EBV) infection. Thus, there is a critical need for a safe and effective vaccine to prevent and treat EBV and its associated diseases. The objective of the proposed study is to develop, characterize, and validate gp42-gH/gL-EBNA1-LMP2 virus-like particles (VLPs) in pre-clinical studies as a candidate vaccine against EBV. Previous approaches to EBV vaccine development have been limited due in part to the oncogenic potential of the virus genome and lack of animal models to test vaccine candidates. This proposal will examine a new strategy to develop a safe and effective vaccine against EBV, using VLPs that can present properly folded EBV proteins. To target both arms of the immune system—antibody-mediated and T-cell mediated—the vaccine will incorporate multiple EBV surface and intracellular antigens. The EBV protein complex gp42-gH/gL and tumor-associated Epstein- Barr nuclear antigen 1 (EBNA1) and latent membrane protein (LMP2) are prime candidates for use in EBV vaccine development. There is strong evidence that antibodies to the EBV protein complex gp42-gH/gL can neutralize EBV infection. EBNA1 and LMP2 are consistently expressed in B cells of all EBV+ BL patients and are recognized by CD4+ and CD8+ T cells. Thus, we hypothesize that gp42-gH/gL-EBNA1-LMP2 VLPs will generate robust EBV-neutralizing antibody responses and EBV-specific T-cell responses in vitro and in a humanized mouse model. The VLPs will be generated, characterized, and validated using wild-type mice (Aim 1), an in vitro model of BL (Aim 2), and humanized mice (Aim 2) A polyvalent vaccine that induces both prophylactic neutralizing antibodies and elicits therapeutic human T-cell responses will not only be an invaluable candidate vaccine in preventing EBV infection, but also of utmost importance in preventing and/or treating EBV-associated disease. If the vaccine is immunogenic, following completion of the proposal, we will utilize the current good manufacturing practice facility available at City of Hope to mass-produce clinical grade gp42-gH/gL-EBNA1-LMP2 VLPs and begin a phase 1 clinical study in 10-15 healthy adults to establish safety profiles and determine the protective efficacy of the candidate vaccine. In the long term, if successful, our approach will introduce a new prophylactic/therapeutic vaccine to the market with a potential for preventing or treating over 200,000 annual cancer cases associated with EBV, including 24,000 cases of BL in African children.

项目概要 伯基特淋巴瘤 (BL) 是撒哈拉以南非洲地区最常见的儿童癌症，数量超过所有儿童癌症 其他形式的儿科肿瘤相结合。如果不及时治疗，BL 是致命的；然而目前的治疗 （强化化疗）在撒哈拉以南非洲地区的有效率仅为50%且难以实施。迄今为止， 绝大多数非洲 BL 病例与 Epstein-Barr 病毒 (EBV) 感染有关。因此，有一个 迫切需要一种安全有效的疫苗来预防和治疗 EBV 及其相关疾病。 拟议研究的目的是开发、表征和验证 gp42-gH/gL-EBNA1-LMP2 病毒样颗粒（VLP）作为 EBV 候选疫苗进行临床前研究。以前的方法 EB 病毒疫苗的开发受到限制，部分原因是病毒基因组的致癌潜力和 缺乏动物模型来测试候选疫苗。该提案将研究开发安全的新策略 以及有效的 EBV 疫苗，使用能够呈现正确折叠的 EBV 蛋白的 VLP。瞄准两者 免疫系统的两个分支——抗体介导的和 T 细胞介导的——疫苗将结合多种 EBV 表面和细胞内抗原。 EBV 蛋白复合物 gp42-gH/gL 和肿瘤相关 Epstein- Barr 核抗原 1 (EBNA1) 和潜伏膜蛋白 (LMP2) 是 EBV 的主要候选者 疫苗开发。有强有力的证据表明，针对 EBV 蛋白复合物 gp42-gH/gL 的抗体可以 中和 EBV 感染。 EBNA1 和 LMP2 在所有 EBV+ BL 患者的 B 细胞中一致表达，并且 被 CD4+ 和 CD8+ T 细胞识别。因此，我们假设 gp42-gH/gL-EBNA1-LMP2 VLPs 将 在体外和体内产生强大的 EBV 中和抗体反应和 EBV 特异性 T 细胞反应 人源化小鼠模型。 VLP 将使用野生型小鼠进行生成、表征和验证（目标 1)、BL 体外模型（目标 2）和人源化小鼠（目标 2） 一种多价疫苗，可诱导预防性中和抗体并引发治疗性人类抗体 T 细胞反应不仅是预防 EBV 感染的宝贵候选疫苗，而且 对于预防和/或治疗 EBV 相关疾病至关重要。如果疫苗具有免疫原性， 提案完成后，我们将利用现有的良好生产规范设施，网址为 City of Hope将量产临床级gp42-gH/gL-EBNA1-LMP2 VLP并开始1期临床 对 10-15 名健康成年人进行研究，以建立安全性概况并确定候选者的保护功效 疫苗。从长远来看，如果成功，我们的方法将引入一种新的预防/治疗疫苗 该市场每年有可能预防或治疗超过 200,000 例与 EBV 相关的癌症病例， 其中包括 24,000 例非洲儿童 BL 病例。