Herpesvirus Pathogenesis and Vaccine Development

疱疹病毒发病机制和疫苗开发

• 批准号: 10692092
• 负责人: Jeffrey Cohen
• 金额: $ 111.64万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10692092
• 关键词: Adopted; Adult; Animal Model; Animals; Antibodies; B-Lymphocytes; Biological Assay; Burkitt Lymphoma; Cells; Congenital Abnormality; Control Animal; Cytomegalovirus; Disease; Electron Microscopy; Epithelial Cells; Epstein-Barr Virus Infections; Epstein-Barr Virus-Related Malignant Neoplasm; Ferrets; Ferritin; Globulins; Glycoproteins; Goals; Herpesviridae; Herpesvirus Vaccines; Hodgkin Disease; Human; Human Herpesvirus 4; Immune; Immune response; Immunoglobulin G; Infection; Infectious Mononucleosis; Lymphoma; Lymphoproliferative Disorders; Molecular Conformation; Monoclonal Antibodies; Mus; Nasopharynx Carcinoma; Pathogenesis; Patients; Population; Prophylactic treatment; Reporting; Stomach Carcinoma; Testing; Vaccinated; Vaccines; Viremia; Virus Diseases; X-Linked lymphoproliferative disorders; cancer cell; design; humanized mouse; in vivo; nanoparticle; neutralizing antibody; nonhuman primate; post-transplant; prevent; vaccine candidate; vaccine development

Over 90% of adults are infected with EBV. Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with a number of B cell and epithelial cell cancers including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and gastric carcinoma. EBV is also associated with post-transplant lymphoproliferative disease and severe disease in patients with X-linked lymphoproliferative disease; no therapies are approved to prevent EBV infection in these patients. Human cytomegalovirus (HCMV) infects over half of the human population and is the most common infectious cause of birth defects. At present there are no licensed vaccines for either EBV or HCMV and hyperimmune globulin to HCMV has been of limited usefulness for prophylaxis or therapy of HCMV infections, while no such antibody product exists for EBV. In FYI 2022, we designed a nanoparticle vaccine consisting of a single-chain EBV glycoprotein H (gH) and glycoprotein L (gL) or a single chain gH/gL and glycoprotein 42 (gH/gL/gp42) that were each fused to bacterial ferritin to form a self-assembling nanoparticle. Structural analysis revealed that single-chain gH/gL and gH/gL/gp42 adopted a similar conformation to the wild-type glycoproteins, and the glycoprotein spikes were observed by electron microscopy. These vaccines elicited neutralizing antibodies in mice, ferrets, and nonhuman primates that inhibited EBV entry into both B cells and epithelial cells. When mixed with a previously reported gp350 nanoparticle vaccine no immune competition was observed. To confirm the efficacy of the EBV vaccines in vivo, humanized mice were challenged with EBV after passive transfer of IgG from mice vaccinated with control, gH/gL/gp42+gp350, or gH/gL+gp350 nanoparticles. Although all control animals were infected, only one mouse in each vaccine group that received immune IgG had detectable transient viremia. Furthermore, no EBV lymphomas were detected in immune animals. This bivalent EBV nanoparticle vaccine represents a promising candidate to prevent EBV infection and EBV-related malignancies in humans.

超过90％的成年人感染了EBV。爱泼斯坦 - 巴尔病毒（EBV）引起感染性单核细胞增多症，并与许多B细胞和上皮细胞癌有关，包括伯基特淋巴瘤，霍奇金淋巴瘤，鼻咽癌和胃癌。 EBV还与X连锁淋巴增生性疾病患者的移植后淋巴细胞增生性疾病和严重疾病有关。没有批准疗法以防止这些患者的EBV感染。 人类巨细胞病毒（HCMV）感染了人口一半以上，是最常见的出生缺陷原因。目前，尚无针对EBV或HCMV的许可疫苗，而HCMV的超免疫球蛋白对预防或HCMV感染的治疗有限，而EBV的这种抗体产物不存在。 在2022年FYI中，我们设计了一种由单链EBV糖蛋白H（GH）和糖蛋白L（GL）或单链GH/GH/GH/GL和糖蛋白42（GH/GL/GL/GL/GP42）组成的纳米颗粒疫苗。结构分析表明，单链GH/GH/GH/GL/GP42采用了与野生型糖蛋白相似的构象，并通过电子显微镜观察到糖蛋白尖峰。这些疫苗引起了抑制EBV进入B细胞和上皮细胞的小鼠，雪貂和非人类灵长类动物的中和抗体。当与先前报道的GP350纳米颗粒疫苗混合时，请观察到没有免疫竞争。为了确认EBV疫苗在体内的疗效，人源化小鼠在从控制，GH/GL/GL/GP42+GP350或GH/GH/GL+GP350纳米颗粒的疫苗接种的小鼠中被动转移后，对人源化小鼠进行了挑战。尽管所有对照动物都被感染，但在每个接受免疫IgG的疫苗组中只有一只小鼠患有可检测的瞬时病毒性血症。此外，在免疫动物中未检测到EBV淋巴瘤。这种二价EBV纳米颗粒疫苗代表了预防人类EBV感染和与EBV相关的恶性肿瘤的有前途的候选人。