BKV and JCV vaccine development

BKV 和 JCV 疫苗开发

• 批准号: 8938133
• 负责人: Christopher Buck
• 金额: $ 52.88万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/8938133
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Adult; Animal Model; Antibodies; Antibody Formation; BK Virus; Brain Diseases; Capsid Proteins; Colorectal Cancer; Development; Disease; Genotype; Goals; Human; Human Papillomavirus; Immunocompromised Host; Immunosuppressive Agents; Individual; Industry; Infection; JC Virus; Kidney; Kidney Diseases; Kidney Transplantation; Legal patent; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mus; Pathology; Patients; Pharmaceutical Preparations; Polyomavirus; Polyomavirus Infections; Preventive; Progressive Multifocal Leukoencephalopathy; Resistance; Risk; Serotyping; Serum; Symptoms; System; Therapeutic immunosuppression; Transplant Recipients; Urinary tract; Urine; Vaccines; Variant; Viral; Virion; Virus; Virus-like particle; Work; base; neutralizing antibody; novel; pressure; prevent; recombinant virus; tool; vaccine development

Two distinct polyomaviruses, called BKV and JCV, chronically infect the human urinary tract. Most healthy adults are stably infected with both viruses and occasionally shed infectious virions in the urine. Although BKV and JCV aren't known to cause overt symptoms in healthy individuals, each of the two viruses can cause severe pathology in immunocompromised individuals. Most notably, BKV causes acute kidney damage in up to 10% of kidney transplant recipients. In AIDS patients and patients taking certain immunosuppressive drugs, JCV can cause a fatal brain disease called progressive multifocal leukoencephalopathy (PML). A further concern is that a controversial body of evidence has linked both BKV and JCV to various forms of cancer, including prostate and colorectal cancer, respectively. Our goal for this project is to develop preventive vaccines that might protect at-risk patients against BKV associated nephropathy (BKVN) or PML. The vaccines would draw on the same approach that led to the current highly successful vaccines against human papillomaviruses - specifically, the BKV or JCV vaccine would be composed of recombinant virus-like particles (VLPs) composed solely of the viral major capsid protein VP1. The VLP vaccine would be aimed at eliciting antibody responses capable of neutralizing the infectivity of BKV or JCV virions. To be successful, viruses must avoid being recognized by neutralizing antibodies elicited by previous infections. This evolutionary pressure drives the development of distinct viral "serotypes" that are not cross-recognized by serum antibodies. For example, it is well established that BKVs are not generally recognized by antibodies elicited during JCV infection. Although it has long been recognized that different BKV isolates are genetically distinct, no prior work has investigated the possibility that some BKV genotypes are resistant to neutralization by antibodies elicited by other other BKV genotypes. In other words, it is unclear whether distinct serotypes exist within the viral species BKV. This question is also unresolved for JCV. Our lab's work in FY2011 revealed that BKV genotype I (BKV-I) and BKV-IV are distinct serotypes that are reciprocally resistant to antibody-mediated cross-neutralization. Work in FY2012 has revealed that BKV genotypes can be divided into as many as five distinct serotypes. Encouragingly, administration of a multivalent VLP-based vaccine to mice elicits highly potent neutralizing antibody responses capable of neutralizing all five BKV serotypes. This suggests that a multivalent BKV VLP vaccine might be effective for protecting kidney transplant recipients against BKVN. We have recently begun extending our BKV findings to JCV. Specifically, we hypothesize that JCV VP1 variants found in PML lesions may allow the virus to escape from antibody-mediated neutralization. If this hypothesis is true, it would suggest that administering patients a VLP-based vaccine containing PML-variant VP1 might protect patients who are candidates for immunosuppressive therapy against PML. This work is the subject of an NCI patent application submitted in FY12. In FY14 we have been building industry partnerships to develop BKV and JCV vaccines.

两个不同的多瘤病毒称为BKV和JCV，长期感染了人类尿路。大多数健康的成年人都稳定地感染了病毒，偶尔会在尿液中脱落感染性病毒体。尽管尚不清楚BKV和JCV在健康个体中引起明显的症状，但两种病毒中的每一种都可能导致免疫功能低下的个体严重病理。最值得注意的是，BKV在多达10％的肾脏移植受者中会造成急性肾脏损伤。在艾滋病患者和服用某些免疫抑制药物的患者中，JCV会引起致命的脑疾病，称为进行性多灶性白细胞术（PML）。另一个问题是，有争议的证据分别将BKV和JCV与各种形式的癌症联系起来，分别将前列腺癌和大肠癌联系起来。我们的该项目的目标是开发预防疫苗，该疫苗可能可以保护高危患者免受BKV相关肾病（BKVN）或PML的影响。疫苗将采用导致当前对人乳头瘤病毒的高度成功疫苗的相同方法 - 具体来说，BKV或JCV疫苗将由仅由病毒主要的Capsid Capsid蛋白VP1组成的重组病毒样颗粒（VLP）组成。 VLP疫苗将旨在引起能够中和BKV或JCV病毒体的感染性的抗体反应。为了取得成功，病毒必须避免通过中和以前感染引起的抗体识别。这种进化压力驱动了未被血清抗体交叉认可的不同病毒“血清型”的发展。例如，众所周知，在JCV感染期间引起的抗体通常不会识别BKV。尽管长期以来已经认识到不同的BKV分离株在遗传上是不同的，但先前的工作没有研究某些BKV基因型对通过其他BKV基因型引起的抗体抗中和的可能性。换句话说，尚不清楚病毒物种BKV中是否存在不同的血清型。对于JCV来说，这个问题也未解决。我们实验室在2011财年的工作表明，BKV基因型I（BKV-I）和BKV-IV是不同的血清型，对抗体介导的跨性和中和化具有相互抵抗。 2012财年的工作表明，BKV基因型可以分为多达五种不同的血清型。令人鼓舞的是，对小鼠的多价基疫苗给药会引起高度有效的中和抗体反应，能够中和所有五种BKV血清型。这表明多价BKV VLP疫苗可能有效地保护肾脏移植受者免受BKVN的侵害。我们最近开始将BKV的发现扩展到JCV。具体而言，我们假设PML病变中发现的JCV VP1变体可能使该病毒从抗体介导的中和中逃脱。如果该假设是正确的，则表明对患者进行含有PML变化VP1的基于VLP的疫苗可能会保护那些候选免疫抑制疗法的患者，以防止PML进行免疫抑制治疗。这项工作是2012财年提交的NCI专利申请的主题。在2014财年，我们一直在建立行业伙伴关系，以开发BKV和JCV疫苗。