A Therapeutic Vaccine for Chronic Hepatitis B

慢性乙型肝炎的治疗疫苗

• 批准号: 8663178
• 负责人: David R. Milich
• 金额: $ 98.14万
• 依托单位: VLP BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-19 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663178
• 关键词: Adjuvant; Animals; Antibodies; Antibody Formation; Antigens; Antiviral Agents; B-Lymphocyte Epitopes; B-Lymphocytes; Biological Assay; Biomanufacturing; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chronic; Chronic Hepatitis B; Cirrhosis; Clinical Trials; Combined Modality Therapy; Complication; Core Protein; Cyclic GMP; Data Collection; Development; Drug Formulations; Drug usage; Employee Strikes; Epitopes; Equilibrium; Exhibits; Goals; Health; Hepadnaviridae; Hepatitis; Hepatitis B; Hepatitis B Core Antigen; Hepatitis B Surface Antigens; Hepatitis B Therapeutic; Hepatitis B Vaccines; Hepatitis B Virus; Hepatocyte; Human; Hybrids; Immune; Immune Sera; Immune Tolerance; Immunization; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Infection; Infection prevention; Laboratories; Legal patent; Licensing; Liver; Liver Failure; Liver Fibrosis; Medical; Outcome; Pharmacotherapy; Phase; Phase I Clinical Trials; Preparation; Primary carcinoma of the liver cells; Process; Research; Research Institute; Running; Site; Small Business Innovation Research Grant; System; T cell response; T-Lymphocyte; Technology; Testing; Therapeutic; Transgenic Mice; Treatment Efficacy; Vaccine Research; Vaccines; Variant; Viral; Viral Antibodies; Viral Antigens; Viral Core Proteins; Viral Envelope Proteins; Viral Load result; Viral Proteins; Viral Vaccines; Virion; Virus; Virus Diseases; Virus-like particle; Woodchuck; Work; anti-hepatitis B; base; cell bank; drug withdrawal; effective therapy; efficacy testing; high risk; immunogenicity; improved; in vivo; meetings; mouse model; neutralizing antibody; novel; pre-clinical; prevent; protective efficacy; recombinant virus; research clinical testing; safety study; stability testing; success; therapeutic vaccine; transmission process; vaccine candidate; vaccine efficacy

DESCRIPTION (provided by applicant): The objective of this proposal is to assess the feasibility of using recombinant virus-like- particles (VLPs) to elicit neutralizing antibodies and prime CD4+ T cells reactive with hepatitis B viral (HBV) antigens as candidate immunotherapeutics for chronic HBV infection. For this purpose, we have defined 8 neutralizing B cell epitopes from the HBV envelope Pre-S1 region, which will be consolidated and inserted onto a species variant of the HBV core protein, namely the woodchuck hepatitis core antigen(WHcAg). Pre-S1 B cell epitopes were chosen because of their preferential expression on HBV virions. The WHO estimates that more than 360 million individuals are chronically infected with HBV and approximately 20- 40% will develop serious complication such as cirrhosis, liver failure and hepatocellular carcinoma. Although a safe and efficacious preventative vaccine for HBV has been available for over 20years, HBV infections continue (with more than 50 million HBV infections per year) to be a major health problem and no effective treatments for chronic infection exist. Antiviral drugs have improved the therapeutic options for chronic HBV, but, their efficacy remains limited due to reactivation of HBV replication upon drug withdrawal. Vaccine-based immunotherapy has been suggested as a possible monotherapy or as a combination therapy with antiviral drugs. However, immune tolerance has prevented therapeutic vaccine efficacy. To circumvent the obstacle of immune tolerance in HBV chronic carriers, we have chosen the WHcAg, which is approximately 66-68% homologous with the HBcAg, as a vaccine carrier. The WHcAg and the HBcAg are not crossreactive at the B cell level and, just as importantly for our purposes, are only partially crossreactive at the CD4+ T cel level. Therefore, CD4+ T cells specific for WHcAg-unique T cell sites will provide cognate T-B cell help for anti- PreS1 antibody production and will not be curtailed by immune tolerance. In fact, in preliminary studies in HBcAg-Tg mice, which are tolerant to HBcAg, immunization with hybrid WHcAg- PreS1 VLPs elicits equivalent high titer anti- PreS1 antibodies in wildtype and HBcAg-Tg mice. Specifically, in Aim 1 we propose to consolidate 8 HBsAg-PreS1 neutralizing B cell epitopes onto the WHcAg VLP carrier and optimize the constructs based on assembly, yield, stability and immunogenicity and the therapeutic efficacy of the VLP-based vaccine candidates will be evaluated in a transgenic (Tg) mouse model of HBV replication. In Aim 2 preclinical development of the WHcAg-PreS1 vaccine will be pursued including cGMP manufacturing and pharm/tox studies.

描述（由申请人提供）：该提案的目的是评估使用重组病毒颗粒（VLP）的可行性，以引起中和抗体和 Prime CD4+ T细胞用丙型肝炎病毒（HBV）抗原作为慢性HBV感染的候选免疫治疗药反应。为此，我们定义了来自HBV包膜Pre-S1区域的8个中和B细胞表位，该区域将被巩固并插入HBV核心蛋白的物种变体上，即Woodchuck Hepatitis Core核心抗原（WHCAG）。选择了S1 B细胞的表位，因为它们在HBV病毒体上的优先表达。世卫组织估计，超过3.6亿人患有HBV，大约20-40％会出现严重的并发症，例如肝硬化，肝衰竭和肝细胞癌。尽管HBV的安全有效的预防性疫苗已经可用于20年以上，但HBV感染仍在继续（每年超过5000万HBV感染）是一个主要的健康问题，并且没有有效的慢性感染治疗方法。抗病毒药改善了慢性HBV的治疗选择，但是由于HBV复制的重新激活，其功效仍然有限 戒毒后。已建议基于疫苗的免疫疗法作为可能的单一疗法或抗病毒药物的联合疗法。但是，免疫耐受性阻止了治疗疫苗的功效。为了避免HBV慢性载体中免疫耐受性的障碍，我们选择了与HBCAG同源约66-68％的WHCAG作为疫苗载体。在B细胞水平上，WHCAG和HBCAG在B细胞水平上没有交叉反应，同样重要的是，对于我们的目的而言，在CD4+ T CEL水平上仅部分交叉反应。因此，针对WHCAG唯一T细胞位点特异性的CD4+ T细胞将为抗PRES1抗体的产生提供同源的T-B细胞帮助，并且不会因免疫耐受性而减少。实际上，在对HBCAG耐受性HBCAG的HBCAG-TG小鼠的初步研究中，用混合WHCAG-PRES1 VLPS免疫引起了野生型和HBCAG-TG小鼠的等效高滴度抗体抗体。具体而言，在目标1中，我们提议将8 HbSAG-PRES1巩固到WHCAG VLP载体上中和B细胞表位，并根据组装，产量，稳定性和免疫原性以及基于VLP的疫苗候选物的治疗功效优化构造，将在Transgenic（TG）中的基因（TG）HBV Replication e Replication Ins Transgenic（TG）中评估。在AIM 2中，将追求WHCAG-PRES1疫苗的临床前开发，包括CGMP制造和药物/TOX研究。