Broad-Range VLP Vaccine Against H5N1 Influenza

针对 H5N1 流感的广谱 VLP 疫苗

基本信息

批准号：
8694582
负责人：
Peter M. Pushko
金额：
$ 35万
依托单位：
MEDIGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8694582
关键词：
Adverse effects Avian Influenza Avian Influenza A Virus Baculoviruses Biochemical Biological Birds Categories Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Characteristics China Collaborations Control Animal Country Data Development Disease Outbreaks Domestic Fowls Drug Formulations Egypt Elderly Environment Epidemic Evaluation Ferrets Genetic Growth H5 influenza virus Hemagglutinin Human Immune response Immunity Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H5N1 Subtype Influenza A Virus, H7N9 Subtype Intramuscular Knowledge Mediating Methods Mission Modeling Morbidity - disease rate Mucosal Immunity Mutation National Institute of Allergy and Infectious Disease Population Preparation Prevention strategy Process Production Protein Engineering Proteins Public Health Recombinants Recording of previous events Research Project Grants Risk Route ST14 gene Safety Solutions Structure Technology Technology Transfer Testing United States National Institutes of Health Vaccinated Vaccination Vaccines Vietnam Viral Hemagglutinins Virus Virus-like particle aged biodefense biosecurity cost cost effective design disorder prevention enzootic high risk immunogenicity improved influenza virus vaccine influenzavirus innovation manufacturing scale-up meetings mortality new technology novel novel strategies pandemic disease pandemic influenza pandemic preparedness parallel processing pathogen preclinical study protective efficacy public health relevance recombinant virus research study response theories vaccine development

项目摘要

DESCRIPTION (provided by applicant): Highly pathogenic avian influenza (HPAI) viruses are Category C NIAID priority pathogens and a global biodefense threat. Vaccines that provide protection against HPAI viruses are required for biodefense and pandemic preparedness. During the past decade, the H5N1 HPAI viruses have diversified genetically and antigenically leading to the need for multiple H5N1 vaccines. Although H5N1 clade 1 vaccines have been prepared, it is unlikely that they will protect against other H5N1 clades. In addition, preparation of vaccines for each potential threat virus is expensive, economically not feasible and can raise serious biosafety and biosecurity concerns. Recombinant virus-like particles (VLPs) represent a promising strategy for prevention of HPAI. VLPs have advantages in safety, efficacy, and manufacturing because they circumvent problems like slow virus growth, unpredictable yields, and host-adaptive mutations. It has been shown that VLPs induce broader immunity against divergent strains than standard influenza vaccines, especially if administered mucosally (Bright et al., 2007; Perrone et al., 2009). Furthermore, we have recently prepared multi-subtype VLP, in which several distinct subtypes of hemagglutinin (HA) were co-localized within the same VLP structure thus providing protection against multiple challenge viruses (Pushko et al., 2011; Tretyakova et al., 2013). The multi-subtype vaccines have advantage of inducing broad-range, yet traditional virus-neutralizing immune responses directed against several influenza subtypes. Here we propose the use of multi-HA VLP platform for the development of multi-H5 VLPs as a unique multi-clade H5N1 VLP vaccine. The multi-H5 VLPs will be rationally designed to co-localize within the VLP the three H5 proteins derived from three distinct H5N1 clades. The resulting triple-H5 VLPs are expected to elicit effective protection against multiple H5N1 HPAI viruses resulting in a safe and effective, broadly protective H5N1 vaccine. Particularly, we propose preparation of VLPs that co-localize H5 proteins derived from Clade 1, Clade 2.2.1.1, and Clade 2.3.2.1 viruses, all recommended by the WHO for H5N1 vaccine development. Multi-H5 VLPs will be prepared by using recombinant baculovirus expression, and genetic stability, biochemical, structural, and antigenic characteristics of VLPs will be evaluated (Sp. Aim 1). Immunogenicity and efficacy of triple-H5 VLPs will be evaluated in experimental ferret challenge model in collaboration with the Centers for Disease Control and Prevention (CDC). Both the homologous (Sp. Aim 2) and heterologous (Sp. Aim 3) H5N1 HPAI challenges are proposed in order to evaluate this novel broad-spectrum H5N1 vaccine. Young and aged ferrets will be included into the challenge studies to mimic the most vulnerable human populations. The effects of intramuscular and intranasal routes of vaccination on immune responses will be evaluated. Mechanisms of broad immunity will be elucidated including humoral, cell-mediated, and mucosal immunity. Process development and technology transfer into manufacturing environment will be carried out. Following completion of preclinical trials and process development activities, a pre-IND meeting with FDA will be planned. If successful, this novel technology may represent an innovative platform for rapid and cost-effective preparation of multivalent influenza vaccines for biodefense and pandemic preparedness.

描述（由申请人提供）：高致病性禽流感 (HPAI) 病毒是 C 类 NIAID 优先病原体，也是全球生物防御威胁。生物防御和大流行病防范需要针对 HPAI 病毒提供保护的疫苗。在过去的十年中，H5N1 HPAI 病毒在基因和抗原性上发生了多样化，导致需要多种 H5N1 疫苗。尽管 H5N1 进化枝 1 疫苗已经制备出来，但它们不太可能针对其他 H5N1 进化枝提供保护。另外，准备针对每种潜在威胁病毒的疫苗价格昂贵，在经济上不可行，并且可能引起严重的生物安全和生物安保问题。重组病毒样颗粒（VLP）代表了预防 HPAI 的一种有前景的策略。 VLP 在安全性、有效性和制造方面具有优势，因为它们规避了病毒生长缓慢、产量不可预测和宿主适应性突变等问题。研究表明，VLP 比标准流感疫苗能诱导更广泛的针对不同毒株的免疫力，尤其是通过粘膜给药时（Bright 等人，2007 年；Perrone 等人，2009 年）。此外，我们最近制备了多亚型 VLP，其中几种不同的血凝素 (HA) 亚型共定位于同一 VLP 结构内，从而提供针对多种攻击病毒的保护（Pushko 等，2011；Tretyakova 等， 2013）。多亚型疫苗的优点是诱导针对多种流感亚型的广泛但传统的病毒中和免疫反应。在这里，我们建议使用多HA VLP平台来开发多H5 VLP作为独特的多进化枝H5N1 VLP疫苗。多 H5 VLP 将经过合理设计，以将源自三个不同 H5N1 进化枝的三种 H5 蛋白共定位在 VLP 内。由此产生的三重 H5 VLP 有望对多种 H5N1 HPAI 病毒产生有效的保护，从而形成安全有效、具有广泛保护性的 H5N1 疫苗。特别是，我们建议制备可共定位来自 Clade 1、Clade 2.2.1.1 和 Clade 2.3.2.1 病毒的 H5 蛋白的 VLP，这些病毒均被 WHO 推荐用于 H5N1 疫苗开发。将通过重组杆状病毒表达制备多 H5 VLP，并评估 VLP 的遗传稳定性、生化、结构和抗原特征（Sp. 目标 1）。将与疾病控制和预防中心 (CDC) 合作，在实验雪貂攻击模型中评估三重 H5 VLP 的免疫原性和功效。为了评估这种新型广谱 H5N1 疫苗，提出了同源 (Sp. Aim 2) 和异源 (Sp. Aim 3) H5N1 HPAI 挑战。年轻和年老的雪貂将被纳入挑战研究中，以模仿最脆弱的人群。将评估肌内和鼻内疫苗接种途径对免疫反应的影响。将阐明广泛免疫的机制，包括体液免疫、细胞介导的免疫和粘膜免疫。将进行工艺开发并将技术转移到制造环境中。临床前试验和工艺开发活动完成后，将计划与 FDA 举行 IND 前会议。如果成功，这项新技术可能代表一个创新平台，可以快速且经济高效地制备用于生物防御和大流行防范的多价流感疫苗。