Virus-Like Particle Vaccines for Pandemic Influenza

用于大流行性流感的病毒样颗粒疫苗

• 批准号: 7846502
• 负责人: Ted M Ross
• 金额: $ 3.96万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846502
• 关键词: Acute; Address; Africa; Anatomy; Animal Model; Animals; Antibodies; Antigens; Asia; Avian Influenza; Avian Influenza A Virus; Biological Assay; Brain; Cells; Clinical; Complement; Development; Effectiveness; Epitopes; Europe; Ferrets; Gene Expression; General Population; Generations; Goals; Hemagglutination; Housing; Human; Immune; Immune response; Immunity; Infection; Influenza; Influenza A Virus, H5N1 Subtype; Intramuscular; Laboratories; Life; Longevity; Lung; Macaca; Mediating; Memory; Modeling; Monkeys; Morbidity - disease rate; Mus; Pathology; Peripheral Blood Mononuclear Cell; Primates; Property; Proteins; Public Health; Recombinants; Recommendation; Research Personnel; Respiratory Mucosa; Rodent; Route; ST14 gene; Serum; Structural Protein; Structure of mucous membrane of nose; Subunit Vaccines; Surface; Testing; Tissues; Treatment Protocols; Universities; Vaccinated; Vaccination; Vaccines; Viral; Viral Genome; Viral Structural Proteins; Virus; Virus Diseases; Virus-like particle; Work; World Health Organization; base; design; experience; immunogenic; immunogenicity; influenza virus vaccine; influenzavirus; meetings; mortality; multidisciplinary; nonhuman primate; novel virus; pandemic disease; pandemic influenza; protective efficacy; response; three dimensional structure; vaccine candidate; vaccine development; vaccine efficacy

DESCRIPTION (provided by applicant): This proposal draws on the collaborative efforts of researchers at the University of Pittsburgh and our corporate partner, Novavax, Inc., to develop a new generation of pandemic influenza vaccines based upon the currently circulating strains of highly pathogenic avian influenza (HPAI) H5N1 isolates. This strategy involves the development of virus-like particles (VLPs) for the elicitation of immune responses in the respiratory mucosa of non-human primates. In addition, we propose to challenge vaccinated monkeys with HPAI H5N1 (A/lndoneisa/05/2005, clade 2) in the University of Pittsburgh's newly constructed ABSL-3 Regional Biocontainment Laboratories (RBL) for non-human primates. These VLPs are comprised of viral structural proteins that assemble spontaneously cells. Morphologically, VLPs resemble live influenza virus, are immunogenic, and represent an alternative to inactivated or subunit vaccines with the advantage that viral structural antigens are presented in a non-infectious form in the absence of a viral genome, while maintaining the integrity of conformationally-dependent antigenic epitopes. Our working hypothesis is that influenza VLP vaccines will provide a broader protection for the general population, which will be correlated with enhanced innate, humoral, and cellular host immune responses. We have assembled a network of experienced researchers to develop these novel VLP vaccines, to produce appropriate highly pathological influenza viruses representing H5N1 strains (HPAI), and to assess the vaccine-induced immune responses and pathology induced by viral infection in a relevant primate model. This application is designed to examine the immunogenicity of our H5N1 pandemic influenza VLP vaccines, in a non-human primate model, and compare to a single HA protein immunogen. These VLP vaccines are highly efficacious in small animals, however, we have determined that traditional immunological assays for analyzing the effectiveness of an influenza vaccine (HAI and mVN assays) are not predictive of protection against HPAI. Therefore, in order to examine protective immunity elicited by these VLP vaccines, we have assembled an interactive team to address the following Specific Aims: Aim 1: To compare the induced immune responses by clade 2 VLP and rHA vaccines in non-human primates. Aim 2: To determine pathological and innate immune responses to clade 2 viral challenge. Aim 3: To determine the protective efficacy and immunological correlates of protection of the clade 2 VLP vaccine against HPAI H5N1 influenza challenge in monkeys.

描述(由申请人提供)：这项建议利用匹兹堡大学的研究人员和我们的企业合作伙伴Novavax，Inc.的合作努力，以目前流行的高致病性禽流感(HPAI)H5N1分离株为基础开发新一代大流行性流感疫苗。这一策略包括开发病毒样颗粒(VLP)，以在非人类灵长类动物的呼吸道粘膜中激发免疫反应。此外，我们建议在匹兹堡大学为非人类灵长类动物新建的ABSL-3区域生物遏制实验室(RBL)向接种HPAI H5N1疫苗的猴子发起挑战(A/INDONISA/05/2005，Clade 2)。这些VLP由病毒结构蛋白组成，可以自发地组装细胞。在形态上，VLP类似于活的流感病毒，具有免疫原性，是灭活疫苗或亚单位疫苗的替代方案，优点是在没有病毒基因组的情况下，病毒结构抗原以非传染性形式呈现，同时保持构象依赖的抗原表位的完整性。我们的工作假设是，流感VLP疫苗将为普通人群提供更广泛的保护，这将与增强的先天、体液和细胞宿主免疫反应相关。我们聚集了一个由经验丰富的研究人员组成的网络，以开发这些新型VLP疫苗，生产代表H5N1毒株的适当的高度病理性流感病毒(HPAI)，并在相关的灵长类动物模型中评估疫苗诱导的免疫反应和病毒感染诱导的病理。这一应用旨在检验我们的H5N1大流行性流感VLP疫苗在非人类灵长类动物模型中的免疫原性，并与单一HA蛋白免疫原进行比较。这些VLP疫苗在小动物中非常有效，然而，我们已经确定，用于分析流感疫苗有效性的传统免疫学分析方法(HAI和MVN分析)不能预测对HPAI的保护。因此，为了检测这些VLP疫苗诱导的保护性免疫，我们组建了一个互动小组，以解决以下具体目标：目的1：比较VLP疫苗和RHA疫苗在非人灵长类动物中诱导的免疫应答。目的2：检测针对分支2病毒攻击的病理和先天免疫反应。目的：研究HPAI H5N1亚型VLP疫苗对猴的免疫保护作用及其免疫学相关性。