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: 7796585
• 负责人: Ted M Ross
• 金额: $ 115.44万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796585
• 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; Regimen; Research Personnel; Respiratory Mucosa; Rodent; Route; ST14 gene; Serum; Structural Protein; Structure of mucous membrane of nose; Subunit Vaccines; Surface; Testing; Tissues; 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）：该提案借鉴了匹兹堡大学研究人员和我们的企业合作伙伴 Novavax, Inc. 的合作成果，基于当前流行的高致病性禽流感 (HPAI) H5N1 分离株开发新一代大流行性流感疫苗。该策略涉及开发病毒样颗粒（VLP），用于在非人类灵长类动物的呼吸道粘膜中引发免疫反应。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 区域生物防护实验室 (RBL) 中用 HPAI H5N1（A/lndoneisa/05/2005，进化枝 2）对接种疫苗的猴子进行攻击。这些 VLP 由自发组装细胞的病毒结构蛋白组成。从形态上看，VLP类似于活流感病毒，具有免疫原性，是灭活疫苗或亚单位疫苗的替代品，其优点是病毒结构抗原在没有病毒基因组的情况下以非感染性形式呈现，同时保持构象依赖性抗原表位的完整性。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，这与增强的先天、体液和细胞宿主免疫反应有关。我们组建了一个由经验丰富的研究人员组成的网络来开发这些新型 VLP 疫苗，生产代表 H5N1 毒株 (HPAI) 的适当高度病理性流感病毒，并在相关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学。此应用旨在检查我们的 H5N1 大流行流感 VLP 疫苗在非人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 疫苗对小动物非常有效，但是，我们已经确定，用于分析流感疫苗有效性的传统免疫学测定（HAI 和 mVN 测定）并不能预测 HPAI 的保护作用。因此，为了检查这些 VLP 疫苗引发的保护性免疫，我们组建了一个互动团队来实现以下具体目标： 目标 1：比较 clade 2 VLP 和 rHA 疫苗在非人灵长类动物中诱导的免疫反应。目标 2：确定对进化枝 2 病毒攻击的病理和先天免疫反应。目标 3：确定 clade 2 VLP 疫苗对猴子 HPAI H5N1 流感攻击的保护功效和免疫学相关性。

项目成果

Modeling host responses in ferrets during A/California/07/2009 influenza infection.

• DOI: 10.1016/j.virol.2010.02.020
• 发表时间: 2010-06-05
• 期刊: Virology
• 影响因子: 3.7
• 作者: Rowe T;León AJ;Crevar CJ;Carter DM;Xu L;Ran L;Fang Y;Cameron CM;Cameron MJ;Banner D;Ng DC;Ran R;Weirback HK;Wiley CA;Kelvin DJ;Ross TM
• 通讯作者: Ross TM

Acute murine H5N1 influenza A encephalitis.

• DOI: 10.1111/j.1750-3639.2011.00514.x
• 发表时间: 2012-03
• 期刊: Brain pathology (Zurich, Switzerland)
• 作者: Bissel SJ;Giles BM;Wang G;Olevian DC;Ross TM;Wiley CA
• 通讯作者: Wiley CA

Seroprevalence following the second wave of Pandemic 2009 H1N1 influenza in Pittsburgh, PA, USA.

• DOI: 10.1371/journal.pone.0011601
• 发表时间: 2010-07-14
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zimmer SM;Crevar CJ;Carter DM;Stark JH;Giles BM;Zimmerman RK;Ostroff SM;Lee BY;Burke DS;Ross TM
• 通讯作者: Ross TM

Properly folded bacterially expressed H1N1 hemagglutinin globular head and ectodomain vaccines protect ferrets against H1N1 pandemic influenza virus.

• DOI: 10.1371/journal.pone.0011548
• 发表时间: 2010-07-12
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Khurana S;Verma S;Verma N;Crevar CJ;Carter DM;Manischewitz J;King LR;Ross TM;Golding H
• 通讯作者: Golding H

The role of RNA folding free energy in the evolution of the polymerase genes of the influenza A virus.

• DOI: 10.1186/gb-2009-10-2-r18
• 发表时间: 2009-02-12
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Brower-Sinning R;Carter DM;Crevar CJ;Ghedin E;Ross TM;Benos PV
• 通讯作者: Benos PV