Virus-Like Particle Vaccines for Pandemic Influenza

描述（由申请人提供）：本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.的合作努力，根据目前流行的高致病性禽流感（HPAI）H5 N1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），用于在非人灵长类动物的呼吸道粘膜中引发免疫应答。此外，我们建议挑战接种疫苗的猴子HPAI H5 N1（A/indoneisa/05/2005，进化枝2）在匹兹堡大学新建成的ABSL-3区域生物防护实验室（RBL）的非人灵长类动物。这些VLP由自发组装细胞的病毒结构蛋白组成。在形态学上，VLP类似于活流感病毒，具有免疫原性，并且代表灭活疫苗或亚单位疫苗的替代方案，其优点在于，在不存在病毒基因组的情况下，病毒结构抗原以非感染性形式呈递，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疫苗将为一般人群提供更广泛的保护，这将与增强的先天性、体液和细胞宿主免疫应答相关。我们已经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，以产生代表H5 N1毒株（HPAI）的适当的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应答和病毒感染诱导的病理学。本申请旨在在非人灵长类动物模型中检查我们的H5 N1大流行性流感VLP疫苗的免疫原性，并与单一HA蛋白免疫原进行比较。这些VLP疫苗在小动物中是高度有效的，然而，我们已经确定用于分析流感疫苗的有效性的传统免疫学测定（HAI和mVN测定）不能预测针对HPAI的保护。因此，为了检查这些VLP疫苗引起的保护性免疫，我们组建了一个互动小组，以解决以下具体目标：目标1：比较进化枝2 VLP和rHA疫苗在非人灵长类动物中诱导的免疫应答。目的2：确定对进化枝2病毒攻击的病理和天然免疫应答。目标3：确定进化枝2 VLP疫苗在猴中针对HPAI H5 N1流感攻击的保护效力和免疫学相关性。

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.