Virus-Like Particle Vaccines for Pandemic Influenza

描述（由申请人提供）：该提案利用匹兹堡大学研究人员和我们的合作伙伴Novavax公司的合作努力，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。这一策略涉及到病毒样颗粒（vlp）的发展，用于在非人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新建的ABSL-3非人类灵长类动物区域生物控制实验室（RBL）中，用HPAI H5N1 （A/ indonesia /05/2005, clade 2）挑战接种过疫苗的猴子。这些VLPs由病毒结构蛋白组成，它们自发地组装细胞。在形态上，VLPs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，这将与增强的先天、体液和细胞宿主免疫反应相关。我们已经组建了一个由经验丰富的研究人员组成的网络，以开发这些新型VLP疫苗，生产适当的高病理性流感病毒，代表H5N1毒株（HPAI），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。本应用程序旨在检验我们的H5N1大流行性流感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试验（HAI和mVN试验）不能预测对高致病性禽流感的保护。因此，为了检验这些VLP疫苗引发的保护性免疫，我们组建了一个互动小组，以解决以下具体目标：目的1：比较进化支2 VLP和rHA疫苗在非人灵长类动物中的诱导免疫反应。目的2：确定对进化支2病毒攻击的病理和先天免疫反应。目的3：确定clade 2 VLP疫苗对猴子高致病性H5N1流感攻击的保护效果和免疫学相关性。

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.