GM-CSF-Adjuvanted Clade C DNA/MVA and MVA/MVA Vaccines

描述（由申请人提供）：由HIV-1引起的获得性免疫缺陷综合征（AIDS）是非洲的主要死因，也是全球第四大死因。该IPCAVD正在开发使用DNA进行初免和MVA进行加强的HIV/AIDS疫苗（DNA/MVA疫苗）以及这些疫苗的更简单且最终更容易部署的形式，使用MVA进行初免和加强（MVA/MVA疫苗）。DNA疫苗和MVA疫苗都是使用单一载体表达病毒样颗粒（VLP）的成熟产品，IPCAVD试图将佐剂GM-CSF构建到这些产品中以顺式表达。在临床前研究中，GM-CSF的共表达具有显著增强的保护作用。IPCAVD的中心假设是GM-CSF通过增强引发的T细胞和Ab应答的粘膜存在来改善保护。在南部非洲和亚洲部分地区流行的进化枝C HIV-1占全世界感染的大约一半，并且占印度病例的>90%，印度是一个感染迅速蔓延的国家，其病例总数超过了南非。该IPCAVD的疫苗开发工作重点是为印度开发C进化枝疫苗。 博士项目主任哈里特罗宾逊在埃默里疫苗中心的实验室、NIAID的Bernard Moss博士实验室和美国疾病控制中心的Tom Folks博士小组之间的长期合作期间，有效地领导了该IPCAVD中疫苗的开发。2004年，GeoVax Inc.亚特兰大佐治亚州的一家研究所获得了疫苗技术的许可，并在埃默里大学、NIAID和CDC之间达成了一项机构间协议，以进一步开发和商业化疫苗。该IPCAVD已由GeoVax提交，罗宾逊博士计划在2007年春季搬到那里，全职从事她和她的团队开发的疫苗的开发和翻译工作。 这个IPCAVD有3个项目和2个核心。GeoVax的Mark Keister博士（P.I.）罗宾逊医生是共同私家侦探(at GeoVax）将领导该项目开发和制造免疫原。拉马阿马拉博士（埃默里大学）将领导SIV 251/恒河猴模型的临床前研究。Mark Mulligan博士（在Emory）将领导临床试验项目（通过HVTN进行），罗宾逊博士作为共同Pi（在GeoVax）监督辅助免疫原性试验的进行。罗宾逊博士（在GeoVax）将领导行政核心。帕梅拉·科兹洛夫斯基博士将在哈佛大学领导一个粘膜抗体核心。关键决策将得到内部和外部咨询委员会的支持。该IPCAVD的优势在于其由私人/公共/学术/工业团队领导，该团队具有进行重点疫苗开发计划的能力，将有前途的产品推向临床试验和商业化。 项目1：项目开发和制造（Hildebrand，D.） 项目1描述（由申请人提供）：由HIV-1引起的获得性免疫缺陷综合征（艾滋病）是非洲的主要死因，也是全球第四大死因。该IPCAVD正在开发使用DNA进行初免和MVA进行加强的HIV/AIDS疫苗（DNA/MVA疫苗）以及这些疫苗的更简单且最终更容易部署的形式，使用MVA进行初免和加强（MVA/MVA疫苗）。DNA疫苗和MVA疫苗都使用单一载体来表达病毒样颗粒（VLP）JPCAVD试图将佐剂GM-CSF构建到这些产物中以顺式表达。在临床前研究中，GM-CSF的共表达具有显著增强的保护作用。IPCAVD的中心假设是GM-CSF通过增强引发的T细胞和Ab应答的粘膜存在来改善保护。在南部非洲和亚洲部分地区流行的进化枝C HIV-1占全世界感染的大约一半，并且占印度病例的>90%，印度是一个感染迅速蔓延的国家，其病例总数超过了南非。该IPCAVD的疫苗开发工作重点是为印度开发C进化枝疫苗。 该制造项目有五个具体目标： * 疫苗载体开发。 * 疫苗载体生产适用性评估。 * 疫苗载体的cGMP合同生产和毒理学试验。 * HVTN 1期试验的监管支持。 * 放行和稳定性试验的开发和实施。 该项目将由Mark Keister博士领导，哈里特罗宾逊博士共同指导。根据GeoVax、Emory、CDC和NIAID之间关于DNA/MVA和MVA/MVA疫苗开发的机构间协议，将由Bernard Moss博士构建所需的MVA载体。

DESCRIPTION (provided by applicant): The acquired immunodeficiency syndrome (AIDS) caused by HIV-1 is the leading cause of death in Africa and the fourth leading cause of death worldwide. This IPCAVD is developing HIV/AIDS vaccines that use DNA for priming and MVA for boosting (DNA/MVA vaccine) as well as a simpler and ultimately easier to deploy form of these vaccines, the use of MVA for both priming and boosting (MVA/MVA vaccine). Both the DNA and MVA vaccines are mature products that use single vectors to express virus like particles (VLP).This IPCAVD seeks to build GM-CSF, an adjuvant, into these products for expression in cis. In preclinical studies, co-expression of GM-CSF has substantially enhanced protection. A central hypothesis for the IPCAVD is that GM-CSF improves protection by enhancing the mucosal presence of elicited T cell and Ab responses. Clade C HIV-1 which is endemic in southern Africa and parts of Asia accounts for about one half of the infections worldwide and >90% of the cases in India, a country with a rapidly spreading infection that has surpassed South Africa in its total number of cases. The vaccine development effort of this IPCAVD is focused on developing a clade C vaccine for India. Dr. Harriet Robinson, the program director, has effectively led the development of the vaccines in this IPCAVD during a long-term collaboration between her laboratory at the Emory Vaccine Center, Dr. Bernard Moss's laboratory at the NIAID and Dr. Tom Folks' group at the US Centers for Disease Control. In 2004, GeoVax Inc. of Atlanta GA licensed the technology for the vaccines and entered into an inter-institutional agreement between Emory, NIAID, and CDC for further development and commercialization of the vaccines. This IPCAVD has been submitted by GeoVax where Dr. Robinson plans to move in the spring of 2007 to work full time on the development and translation of the vaccines that she and her team have developed. This IPCAVD has 3 projects and 2 cores. Dr. Mark Keister of GeoVax (P.I.) with Dr. Robinson as co-P.I. (at GeoVax) will lead the project developing and manufacturing immunogens. Dr. Rama Amara (at Emory) will lead preclinical studies in the SIV251/rhesus macaque model. Dr. Mark Mulligan (at Emory) will lead the project on clinical trials (conducted through the HVTN) with Dr. Robinson as co-Pi (at GeoVax) overseeing the conduct of ancillary immunogenicity assays. Dr. Robinson (at GeoVax) will lead the administrative core. Dr. Pamela Kozlowski will lead a mucosal Ab core at Harvard University. Critical decisions will be supported by both Internal and External Advisory Committees. A strength of this IPCAVD is its leadership by a private/public/academic/industrial team with demonstrated ability to conduct a focused vaccine development program to bring promising products to clinical trials and commercialization. PROJECT 1: PROJECT DEVELOPMENT AND MANFACTURE (Hildebrand, D.) PROJECT 1 DESCRIPTION (provided by applicant): The acquired immunodeficiency syndrome (AIDS) caused by HIV-1 is the leading cause of death in Africa and the fourth leading cause of death worldwide. This IPCAVD is developing HIV/AIDS vaccines that use DNA for priming and MVA for boosting (DNA/MVA vaccine) as well as a simpler and ultimately easier to deploy form of these vaccines, the use of MVA for both priming and boosting (MVA/MVA vaccine). Both the DNA and MVA vaccines use single vectors to express virus like particles (VLP).This IPCAVD seeks to build GM-CSF, an adjuvant, into these products for expression in cis. In preclinical studies, co-expression of GM-CSF has substantially enhanced protection. A central hypothesis for the IPCAVD is that GM-CSF improves protection by enhancing the mucosal presence of elicited T cell and Ab responses. Clade C HIV-1 which is endemic in southern Africa and parts of Asia accounts for about one half of the infections worldwide and >90% of the cases in India, a country with a rapidly spreading infection that has surpassed South Africa in its total number of cases. The vaccine development effort of this IPCAVD is focused on developing a clade C vaccine for India. This manufacturing project has five specific aims: * Vaccine vector development. * Assessment of vaccine vectors for suitability for manufacture. * cGMP contract manufacture and toxicology testing of vaccine vectors. * Regulatory support for an HVTN phase 1 trial. * Development and conduct of release and stability assays. The project will be led by Dr. Mark Keister and co-directed by Dr. Harriet Robinson. Construction of the needed MVA vector will be by Dr. Bernard Moss under an Inter-Institutional Agreement for the development of DNA/MVA and MVA/MVA vaccines between GeoVax, Emory, CDC and the NIAID.