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

描述(申请人提供)：由艾滋病毒-1引起的获得性免疫缺陷综合征(艾滋病)是非洲的主要死亡原因，也是全球第四大死亡原因。该IPCAVD正在开发使用DNA进行启动和使用MVA进行加强免疫的艾滋病毒/艾滋病疫苗(DNA/MVA疫苗)，以及一种更简单且最终更易于部署的这些疫苗形式，即使用MVA进行启动和加强(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GM-CSF作为佐剂植入这些产品中，以便在顺式系统中表达。在临床前研究中，GM-CSF的共表达显著增强了保护作用。关于IPCAVD的一个中心假说是，GM-CSF通过增强粘膜上激发的T细胞和抗体反应来增强保护作用。在南部非洲和亚洲部分地区流行的C分支HIV-1约占全球感染病例的一半，印度占病例总数的90%，印度是一个感染迅速蔓延的国家，病例总数已超过南非。IPCAVD的疫苗开发工作重点是为印度开发一种C分支疫苗。 2004年，佐治亚州亚特兰大的GeoVax公司获得了疫苗技术的许可，并在Emory、NIAID和CDC之间达成了一项机构间协议，进一步开发和商业化疫苗。这份IPCAVD是由GeoVax提交的，罗宾逊博士计划在2007年春天搬到那里，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。马克·凯斯特博士，GeoVax(P.I.)与罗宾逊博士共同担任P.I.(在GeoVax)将领导该项目开发和制造免疫原。Emory的Rama Amara博士将领导SIV251/恒河猴模型的临床前研究。马克·穆利根博士(Emory)将领导临床试验项目(通过HVTN进行)，罗宾逊博士将作为联合PI(在GeoVax)监督辅助免疫原性分析的进行。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领导哈佛大学的粘膜抗体核心研究。关键决定将得到内部和外部咨询委员会的支持。IPCAVD的一个优势是它由一个私人/公共/学术/工业团队领导，该团队被证明有能力实施有重点的疫苗开发计划，将有前途的产品带到临床试验和商业化。 项目1：项目开发和管理(希尔德布兰德，D.) 项目1说明(申请人提供)：艾滋病毒-1引起的获得性免疫缺陷综合征(艾滋病)是非洲的主要死亡原因，也是全球第四大死亡原因。该IPCAVD正在开发使用DNA进行启动和使用MVA进行加强免疫的艾滋病毒/艾滋病疫苗(DNA/MVA疫苗)，以及一种更简单且最终更易于部署的这些疫苗形式，即使用MVA进行启动和加强(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)，这种IPCAVD试图将GM-CSF(一种佐剂)整合到这些产物中，以便在顺式系统中表达。在临床前研究中，GM-CSF的共表达显著增强了保护作用。关于IPCAVD的一个中心假说是，GM-CSF通过增强粘膜上激发的T细胞和抗体反应来增强保护作用。在南部非洲和亚洲部分地区流行的C分支HIV-1约占全球感染病例的一半，印度占病例总数的90%，印度是一个感染迅速蔓延的国家，病例总数已超过南非。IPCAVD的疫苗开发工作重点是为印度开发一种C分支疫苗。 这个制造项目有五个具体目标： *疫苗媒介的发展。 *评估疫苗载体是否适合生产。 *疫苗媒介的cGMP合同制造和毒理学测试。 *对HVTN第一阶段试验的监管支持。 *开发和进行释放度和稳定性分析。 该项目将由马克·凯斯特博士领导，哈里特·罗宾逊博士共同指导。所需MVA载体的构建将由Bernard Moss博士根据GeoVax、Emory、CDC和NIAID之间的DNA/MVA和MVA/MVA疫苗开发机构间协议进行。

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.