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

说明（由申请人提供）：由艾滋病毒-1引起的获得性免疫缺陷综合症（艾滋病）是非洲的主要死亡原因，也是全世界第四大死亡原因。IPCAVD正在开发使用DNA启动和MVA增强的艾滋病毒/艾滋病疫苗（DNA/MVA疫苗），以及更简单和最终更容易部署的这些疫苗形式，即使用MVA启动和增强（MVA/MVA疫苗）。DNA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。该IPCAVD旨在将GM-CSF（一种佐剂）构建到这些产品中以顺式表达。在临床前研究中，GM-CSF的共表达显著增强了保护作用。IPCAVD的一个中心假设是GM-CSF通过增强粘膜中诱导的T细胞和Ab反应来提高保护作用。在非洲南部和亚洲部分地区流行的C支HIV-1约占全世界感染病例的一半，占印度病例的50%，印度是一个感染迅速蔓延的国家，其病例总数已超过南非。IPCAVD疫苗开发工作的重点是为印度开发一种C级疫苗。

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.