Recombinant Papillomavirus-based HIV Vaccine Targeting Genital Mucosa

针对生殖器粘膜的基于重组乳头瘤病毒的 HIV 疫苗

• 批准号: 8993591
• 负责人: Marie-Claire Elisabeth Gauduin
• 金额: $ 27.75万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-25 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8993591
• 关键词: Acquired Immunodeficiency Syndrome; Animals; Antigens; Attenuated; B-Lymphocytes; Biopsy; Blood; Cell Culture Techniques; Cytomegalovirus; Development; Electron Microscopy; Elements; Epithelial Cells; Epitopes; Female; Gene Delivery; Gene Expression; Genital system; Genome; HIV; HIV vaccine; Human; Human Papillomavirus; Immune response; Immune system; Immunity; Immunization; Immunologic Techniques; In Vitro; Infection; Infection prevention; Laboratories; Lead; Length; Life; Macaca; Macaca mulatta; Methodology; Modeling; Molecular; Molecular Biology Techniques; Monitor; Mucous Membrane; Nature; Organ; Organism; Papillomavirus; Plasmids; Recombinant DNA; Recombinants; Research; Route; SIV; SIV Vaccines; Safety; Site; Staging; Stem cells; Surface; System; T cell response; T-Lymphocyte Epitopes; Testing; Transfection; Vaccinated; Vaccines; Vagina; Viral; Viral Antigens; Viral Vector; Virus; Virus Diseases; Virus Replication; Virus-like particle; Work; base; design; env Genes; gene delivery system; genetic vaccine; immunogenic; improved; in vivo; mucosal site; novel; novel vaccines; particle; prevent; public health relevance; seroconversion; success; transmission process; vaccine development; vector

 DESCRIPTION (provided by applicant): Twenty years of research in the field of HIV vaccine have shown that the use of replicating virus to stimulate the immune system is one of our best hopes to develop a vaccine. Recently a cytomegalovirus based vaccine strategy has successfully protected half of the animals vaccinated. However, this success rate needs to be improved, notably by the use of live viral vectors that restrict HIV replication at the mucosal portal of entry. The capacity of humoral and cellular immune responses in mucosal tissues to block or contain replication at the initial stage of virus transmission may have a profound impact on the ability of a vaccinated host to resist infection. An ideal vaccine should provide a life-lon stimulation of the immune system with viral antigens and should focus the immune response at the site of primary replication of HIV. Recent breakthroughs in vaccine development have used highly immunogenic viruses like particles (VLP) as antigen carriers to stimulate the immune system. This is particularly true for Papillomaviruses (PV). These VLP can also be used to encapsidate either fully infectious PV genome or expression plasmids. These particles are infectious both in cell culture and in vivo. A PV called RhPV has been isolated from a Rhesus macaque giving the opportunity to test PV as SIV antigen vectors. Our collaborator has recently been using pseudotyped RhPV successfully to inoculate Rhesus macaques giving the possibility to manipulate this virus without losing infectivity. The use of RhPV as a SIV vaccine in macaque will be the best model possible to investigate the potential of HPV as an anti-HIV vaccine in human. Therefore, specific aims of the R21 will be: 1) To design and optimize a RhPV vector that leads to long-term expression of SIV antigens in rhesus macaques vaccinated by vaginal, route; and, 2) To experimentally infect female macaques with a chimeric RhPV/SIV and investigate the nature of the immune responses induced. Our work should provide a "proof-of-concept" for the development of HIV vaccines using the papillomavirus as a delivery system at the mucosa to elicit long-term protection against HIV infection.

 描述（由申请人提供）：在艾滋病毒疫苗领域20年的研究表明，使用复制病毒刺激免疫系统是我们开发疫苗的最大希望之一。最近，一种基于巨细胞病毒的疫苗策略成功地保护了一半接种疫苗的动物。然而，这一成功率需要提高，特别是通过使用活病毒载体，限制艾滋病毒复制的粘膜入口。在病毒传播的初始阶段，粘膜组织中的体液和细胞免疫应答阻断或抑制复制的能力可能对接种疫苗的宿主抵抗感染的能力产生深远影响。理想的疫苗应该用病毒抗原对免疫系统提供终身刺激，并将免疫应答集中在HIV的主要复制部位。 疫苗开发的最新突破是使用高免疫原性病毒样颗粒（VLP）作为抗原载体来刺激免疫系统。这对于乳头瘤病毒（PV）尤其如此。这些VLP也可用于纯化完全感染性PV基因组或表达质粒。这些颗粒在细胞培养物和体内都具有感染性。从恒河猴中分离出一种称为RhPV的PV，从而有机会测试PV作为SIV抗原载体。我们的合作者最近成功地使用假型RhPV感染恒河猴，从而有可能在不失去感染性的情况下操纵这种病毒。 在猕猴中使用RhPV作为SIV疫苗将是研究HPV作为人类抗HIV疫苗的潜力的最佳模型。因此，R21的具体目标将是：1）设计和优化RhPV载体，其导致SIV抗原在通过阴道途径接种的恒河猴中的长期表达;和，2）用嵌合RhPV/SIV实验性感染雌性恒河猴并研究诱导的免疫应答的性质。我们的工作应该提供了一个“概念验证”的艾滋病毒疫苗的发展，使用乳头瘤病毒作为一个交付系统在粘膜引起长期保护艾滋病毒感染。