Trans-complementing papillioma virus for AIDS vaccine

用于艾滋病疫苗的反式互补乳头状瘤病毒

• 批准号: 9011505
• 负责人: Marie-Claire Elisabeth Gauduin
• 金额: $ 77.65万
• 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: 2015-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9011505
• 关键词: Acquired Immunodeficiency Syndrome; Animals; Antibody Formation; Antigens; Attenuated; Attenuated Vaccines; B-Lymphocytes; Biopsy; Blood; CD8B1 gene; Cell Culture Techniques; Cells; Complement; Cytomegalovirus; Development; Dose; Electron Microscopy; Elements; Epithelial; Female; Genes; Genital system; Genome; HIV; HIV vaccine; Health; Human; Human Papillomavirus; Immune response; Immune system; Immunity; Immunization; Immunologic Techniques; In Vitro; Infection; Laboratories; Length; Life; Macaca; Macaca mulatta; Memory; Methodology; Modeling; Molecular Biology Techniques; Monitor; Mucosal Immunity; Mucous Membrane; Nature; Oral; Organism; Papillomavirus; Pilot Projects; Plasmids; Protocols documentation; Recombinant DNA; Recombinants; Research; Route; SIV; SIV Vaccines; Safety; Site; Staging; Surface; System; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Time; Transfection; Vaccinated; Vaccines; Vagina; Viral; Viral Antigens; Viral Vector; Virus; Virus Diseases; Virus Replication; Virus-like particle; Work; base; design; gene delivery system; genetic vaccine; immunogenic; improved; in vivo; mucosal site; novel; novel vaccines; pandemic disease; particle; prevent; protective efficacy; rectal; response; seroconversion; success; transmission process; vaccine development; vector; vector vaccine; viral transmission

 DESCRIPTION (provided by applicant): Over 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 virus-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. Pseudotyped RhPV has recently been used by our collaborator to successfully inoculate Rhesus macaques giving the possibility to manipulate this virus without losing infectivity. The use of RhPV as a SIV vaccine in macaque followed by SIVmac challenge will be the best model possible to investigate the potential of HPV as an anti-HIV vaccine in humans. However the limiting packaging capacity of RhPV leads us to propose a completely new live vaccine strategy based on mucosal infection with trans-complementing papillomavirus that would still be replicative and would promote antibody production and anti-SIV central memory CD8+ T cells expansion at the oral, rectal and vaginal mucosa for a prolonged period of time. Therefore, specific aims of proposal will be: 1) To design a RhPV vector that leads to long-term expression of SIV antigens in rhesus macaques vaccinated by vaginal, rectal and/or oral routes; 2) To experimentally infect female macaques with this trans-complementing RhPV/SIV vector and investigate the nature of the immune responses induced and safety over 12 months; and, 3) To investigate the protective efficacy of the trans-complementing RHPV/SIV vaccine following intravaginal or intrarectal challenge with multiple low-dose homologous SIV strains challenge. Our work should provide a "proof-of-concept" in which we will question the capacity of RhPV, as a vaccine vector, to generate strong and long-term anti-SIV immunity at the genital site.

 描述（由适用提供）：在HIV疫苗领域进行了20多年的研究表明，使用复制病毒刺激免疫系统是开发疫苗的最佳希望之一。最近，基于巨细胞病毒的疫苗策略成功地保护了一半的动物接种疫苗。但是，需要提高这种成功率，特别是通过使用限制进入粘膜入境门户的HIV复制的活病毒媒介。在病毒传播的初始阶段，粘膜组织中的体液和细胞免疫调查会阻塞或包含复制的能力可能对疫苗接种宿主抵抗感染的能力产生深远的影响。理想的疫苗应用病毒抗原对免疫系统进行救生刺激，并应将免疫激发聚焦于HIV的主要复制部位。 疫苗发育中最近的突破已使用高度免疫原性病毒样颗粒（VLP）作为抗原载体来刺激免疫系统。对于乳头瘤病毒（PV）尤其如此。这些VLP也可用于封装完全感染的PV基因组或表达质粒。这些颗粒在细胞培养和体内都具有感染性。已经从恒河猕猴中分离出一种称为RHPV的PV，从而有机会将PV作为SIV抗原矢量进行测试。我们的合作者最近使用了伪型RHPV来成功接种恒河猕猴，从而有可能在不感染的情况下操纵这种病毒。 在猕猴中，将RHPV用作SIV疫苗，然后是SIVMAC挑战，将是研究HPV作为人类抗HIV疫苗潜力的最佳模型。然而，RHPV的限制包装能力使我们提出了一种基于粘膜感染的全新活疫苗策略，并具有反式填充乳头瘤病毒，它仍然具有复制性，并将促进抗体的产生和抗SIV中央记忆CD8+ T细胞在口服，直肠和阴道Mucosa的扩展，以供延长的时间延长。因此，提案的具体目的将是：1）设计RHPV载体，该旋转载体在通过阴道，直肠和/或口腔途径接种的恒河猕猴中长期表达SIV抗原； 2）用这种反式融合的RHPV/SIV载体在实验中感染雌性猕猴，并研究诱导的免疫反应的性质和12个月内的安全性； 3）研究在阴道内或直肠内攻击后，具有多种低剂量同源SIV菌株挑战后，反式汇编RHPV/SIV疫苗的受保护效率。我们的工作应提供“概念验证”，在该概念上，我们将质疑RHPV作为疫苗向量的能力，以在生殖器部位产生强大和长期的抗SIV免疫。