Efficacy of Strain 68-1 RhCMV Vectors Expressing 5' Leader Polypeptides

表达 5 前导多肽的菌株 68-1 RhCMV 载体的功效

• 批准号: 9266296
• 负责人: Scott G Hansen
• 金额: $ 85.62万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-25 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266296
• 关键词: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Address; Adoptive Transfer; Alleles; Anti-Retroviral Agents; Antibody Response; Antigens; Autopsy; Biochemical; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Clinical Trials; Combined Vaccines; Cytomegalovirus; Data; Development; Dose-Limiting; Epitopes; Frequencies; Genetic; Genetic Transcription; HIV; HIV vaccine; Health Priorities; Hour; Human; Immune; Immune response; Immunologics; Infection; Intercept; International; Kinetics; Macaca mulatta; Measures; Messenger RNA; Modeling; Monkeys; Open Reading Frames; Pathogenicity; Peptide Leader Sequences; Peptides; Proteins; RNA Sequences; RNA Splicing; Regulation; Research; Ribosomes; SIV; Site; T cell response; T memory cell; T-Lymphocyte; Time; Tissues; Translating; Vaccinated; Vaccination; Vaccines; Viral; Viral Proteins; Virus; Virus Replication; base; clinical development; cost effective; design; gene product; immunogenic; immunogenicity; improved; novel; pandemic disease; polypeptide; pre-clinical; preclinical study; prophylactic; protective efficacy; public health relevance; response; stem; vaccine efficacy; vector; vector vaccine; viral RNA; virology

 DESCRIPTION (provided by applicant): The development of an effective HIV/AIDS vaccine remains a high international health priority as the most cost-effective means to stem the AIDS pandemic. At this point in time, there are very few general HIV/AIDS vaccine strategies that remain viable for clinical development as a prophylactic HAV/AIDS vaccine - that is, vaccine platforms that have shown promising efficacy in preclinical studies and not been proved ineffective in human clinical trials. Among these is the approach developed by our group in which persistent Cytomegalovirus (CMV)-derived vectors are used to elicit high-frequency, indefinitely persistent HIV/SIV- specific effector-memory T cell responses. In the preclinical rhesus macaque (RM) - SIV model, we have demonstrated that after mucosal SIV challenge >50% of monkeys vaccinated with strain 68-1 RhCMV/SIVgag, /SIVpol, /SIVenv, /SIVrevtatnef vectors show complete, durable protection and eventual clearance by virologic and immunologic criteria. Protection is likely determined by the ability of effector T cells to intercept a nascent HIV/SIV infection immediately upon acquisition (with no response delay due to requirement for anamnestic expansion and effector differentiation). If this assumption is correct one could speculate that a greater efficacy could be achieved if the earliest HIV/SIV immunogens could be targeted within hours after initial infection. Recently a novel set of 5' leader sequence-encoded HIV and SIV polypeptides was discovered, and these polypeptides are expressed very early in HIV/SIV-infected cells and were highly immunogenic. Therefore, the 5' leader polypeptides (5'-LP) are an extremely attractive vaccine target considering that every spliced and unspliced HIV/SIV mRNA contains the 5' leader sequence, and thus polypeptides encoded from this region will be ubiquitously expressed rapidly and early following infection. Thus, the major objective of the research proposed here will be to determine whether RhCMV vectors expressing SIV 5' leader polypeptides can protect rhesus macaques from mucosal challenge with highly pathogenic SIVmac239, and if these vectors in combination with vectors expressing conventional SIV open reading frames, can enhance the overall protective efficacy of the RhCMV-vectored vaccine. These objectives will be accomplished by experimentally addressing the following Specific Aims: (i) To characterize the immunogenicity of strain 68-1 RhCMV/5'-LP vectors in rhesus macaques and to use this immunogenicity, in combination with biochemical analysis, to define the 5'-LP epitopes expressed by SIV-infected CD4+ T cells; (ii) To determine the efficacy of strain 68-1 RhCMV/5'-LP vector vaccination against limiting-dose, intra-rectal SIV challenge; and if Go/No-Go criteria are met, (iii) To determine the immunogenicity and efficacy of a combination vaccine containing both strain 68-1 RhCMV/5'- LP vectors and strain 68-1 RhCMV vectors expressing Gag, Rev/Nef/Tat, Pol, Env.

 描述（由申请人提供）：作为遏制艾滋病流行的最具成本效益的手段，开发有效的艾滋病毒/艾滋病疫苗仍然是国际卫生领域的高度优先事项。目前，很少有通用的 HIV/AIDS 疫苗策略能够作为预防性 HAV/AIDS 疫苗进行临床开发，即在临床前研究中显示出有希望的功效且在人体临床试验中尚未被证明无效的疫苗平台。其中包括我们小组开发的方法，其中使用持久性巨细胞病毒 (CMV) 衍生载体来引发高频、无限期持久的 HIV/SIV 特异性效应记忆 T 细胞反应。在临床前恒河猴 (RM) - SIV 模型中，我们已经证明，在粘膜 SIV 攻击后，超过 50% 的接种 68-1 RhCMV/SIVgag、/SIVpol、/SIVenv、/SIVrevtatnef 载体疫苗的猴子显示出完整、持久的保护，并根据病毒学和免疫学标准最终清除。保护可能取决于效应 T 细胞拦截新生细胞的能力。 获得后立即感染 HIV/SIV（不会因需要记忆扩展和效应器分化而导致反应延迟）。如果这一假设正确，人们可以推测，如果最早的 HIV/SIV 免疫原能够在初次感染后数小时内被靶向，则可以实现更大的功效。最近发现了一组新的5'前导序列编码的HIV和SIV多肽，这些多肽在HIV/SIV感染的细胞中很早就表达并且具有高度免疫原性。因此，考虑到每个剪接和未剪接的HIV/SIV mRNA都含有5'前导序列，5'前导多肽（5'-LP）是一个极具吸引力的疫苗靶点，因此从该区域编码的多肽将在感染后早期快速普遍表达。因此，本文提出的研究的主要目的是确定表达SIV 5'前导多肽的RhCMV载体是否可以保护恒河猴免受高致病性SIVmac239的粘膜攻击，以及这些载体与表达常规SIV开放阅读框的载体组合是否可以增强RhCMV载体疫苗的整体保护功效。这些目标将通过实验解决以下具体目标来实现： (i) 表征恒河猴中菌株 68-1 RhCMV/5'-LP 载体的免疫原性，并利用这种免疫原性，结合生化分析，确定 SIV 感染的 CD4+ T 细胞表达的 5'-LP 表位； (ii) 确定菌株 68-1 RhCMV/5'-LP 载体疫苗接种对抗限制剂量、直肠内 SIV 攻击的功效； (iii)确定含有毒株68-1 RhCMV/5'-LP载体和表达Gag、Rev/Nef/Tat、Pol、Env的毒株68-1 RhCMV载体的组合疫苗的免疫原性和功效。