Development of an Ad5 [E1-, E2b-] HIV-1 vaccine for use in Ad5 Immunized Vaccinee

开发用于 Ad5 免疫疫苗的 Ad5 [E1-, E2b-] HIV-1 疫苗

• 批准号: 8020031
• 负责人: Frank R. Jones
• 金额: $ 113.34万
• 依托单位: ETUBICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8020031
• 关键词: Acquired Immunodeficiency Syndrome; Adenovirus Infections; Adenovirus Vector; Adenoviruses; Animals; Antigens; Cell Line; Cells; Characteristics; Clinical Trials; Communicable Diseases; DNA biosynthesis; DNA-Directed DNA Polymerase; Development; Excision; Failure; Frequencies; Gagging; Gene Delivery; Generations; Genetic; Goals; HIV; HIV vaccine; HIV-1; Head; Health; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunologics; Infection; Interferons; Intramuscular; Intravenous; Lead; Light; Lymphocyte; Mus; Phase; Polymerase; Production; Proteins; Regimen; Route; SIV; Sampling; Schedule; Small Business Innovation Research Grant; Sucrose; System; T-Lymphocyte; TimeLine; Transgenes; Triad Acrylic Resin; Vaccinated; Vaccination; Vaccines; Viral Proteins; Virus; base; cytotoxicity; gag Gene Products; immunogenicity; in vivo; intraperitoneal; novel vaccines; phase 2 study; pre-clinical; preclinical study; response; safety testing; transgene expression; vector; vector vaccine; vector-based vaccine; vector-induced; viral DNA

DESCRIPTION (provided by applicant): Current generation Adenovirus (Ad) vector vaccines deleted at the E1 or the E1, E3 regions have resulted in experimental potential to immunize against a variety of infectious diseases such as HIV. These Ad vectors permit the delivery of genes, which express proteins that stimulate the immune system. An advanced generation of Ad vectors with unique deletions of the E1 and E2b region (E2b encodes the viral DNA polymerase (pol) and the preterminal protein (pTP) has previously been described. The deletion of these genetic regions renders the Ad5 [E1-, E2b-] virus completely replication incompetent. The new human Ad5 [ E1-,E2b-] vectors have several advantages. Ad viral DNA replication is significantly diminished and the removal of the E2b region results in a 10,000-fold reduction in the production of Ad late gene products, further reducing the potential of Ad encoded viral proteins from impacting host immune responses. Moreover, use of Ad5 [E1-, E2b-] vectors have been shown to have decreased cytotoxicity. The Ad5 [E1-, E2b-] vectors can also lead to an increased quantity and sustained expression of inserted transgenes. These characteristics of Ad5 [E1-, E2b] vectors suggest that they are superior to Ad5 [ El-] vectors. In light of these advantages, our strategy is to employ the use of Ad5 [E1-, E2b-] vectors as a new platform for vaccine based vectors. Specifically, we chose to use this new Ad5 platform as a vaccine platform for HIV-1. Our Phase 1 goal to investigate Ad5 [E1-, E2b-] vectors was very successful. Multiple immunizations induced robust immunologic responses to transgene products. We observed that animals could be immunized with one antigen and then subsequently immunized with a second differing antigen in the presence of Ad5 immunity. In comparison with the current generation Ad5 [E1-] vector, our [E1-, E2b-] vector induced higher levels of interferon-? and lL-2 secreting lymphocytes both in Ad5 naive and Ad5 immune. Studies also demonstrate that animals could be immunized with a triad mixture of Ad5 [E1-, E2b-] gag, nef, pol. Our analysis of samples from our initial vaccine trial in NHPs suggest that they can be successfully immunized against the HIV gag protein in the presence of pre-existing Ad5 hyper immunity. In Phase II, studies will be performed in mice and NHPs to further develop the vaccination regimen. The Aims of the Phase II study are to (1) prepare SIV and human Ad5 [E1-, E2b-]-gag, pol, nef vaccine platforms. (2) determine the optimal frequency and optimal route of triad vaccination in mice by investigating immunizations on a weekly, bi-weekly and monthly schedule and also compare intradermal, intramuscular, intraperitoneal and intravenous routes of immunization with a triad mix of Ad5 [E1-, E2b-]-gag/pol/nef vectors. (3) determine the duration of transgene expression in vivo. (4) test safety and immunogenicity of the triad vaccine in Ad5 na¿ve and Ad5 immune NHP, and (5) perform SIV challenge studies of vaccinated NHPs. Etubics will perform these pre-clinical studies to advance this new vaccine platform into clinical trials. PUBLIC HEALTH RELEVANCE: With approximately 5,000 new HIV-1 infections occurring daily and the failure of the Merck 'STEP" HIV vaccine trial, the need for a viable HIV-1 vaccine is urgent. During this study, we will further develop our advanced adenoviral vector delivery system for HIV vaccines. The system is needed to break through the barrier presented by vaccinees who have had prior adenovirus infections which includes many humans worldwide.

描述(由申请人提供)：当前代腺病毒(Ad)载体疫苗在E1或E1、E3区域缺失，已导致对各种传染病(如艾滋病毒)进行免疫的实验潜力。这些Ad载体允许传递基因，这些基因表达刺激免疫系统的蛋白质。先前已经描述了具有独特的E1和E2b区(E2b编码病毒DNA聚合酶(Poll)和前末端蛋白(PTP)的E2b区缺失的高级一代Ad载体。这些基因区域的缺失使Ad5[E1-，E2b-]病毒完全不能复制。新的人Ad5[e1-，e2b-]载体有几个优点。Ad病毒DNA复制显著减少，E2b区的去除导致Ad Late基因产物的产生减少10,000倍，进一步降低了Ad编码的病毒蛋白影响宿主免疫反应的可能性。此外，Ad5[E1-，E2b-]载体的使用已被证明具有较低的细胞毒性。Ad5[e1-，E2b-]载体还可以增加插入外源基因的数量和持续表达。Ad5[E1-，E2b]载体的这些特性表明它们优于Ad5[EL-]载体。鉴于这些优势，我们的策略是使用Ad5[E1-，E2b-]载体作为疫苗载体的新平台。具体地说，我们选择使用这个新的Ad5平台作为HIV-1的疫苗平台。 我们的第一阶段目标是研究Ad5[E1-，E2b-]载体，这是非常成功的。多重免疫诱导了对转基因产物的强大免疫反应。我们观察到，动物可以用一个抗原免疫，然后在有Ad5免疫的情况下用第二个不同的抗原免疫。与当前一代Ad5[E1-]载体相比，我们的[E1-，E2b-]载体诱导了更高水平的干扰素-？和分泌IL-2的淋巴细胞，在Ad5幼稚和Ad5免疫。研究还表明，可以用Ad5[E1-，E2b-]Gag，nef，pol三联体免疫动物。我们对NHP最初疫苗试验样本的分析表明，在存在预先存在的Ad5超级免疫的情况下，它们可以成功地针对HIV Gag蛋白进行免疫。 在第二阶段，将在小鼠和NHP中进行研究，以进一步开发疫苗接种方案。第二阶段研究的目的是(1)制备SIV和人Ad5[E1-，E2b-]-Gag，Pol1，NEF疫苗平台。(2)通过每周、每两周和每月一次的免疫研究，确定小鼠接种三联体的最佳频率和最佳途径，并比较Ad5[E1-，E2b-]-Gag/Pol1/nef三联体混合载体的皮内、肌肉、腹膜和静脉免疫途径。(3)确定转基因在体内表达的持续时间。(4)在Ad5 NA和Ad5免疫NHP中测试三联疫苗的安全性和免疫原性；(5)对接种的NHP进行SIV攻击研究。Etubics将进行这些临床前研究，以推动这一新的疫苗平台进入临床试验。与公共卫生相关：由于每天约有5,000例新的HIV-1感染病例，加上默克步骤HIV疫苗试验的失败，迫切需要一种可行的HIV-1疫苗。在这项研究期间，我们将进一步开发用于HIV疫苗的先进的腺病毒载体递送系统。该系统需要突破既往腺病毒感染的接种者带来的障碍，其中包括世界各地的许多人。

项目成果

Prevention of influenza virus shedding and protection from lethal H1N1 challenge using a consensus 2009 H1N1 HA and NA adenovirus vector vaccine.

• DOI: 10.1016/j.vaccine.2011.07.073
• 发表时间: 2011-09-16
• 期刊: VACCINE
• 影响因子: 5.5
• 作者: Jones, Frank R.;Gabitzsch, Elizabeth S.;Xu, Younong;Balint, Joseph P.;Borisevich, Viktoriya;Smith, Jennifer;Smith, Jeanon;Peng, Bi-Hung;Walker, Aida;Salazar, Magda;Paessler, Slobodan
• 通讯作者: Paessler, Slobodan