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（由适用提供）：在E1或E1上删除的当前一代腺病毒（AD）载体疫苗，E3区域已产生了实验潜力，以对各种感染性疾病（如HIV）进行免疫接种。这些AD载体允许传递基因，该基因表达刺激免疫系统的蛋白质。 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优势。 e2b-]载体也可以导致插入的翻译的数量增加，并持续表达AD5的特征[E1-，E2B]载体，这表明它们优于AD5 [EL]载体。具体来说，我们选择将此新的AD5平台用作HIV-1的疫苗平台。 我们研究AD5 [E1-，E2B-]向量的第一阶段目标非常成功。多种免疫刺激会诱导鲁棒的免疫反应转化产物。我们观察到可以用一种抗原免疫动物，然后在AD5免疫史的存在下用第二种不同的抗原免疫。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 - ？在AD5 NAIVE和AD5免疫中，LL-2分泌淋巴细胞。研究还表明，可以用AD5 [E1-，E2B-] GAG，NEF，POL的三合会混合物免疫动物。我们对NHP中最初疫苗试验样品的分析表明，在存在先前存在的AD5超级免疫力的情况下，它们可以成功免疫HIV GAG蛋白。 在第二阶段，将在小鼠和NHP中进行研究，以进一步开发疫苗方案。第二阶段研究的目的是（1）准备SIV和人类AD5 [E1-，E2B-] - GAG，POL，NEF疫苗平台。 （2）通过每周，每两周和每月的时间表研究免疫抑制，确定小鼠中三合会疫苗的最佳频率和最佳途径，并与AD5 [e1- pol的Triad triad com of Ad5 [e1-，e2b-gag-gag/nef triad of triad of triad of Admunosuppression complosefem insecy of Ademant of Ady plosunosupression plosepression of the of the heekeek and每月的时间表。 （3）确定体内转化表达的持续时间。 （4）三合会疫苗在AD5NA¿和AD5免疫NHP中的测试安全性和免疫原性，以及（5）对接种NHP的SIV挑战研究。 Etubics将进行这些临床前研究，以将该新的疫苗平台推向临床试验。公共卫生相关性：每天发生大约5,000个新的HIV-1感染以及默克“步骤” HIV疫苗试验的失败，迫切需要使用可行的HIV-1疫苗。在这项研究中，我们将进一步开发用于HIV疫苗的晚期腺病毒载体输送系统。需要该系统打破疫苗所呈现的障碍，这些疫苗先前患有腺病毒感染，其中包括全球许多人。

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