Optimization of an innate immune stimulating adjuvant for an HIV DNA vaccine

HIV DNA 疫苗先天免疫刺激佐剂的优化

• 批准号: 8789040
• 负责人: Kenneth C Bagley
• 金额: $ 23.88万
• 依托单位: PROFECTUS BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789040
• 关键词: Adjuvant; Antibodies; Antibody Formation; Antigens; Antiviral Agents; Attenuated Vaccines; Avidity; Biological Assay; CD8B1 gene; CMV promoter; Cells; Consensus; DNA; DNA Vaccines; Deletion Mutation; Dose; Electroporation; Epidemic; Funding; Genes; Genetic; Goals; Gold; HIV; HIV Envelope Protein gp120; HIV Infections; HIV Vaccine Trials Network; HIV vaccine; IgG1; Immune; Immune response; Immunity; Infection; Interferon Type I; Interferon Type II; Interferons; Interleukin-12; Interleukin-2; Lead; Length; Life; Lytic; Macaca; Mus; Muscle Cells; PTPRC gene; Pathway interactions; Performance; Phase; Phase I Clinical Trials; Plasmids; Regimen; SIV; Secondary Immunization; Signal Transduction; Small Business Innovation Research Grant; T cell response; T-Lymphocyte; TNF gene; Technology; Testing; Tissues; Vaccinated; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Viral; Viral Antibodies; Virus; Virus Diseases; base; chemokine; combat; cytokine; gag-pol Fusion Proteins; immunogenicity; in vivo; induced pluripotent stem cell; meetings; mouse model; novel; prevent; promoter; public health relevance; response; success; vector vaccine

DESCRIPTION: There is a growing consensus that protection against HIV infection will require BOTH antiviral antibody responses as well as polyfunctional CD4+ and CD8+ T cells with potent lytic activity. To stimulate the breadth, potency, and rate of response required, Profectus Biosciences intends to utilize its platform technologies based on electroporation of DNA vaccines combined with genetic adjuvants. As a step in that direction, a recent phase 1 clinical trial, HVTN-080, showed that electroporation in combination with our IL-12 adjuvant can double the CD4+ and CD8+ T cell response rate in vaccinees over electroporation alone1. Even with this success, we recognize that a truly effective HIV vaccine will require a regimen that can consistently provide high magnitude, long-lived responses at rates >95% with as few booster immunizations as possible. We believe that adjuvants are a key to developing such a vaccine. Under a previous phase I SBIR, we identified a new class of genetic adjuvants that exploit the RIG-1 signaling cascades and trigger potent anti-viral innate immune responses. These innate responses integrate with TLR evoked innate responses and DAMPs/alarmins to evoke potent anti-viral adaptive immune responses. We demonstrated that these new adjuvants have comparable activity to the "gold standard" genetic adjuvant IL-12. Unfortunately, the performance of these adjuvants fell short of reaching our milestone for progression to phase II, which was superiority over IL-12. We have subsequently discovered that type I interferons produced by these new adjuvants severely attenuate vaccine antigen expression from our DNA vaccine plasmid that is driven by a CMV promoter. Under this follow-on phase I SBIR, we will identify a lead interferon insensitive promoter to drive our vaccine antigen and adjuvant expression and test this promoter in mouse studies with our lead RIG-1 pathway activating adjuvant comparing its activity to IL-12. We fully anticipate that our lead RIG-1 pathway activating adjuvant driven from an interferon insensitive promoter will yield the results that we originally anticipated for this adjuvant and will therefore meet or exceed our milestone for proceeding to phase II. Under phase II, we will combine this lead RIG-1 pathway activating adjuvant with our other adjuvants in macaques to evoke potent antiviral innate and adaptive immune responses of the type believed best suited to prevent/combat HIV infections.

描述：越来越多的人认为，预防 HIV 感染需要抗病毒抗体反应以及具有有效裂解活性的多功能 CD4+ 和 CD8+ T 细胞。为了刺激所需的反应广度、效力和速度，Profectus Biosciences 打算利用其基于 DNA 疫苗电穿孔与遗传佐剂相结合的平台技术。作为朝着这个方向迈出的一步，最近的一项 1 期临床试验 HVTN-080 表明，与单独使用电穿孔相比，电穿孔与我们的 IL-12 佐剂相结合可使疫苗接种者的 CD4+ 和 CD8+ T 细胞反应率提高一倍1。即使取得了这一成功，我们认识到，真正有效的 HIV 疫苗将需要一种能够持续提供高强度、长期反应的治疗方案，反应率 >95%，同时尽可能少地加强免疫。我们相信佐剂是开发这种疫苗的关键。在之前的 I 期 SBIR 中，我们发现了一类新型遗传佐剂，它们利用 RIG-1 信号级联并触发有效的抗病毒先天免疫反应。 These innate responses integrate with TLR evoked innate responses and DAMPs/alarmins to evoke potent anti-viral adaptive immune responses.我们证明这些新佐剂具有与“金标准”遗传佐剂 IL-12 相当的活性。不幸的是，这些佐剂的性能未能达到我们进入 II 期的里程碑，这比 IL-12 更优越。我们随后发现，这些新佐剂产生的 I 型干扰素严重削弱了由 CMV 启动子驱动的 DNA 疫苗质粒的疫苗抗原表达。在后续的 I 期 SBIR 中，我们将鉴定一个主要的干扰素不敏感启动子来驱动我们的疫苗抗原和佐剂表达，并在小鼠研究中使用我们的主要 RIG-1 通路激活佐剂测试该启动子，比较其与 IL-12 的活性。我们完全预计，由干扰素不敏感启动子驱动的主要 RIG-1 通路激活佐剂将产生我们最初对该佐剂预期的结果，因此将达到或超过我们进入 II 期的里程碑。在第二阶段，我们将把这种主要的 RIG-1 通路激活佐剂与我们的其他佐剂在猕猴身上结合起来，以激发有效的抗病毒先天和适应性免疫反应，这种反应被认为最适合预防/对抗 HIV 感染。