A Novel Immune Modulator/ Adjuvant for HIV Vaccines

HIV 疫苗的新型免疫调节剂/佐剂

• 批准号: 7555097
• 负责人: WILLIAM C RASCHKE
• 金额: $ 29.97万
• 依托单位: VIROGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7555097
• 关键词: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Adenovirus Vector; Adenoviruses; Adjuvant; Animals; Antibody Formation; Antigen-Presenting Cells; Antigens; CD8B1 gene; Capsid; Clinical Research; Clinical Trials; Code; Country; DNA; DNA Vaccines; Data; Dose; Effectiveness; Emergency Situation; Emerging Communicable Diseases; Epidemic; Epitopes; Evaluation; Fiber; Gagging; Generations; Grant; HIV; HIV Antigens; HIV Infections; HIV vaccine; HIV-1; Human; Immune; Immune response; Immunity; Immunization; Immunologic Adjuvants; In Vitro; Inflammatory; Interleukin-12; Mass Immunization; Methods; Modality; Mus; Personal Satisfaction; Phase; Preparation; Preventive; Production; Proteins; Protocols documentation; Public Health; Recombinants; Risk; Safety; Serum; Standardization; System; T-Cell Proliferation; T-Lymphocyte; Testing; Vaccine Clinical Trial; Vaccines; Viral Vector; adenovirus penton protein; aluminum sulfate; base; cesium chloride; chemokine; cytokine; gag Gene Products; in vivo; novel; pandemic disease; pathogen; plasmid DNA; pol genes; prevent; promoter; response; tat Protein; therapeutic vaccine; vaccine development; vaccine efficacy; vector-based vaccine; viral DNA; volunteer

DESCRIPTION (provided by applicant): During the past two decades of HIV vaccine development, a wide variety of AIDS vaccine strategies have been explored. Among the many tested, DNA and viral vector-based vaccines that activate cellular immune responses have shown some promise despite their limitations. Vaccines based on plasmid DNA are ideal candidates as vaccines due to their safety record in various clinical trials as well as ease of manufacturing, storage and delivery for mass immunization when the need arises. Furthermore, DNA vaccines offer an effective method of delivering multiple immunogens/epitopes representing a single or several pathogens. The efficacy of the DNA vaccines can be enhanced by the addition of adjuvants such as CpG motifs or immunomodulatory cytokines to the vaccine formula. These observations strongly indicate that DNA vaccines delivered with immunostimulatory adjuvants could be the new generation of vaccines for emerging infectious diseases. We developed a novel adjuvant consisting of an empty capsid of an adenoviral vector, termed CAP and used it as an immunological adjuvant to a DNA vaccine. Our preliminary studies indicate that CAP activated splenic APC in vitro and induced pro-inflammatory cytokines including IL-12 both in vivo and in vitro. In addition, coadministration of CAP and plasmid DNA coding for gag antigen, resulted in a dramatic increase in gag-specific CD4 and CD8 T cell proliferation and Th1 cytokine production. These data suggest that CAP can function as an immunomodulatory adjuvant with the ability to enhance immunogen-specific Th1 cytokine production. To test our hypothesis, we propose to further evaluate CAP as an immunological adjuvant to HIV vaccines to promote HIV-specific cellular and humoral responses. We will use two types of immunogens 1) plasmid DNA encoding HIV-1 (NL4-3 Clade B) gag, pol, tat and rev and 2) recombinant gag and tat proteins (rGag and rTat) along with CAP and evaluate its potency in prime-boost protocols. The specific aims of the grant are to evaluate CAP as an adjuvant to DNA or protein-based HIV vaccines and to determine the effectiveness of prime-boost combinations in naive as well as mice with pre-existing anti-Ad immunity. PUBLIC HEALTH RELEVANCE: The AIDS epidemic is a global emergency and preventive and therapeutic vaccines for AIDS offer the best hope of ending the pandemic. We are evaluating the use of a preparation derived from a product already approved for human use to enhance the potency of HIV vaccines. The initial results which we plan to extend in this study, show the enhancement is not only due to greater immune responses but also a shift of the type of response to one better suited to protect against HIV.

描述（由申请人提供）：在过去的二十年中，艾滋病毒疫苗开发，已经探索了各种艾滋病疫苗策略。在众多测试中，激活细胞免疫反应的基于DNA和病毒载体的疫苗尽管有局限性。基于质粒DNA的疫苗是理想的候选疫苗作为疫苗，因为它们在各种临床试验中的安全记录以及在需要时易于制造，存储和输送的质量免疫。此外，DNA疫苗提供了一种有效的方法，可以传递代表单一病原体或几种病原体的多种免疫原子/表位。通过在疫苗配方中添加辅助剂，例如CPG基序或免疫调节性细胞因子，可以增强DNA疫苗的功效。这些观察结果强烈表明，用免疫刺激佐剂传递的DNA疫苗可能是新一代的新一代疫苗，用于新兴的传染病。 我们开发了一种新型的佐剂，该佐剂由腺病毒载体的空衣壳组成，称为CAP，并将其用作DNA疫苗的免疫辅助。我们的初步研究表明，CAP在体外和体外和体外都在体外激活了脾脏APC，并诱导了包括IL-12的促炎细胞因子。此外，对GAG抗原编码的CAP和质粒DNA的共同给药，导致GAG特异性CD4和CD8 T细胞增殖以及Th1细胞因子的产生急剧增加。这些数据表明，CAP可以充当免疫调节辅助剂，具有增强免疫原异性Th1细胞因子产生的能力。为了检验我们的假设，我们建议进一步评估CAP作为HIV疫苗的免疫佐剂，以促进HIV特异性的细胞和体液反应。我们将使用两种类型的免疫原1）编码HIV-1（NL4-3进化枝B）GAG，POL，TAT和REV的质粒DNA以及2）重组GAG和TAT蛋白（RGAG和RTAT）以及CAP以及CAP以及评估其在Prime-Books方案中的效力。该赠款的具体目的是评估CAP作为DNA或基于蛋白质的HIV疫苗的辅助，并确定在天真的和具有抗AD抗AD免疫力的小鼠和小鼠中质量增强组合的有效性。公共卫生相关性：艾滋病流行是一种全球紧急情况，艾滋病的预防和治疗疫苗，为结束大流行带来了最大的希望。我们正在评估使用已经批准的人类使用的产品来提高艾滋病毒疫苗效力的产品的使用。我们计划在这项研究中扩展的最初结果表明，增强不仅是由于更大的免疫反应，而且还引起了对一种更好适合保护HIV的反应类型的转变。