FLSC Combined with Tat Toxoid as an HIV Prophylactic Vaccine

FLSC 与 Tat 类毒素联合作为 HIV 预防疫苗

• 批准号: 7854606
• 负责人: ROBERT C GALLO
• 金额: $ 47.83万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7854606
• 关键词: AIDS Vaccines; AIDS related cancer; Acquired Immunodeficiency Syndrome; Adjuvant; Amino Acids; Animals; Antibodies; Antibody Formation; Antigens; Antiviral Agents; Binding; Biological Assay; Blood specimen; CD4 Positive T Lymphocytes; Cell Count; Cells; Collaborations; Data; Drug Formulations; Epitopes; Exhibits; Face; Fc Receptor; Funding; Goals; HIV; HIV Envelope Protein gp120; Human Virology; Immune response; Immunization; Infection Control; Institutes; Length; Link; Macaca mulatta; Malignant Neoplasms; Mediating; Metabolic Clearance Rate; Modeling; Phase; Plasma; Procedures; Production; Publishing; Sampling; T-Lymphocyte; Testing; Toxoids; United States National Institutes of Health; Vaccines; Viral Load result; Viremia; Whole Blood; base; extracellular; immunogenic; improved; meetings; prophylactic; public health relevance; rectal; research clinical testing; research study; response; simian human immunodeficiency virus; tat Protein; transmission process; vaccine candidate; vaccine development

DESCRIPTION (provided by applicant): There is increasing evidence that antibodies targeting the CD4 induced (CD4i) epitopes on the HIV envelope spike can facilitate control of viremia and quite possibly protection from transmission after exposure (reviewed in (1, 2)). We have developed a gp120 based immunogen that induces responses that target these highly conserved regions called the Full Length Single Chain (FLSC). In rhesus macaques, a FLSC molecule derived from HIV (BaL) induced immune responses that target these CD4i epitopes and protect against a rectal heterologous challenge in 2 independent studies, one published (3) and another unpublished. Our next challenge is to develop a vaccine which will induce a sustainable immune response. For envelope based vaccines developed thus far, the antibody response is generally not sustained for more than 4 months (reviewed in (4)). Without continued boosting, any protection observed after an initial exposure would wane, making a recent vaccinee susceptible under repeat exposures. To meet this challenge, we propose a co formulation with the Tat toxoid, a biologically inactive but highly immunogenic form of Tat (5-7). Extracellular Tat protein that is released from acutely infected cells causes the suppression of the T cell immune responses including key helper responses that support the induction of antibodies (reviewed in (8, 9). We would propose that inducing an antibody response that would inactivate and clear this extracellular Tat would protect humoral responses to the FLSC. The result would be the sustained production of CD4i antibodies that would protect against multiple challenges. Consequently, our hypothesis is that combining biologically inert but still immunogenic Tat ("Tat Toxoid") with FLSC will prolong and increase protective antibodies induced by FLSC in the face of repeated challenge. We propose to test this hypothesis through the following aims: Aim 1. Assess the efficacy provided by the FLSC/Tat toxoid co-administration against rectal challenge with SHIV162p3. Aim 2. Determine if the co-administration with Tat toxoid improves the quantity and sustainability of envelope specific cellular responses and CD4i directed antibody responses before and after challenge. If successful, we will use the data generated by these studies to support further clinical evaluation of the proposed vaccine candidate. Of course, a successful vaccine against HIV would have an enormous global impact on AIDS and AIDS related malignancies. PUBLIC HEALTH RELEVANCE: Our goal is to evaluate in a rhesus macaque SHIV model whether a combination of the Full Length Single Chain (FLSC) and Tat toxoid can potentially be preventative vaccine for AIDS and AIDS malignancies.

描述(由申请人提供)：越来越多的证据表明，针对HIV包膜尖峰上的CD4诱导(CD4i)表位的抗体可以帮助控制病毒血症，并很可能防止病毒在暴露后传播(在(1，2)中回顾)。我们已经开发了一种基于gp120的免疫原，它可以诱导针对这些高度保守的区域的反应，称为全长单链(FLSC)。在恒河猴中，来自艾滋病毒(Bal)的一种FLSC分子诱导了针对这些CD4i表位的免疫反应，并在两项独立研究中保护直肠免受异源挑战，一项已发表(3)，另一项未发表。我们的下一个挑战是开发一种能够诱导可持续免疫反应的疫苗。对于迄今为止开发的基于包膜的疫苗，抗体反应通常不会持续超过4个月(在(4)中回顾)。如果没有持续的加强，在首次接触后观察到的任何保护作用都将减弱，使最近的疫苗接种者在重复接触下容易受到影响。为了应对这一挑战，我们提出了与TAT类毒素的联合配方，TAT类毒素是一种生物活性较低但具有高度免疫原性的TAT(5-7)形式。急性感染细胞释放的细胞外TAT蛋白会抑制T细胞免疫反应，包括支持抗体诱导的关键辅助反应(见(8，9))。我们建议，诱导一种抗体反应，使这种细胞外TAT失活并清除，将保护对FLSC的体液反应。其结果将是持续产生CD4i抗体，以抵御多重挑战。因此，我们的假设是，将生物惰性但仍具有免疫原性的TAT(“TAT类毒素”)与FLSC结合将延长并增加FLSC在反复挑战时诱导的保护性抗体。我们建议通过以下目的来验证这一假说：目的1.评估FLSC/TAT类毒素联合应用对抗SHIV162p3直肠攻击的有效性。目的2.确定联合应用TAT类毒素是否能改善攻击前后包膜特异性细胞应答和CD4i导向抗体应答的数量和可持续性。如果成功，我们将利用这些研究产生的数据来支持对拟议的候选疫苗进行进一步的临床评估。当然，一种成功的艾滋病毒疫苗将对艾滋病和艾滋病相关恶性肿瘤产生巨大的全球影响。 公共卫生相关性：我们的目标是在恒河猴SHIV模型中评估全长单链(FLSC)和TAT类毒素的组合是否有可能成为艾滋病和艾滋病恶性肿瘤的预防性疫苗。