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: 7944078
• 负责人: ROBERT C GALLO
• 金额: $ 45.86万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7944078
• 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epitopes and protect against a rectal heterologous challenge in 2 independent studies, one published (3) and another unpublished.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包膜刺突上CD4诱导（CD4i）表位的抗体可以促进病毒血症的控制，并且很可能在暴露后防止传播（见（1,2））。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称为全长单链（FLSC）的区域的反应。在恒河猴中，来自HIV （BaL）的FLSC分子诱导了针对这些CD4i表位的免疫反应，并保护其免受直肠异源攻击，两项独立研究（一项已发表(3)，另一项未发表）。我们的下一个挑战是研制一种疫苗，它能引起持续的免疫反应。对于目前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（见(4)）。如果不继续加强，初次接触后观察到的任何保护作用都会减弱，使最近接种疫苗的人在重复接触时变得易感。为了应对这一挑战，我们提出了一种与Tat类毒素的联合制剂，Tat类毒素是一种生物无活性但具有高度免疫原性的Tat（5-7）。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，包括支持诱导抗体的关键辅助反应（见（8,9））。我们建议诱导一种抗体反应来灭活和清除这种细胞外Tat，从而保护对FLSC的体液反应。其结果将是CD4i抗体的持续产生，从而抵御多种挑战。因此，我们的假设是，将生物惰性但仍具有免疫原性的Tat（“Tat Toxoid”）与FLSC结合，将延长和增加FLSC在面对反复挑战时诱导的保护性抗体。我们建议通过以下目的来检验这一假设：目的1。评估FLSC/Tat类毒素联合SHIV162p3抗直肠侵袭的疗效。目标2。确定是否与Tat类毒素共同给药可改善攻毒前后包膜特异性细胞反应和CD4i定向抗体反应的数量和可持续性。如果成功，我们将使用这些研究产生的数据来支持对拟议候选疫苗的进一步临床评估。当然，一种成功的艾滋病毒疫苗将对艾滋病和与艾滋病有关的恶性肿瘤产生巨大的全球影响。