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epitopes and protect against a rectal heterologous challenge in 2 independent studies, one published (3) and another unpublished.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（由申请方提供）：越来越多的证据表明，靶向HIV包膜刺突上的CD 4诱导（CD 4 i）表位的抗体可促进控制病毒血症，并很可能在暴露后防止传播（综述见（1，2））。我们已经开发了一种基于gp 120的免疫原，其诱导靶向这些高度保守区域的反应，称为全长单链（FLSC）。在恒河猴中，一种源自HIV（BaL）的FLSC分子诱导了靶向这些CD 4 i表位的免疫应答，并在2项独立研究（1项已发表（3），另一项未发表）中保护免受直肠异源攻击。我们的下一个挑战是开发一种疫苗，它将诱导可持续的免疫反应。对于迄今为止开发的基于包膜的疫苗，抗体应答通常不会持续超过4个月（在（4）中综述）。如果没有持续的加强，在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下易感。为了应对这一挑战，我们提出了与达特类毒素的共制剂，所述类毒素是达特的生物学无活性但高度免疫原性的形式（5-7）。从急性感染的细胞释放的细胞外达特蛋白引起T细胞免疫应答的抑制，包括支持抗体诱导的关键辅助应答（综述见（8，9））。我们认为，诱导抗体应答，清除细胞外的达特，将保护对FLSC的体液应答。其结果将是持续产生CD 4 i抗体，以抵御多种挑战。因此，我们的假设是将生物惰性但仍具有免疫原性的达特（“达特类毒素”）与FLSC组合将延长并增加FLSC在面对重复攻击时诱导的保护性抗体。我们建议通过以下目标来测试这一假设：目标1。评估FLSC/达特类毒素共同给药对SHIV 162 p3直肠攻击的功效。目标2.确定与达特类毒素共同给药是否改善了攻击前后包膜特异性细胞应答和CD 4 i导向抗体应答的数量和持续性。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价。当然，一种成功的艾滋病毒疫苗将对艾滋病和艾滋病相关的恶性肿瘤产生巨大的全球影响。 公共卫生关系：我们的目标是在恒河猴SHIV模型中评估全长单链（FLSC）和达特类毒素的组合是否可以潜在地成为AIDS和AIDS恶性肿瘤的预防性疫苗。