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

基本信息

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
项目类别：
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

项目摘要

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epitopes and protect against a rectal heterologous challenge in 2 independent studies, one published (3) and another unpublished.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（在 (1, 2) 中进行了综述）。我们开发了一种基于 gp120 的免疫原，可诱导针对这些高度保守的区域（称为全长单链 (FLSC)）的反应。在恒河猴中，源自 HIV (BaL) 的 FLSC 分子诱导了针对这些 CD4i 表位的免疫反应，并在 2 项独立研究中保护其免受直肠异源攻击，其中一项已发表 (3)，另一项尚未发表。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) 中进行了综述）。如果不继续加强接种，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 类毒素的联合制剂，Tat 类毒素是一种无生物活性但具有高免疫原性的形式 (5-7)。从急性感染细胞中释放的胞外 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（在 (8, 9) 中进行了综述。我们建议诱导一种抗体反应，该反应会灭活和明确这种细胞外 Tat 会保护对 FLSC 的体液反应，其结果将是持续产生 CD4i 抗体，从而抵御多种挑战。因此，我们的假设是，结合了生物惰性但仍具有免疫原性的 Tat。 (“Tat 类毒素”) 与 FLSC 在面对反复挑战时将延长和增加 FLSC 诱导的保护性抗体。我们建议通过以下目标来检验这一假设：目标 1. 评估 FLSC/Tat 类毒素共提供的功效。针对 SHIV162p3 直肠攻击的给药目标 2. 确定与 Tat 类毒素共同给药是否可以改善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。挑战之前和之后。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，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。公共健康相关性：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。