Novel Mucosal Adjuvant for an HIV DNA Vaccine

描述(由申请人提供)：本文件包含Proectus BioSciences要求不得向政府以外的人发布的专有信息，除非是出于审查和评估的目的。摘要DNA疫苗是开发针对HIV等嗜黏膜病原体的预防性和治疗性疫苗的有效途径。不幸的是，肌肉或皮肤中的DNA免疫并不能诱导粘膜免疫。然而，DNA疫苗确实提供了一个独特的机会来共表达可以诱导粘膜免疫的佐剂。视黄酸(RA)指示NAVE淋巴细胞归巢于粘膜组织，而视黄醛脱氢酶(RALDHs)是将视网膜转化为RA的关键酶。维甲酸受体(RAR)与维甲酸结合，指示细胞上调粘膜归巢分子，使其自身成为维甲酸产生者。我们建议使用显性阳性突变体RAR(DP-RAR)1RALDH亚型2(RALDH2)作为黏膜归巢佐剂(S)用于HIV DNA疫苗。我们推测，肌肉注射表达抗原和产生RA的佐剂的质粒会触发粘膜免疫反应。我们将展示RA佐剂(S)的潜力，具体目的如下：(1)证明共用HIV抗原表达质粒和DP-RAR 1RALDH2可在小鼠中诱导黏膜抗原特异性免疫反应；(2)在痘苗-HIV病毒小鼠模型中，佐剂带有RA诱导结构的HIV PDNA疫苗将提高对黏膜攻击的保护作用。如果DP-RAR 1 RALDH2佐剂显著增强粘膜免疫反应和/或显著增强对病毒攻击的保护，将在灵长类研究中进一步评估其作为先进HIV DNA疫苗/佐剂组合的成分在第二阶段SBIR应用中的作用。2. 公共卫生相关性：该项目的目标是开发新的黏膜佐剂，以提高艾滋病毒DNA疫苗的效力。这些佐剂将基于一种结构，如显性阳性的维甲酸受体和启动维甲酸产生的酶RALDH2。

DESCRIPTION (provided by applicant): This document contains proprietary information that Profectus BioSciences requests not be released to persons outside the Government, except for purposes of review and evaluation. Abstract DNA vaccination is an appealing approach for developing prophylactic and therapeutic vaccines for mucosa tropic pathogens such as HIV. Unfortunately, DNA immunization in the muscle or skin does not induce mucosal immunity. DNA vaccination does, however, offer a unique opportunity to co-express adjuvants that could induce mucosal immunity. Retinoic acid (RA) instructs naove lymphocytes to home to mucosal tissues and Retinaldehyde dehydrogenases (RALDHs) are the key enzymes that convert retinal to RA. The RA receptor (RAR) binds RA and instructs cells to up-regulate mucosal homing molecules and to become RA producers themselves. We propose to use a dominant-positive mutant of the RAR (DP-RAR) 1 RALDH isoform 2 (RALDH2) as a mucosal homing adjuvant(s) for an HIV DNA vaccine. We postulate that intramuscular administration of plasmids expressing the antigens and the RA-producing adjuvants will trigger mucosal immune responses. We will demonstrate the potential of the RA adjuvant(s) with the following specific aims: (1) demonstrate that coadministration of plasmids expressing HIV antigens and DP-RAR 1 RALDH2 will induce mucosal antigen-specific immune responses in mice; and (2) demonstrate that adjuvanting a HIV pDNA vaccine with a RA inducing construct will improve protection against a mucosal challenge in the Vaccinia-HIV virus mouse model. If the DP-RAR 1 RALDH2 adjuvant significantly enhances mucosal immune responses and/or significantly enhances protection from virus challenge, it will be further evaluated in primate studies as components of an advanced HIV DNA vaccine/adjuvant combination in a Phase II SBIR application. 2 PUBLIC HEALTH RELEVANCE: The objective of this project is to develop novel mucosal adjuvants that will improve the efficacy of HIV DNA vaccines. These adjuvants will be based on a constructs such as a dominant-positive retinoic acid receptor and the enzyme RALDH2 that initiate retinoic acid production.