Novel Mucosal Adjuvant for an HIV DNA Vaccine

描述（由申请人提供）：本文件包含专有信息，除非用于审查和评估，否则Profectus BioSciences不要求向政府以外的人员发布。摘要DNA疫苗接种是开发预防和治疗性HIV等粘膜致病菌疫苗的一种有吸引力的途径。不幸的是，肌肉或皮肤中的DNA免疫不能诱导粘膜免疫。然而，DNA疫苗确实提供了一个独特的机会，共同表达佐剂，可以诱导粘膜免疫。视黄酸（Retinoic acid， RA）引导淋巴细胞回到粘膜组织，视黄醛脱氢酶（Retinaldehyde dehydrogenase, RALDHs）是将视网膜转化为RA的关键酶。类风湿性关节炎受体（RA receptor， RAR）结合类风湿性关节炎，指导细胞上调粘膜归巢分子，自身成为类风湿性关节炎的产生者。我们建议使用RAR (DP-RAR) 1 RALDH亚型2 （RALDH2）的显性阳性突变体作为HIV DNA疫苗的粘膜归巢佐剂。我们假设肌内注射表达抗原的质粒和产生ra的佐剂将触发粘膜免疫反应。我们将展示RA佐剂的潜力，具体目的如下：(1)证明表达HIV抗原和dp - rar1 RALDH2的质粒共同给药将诱导小鼠粘膜抗原特异性免疫反应；(2)证明在牛痘-HIV病毒小鼠模型中，佐剂含有RA诱导结构的HIV pDNA疫苗可以提高对粘膜攻击的保护作用。如果dp - rar1 RALDH2佐剂显著增强粘膜免疫应答和/或显著增强对病毒攻击的保护，它将在灵长类动物研究中作为高级HIV DNA疫苗/佐剂组合的组分在II期SBIR应用中进行进一步评估。2

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.