Novel Mucosal Adjuvant for an HIV DNA Vaccine

用于 HIV DNA 疫苗的新型粘膜佐剂

• 批准号: 7928361
• 负责人: Kenneth C Bagley
• 金额: $ 21.21万
• 依托单位: PROFECTUS BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7928361
• 关键词: Adjuvant; Animal Model; Antibodies; Antigens; Cells; DNA; DNA Vaccines; Dendritic Cells; Drug Formulations; Enzymes; Evaluation; Government; HIV; HIV Antigens; HIV vaccine; Home environment; Homing; Human; Immune response; Immunity; Immunization; Infection; Intramuscular; Lymphocyte; Measurable; Measures; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Muscle; Muscle Cells; Persons; Phase; Phenotype; Plasmids; Primates; Production; Protein Isoforms; Recombinants; Retinal; Retinoic Acid Receptor; Safety; Site; Skin; Small Business Innovation Research Grant; Staging; Tretinoin; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Vaccinia; Vaccinia virus; Variant; Vesicular stomatitis Indiana virus; Virus; abstracting; base; follow-up; imprint; improved; lymph nodes; mouse model; mucosal site; mutant; novel; pathogen; product development; prophylactic; public health relevance; receptor; receptor binding; response; retinaldehyde dehydrogenase; therapeutic vaccine; trafficking; vector vaccine

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.

描述（由申请人提供）：本文件包含Profectus BioSciences要求不得向政府以外的人员发布的专有信息，除非用于审查和评估目的。摘要DNA疫苗是一种有效的预防和治疗HIV等粘膜嗜性病原体感染的疫苗。不幸的是，肌肉或皮肤中的DNA免疫不诱导粘膜免疫。然而，DNA疫苗接种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）指导新生淋巴细胞归巢至粘膜组织，而视黄醛脱氢酶（RALDH）是将RA转化为RA的关键酶。RA受体（RAR）结合RA并指示细胞上调粘膜归巢分子并自身成为RA生产者。我们建议使用RAR（DP-RAR）1 RALDH同种型2（RALDH 2）的显性阳性突变体作为HIV DNA疫苗的粘膜归巢佐剂。我们假设肌肉注射表达抗原的质粒和产生RA的佐剂将引发粘膜免疫应答。我们将证明RA佐剂的潜力，其具有以下特定目的：（1）证明表达HIV抗原和DP-RAR 1 RALDH 2的质粒的共施用将在小鼠中诱导粘膜抗原特异性免疫应答;和（2）证明用RA诱导构建体佐剂化HIV pDNA疫苗将在牛痘-HIV病毒小鼠模型中改善针对粘膜攻击的保护。如果DP-RAR 1 RALDH 2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，则将在灵长类动物研究中进一步评价其作为II期SBIR应用中的高级HIV DNA疫苗/佐剂组合的组分。2 公共卫生相关性：该项目的目标是开发新型粘膜佐剂，以提高HIV DNA疫苗的效力。这些佐剂将基于诸如显性阳性视黄酸受体和启动视黄酸产生的酶RALDH 2的构建体。