MUCOSAL IMMUNITY TO HIV ENV BY ORAL VACCINATION

通过口服疫苗对 HIV ENV 产生粘膜免疫

• 批准号: 6609834
• 负责人: Danuta B Kozbor
• 金额: $ 1.89万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6609834
• 关键词: AIDS vaccines; Adenoviridae; HIV envelope protein gp160; adeno associated virus group; human immunodeficiency virus; laboratory mouse; mucosal immunity; oral administration; recombinant virus; vaccine development; vaccinia virus; vector vaccine

DESCRIPTION: (Adapted from Applicant's Abstract) Accumulating evidence suggests that a combined regimen of immunization, in which a non-viral vector such as a DNA vaccine is given, followed by a viral vector such as vaccinia virus, results in robust CTL and CD4 T cell responses in mice and non-human primates. An important area of induction of cellular immunity to HIV that has not been much studied is the ability to induce CTL and humoral responses at mucosal surfaces. Yet, since most exposure to HIV occurs via mucosal surfaces, a successful prophylactic vaccine against HIV is likely to require a mucosal component. In these studies, we are seeking to define prime/boost strategies for the induction of high levels of mucosal immunity to HIV envelope (env) glycoprotein. We propose to explore the possibility of using poly(DL-lactide-co-glycolide) (PLG) microparticles as vehicles for oral vaccination with plasmid DNA encoding gp160 in combination with recombinant viral vectors expressing the env gene products to enhance the antigen-specific mucosal and systemic immunity. The recombinant viruses used in these studies will include a replication-attenuated modified vaccinia virus Ankara (MVA), adeno-associated virus (AAV), and the E1/E3-deleted adenoviral (Ad) vector. The live vectors will be associated with liposomes for protection against gastric environment, increased transduction and vector dissemination in vivo. The overall goal of this effort is to derive ways to maximize the immunogenicity and safety of the HIV vaccine by inducing long-lasting protective immunity to the HIV env in mucosal and systemic sites. Furthermore, because systemic immunization with DNA plasmid or vaccinia virus does not induce antigen-specific immunity in mucosal tissues, the inductive sites of the mucosal immune system may still be naive to the live vectors delivered by oral vaccination. We hypothesize that oral vaccination with PLG-encapsulated DNA plasmid and liposome-associated non-replicating viral vectors expressing gp160 will augment the magnitude of immune responses to HIV env in mucosal and systemic tissues, and help to overcome the problem of preexisting immunity to the live vectors. The following specific aims will be pursued: i) to evaluate levels of env-specific cellular and humoral responses in systemic and mucosal tissues (Peyer's patches and lamina propria) of gastrointestinal track after oral vaccination with a) PLG-encapsulated DNA plasmid encoding gp160, b) liposome-associated recombinant viral vectors expressing gp160, and c) a combination of PLG-encapsulated DNA plasmid and liposome-associated viral vectors expressing the env glycoprotein; ii) to determine whether oral vaccination overcomes the barrier to recombinant vaccinia or adenovirus immunization caused by preexisting immunity to these pathogens, and whether multiple oral immunizations with liposome-associated AAV-env enhance gp160-specific immunity; and iii) to analyze levels of protection in mucosal tissues induced by the oral vaccination against intrarectal challenge with recombinant vaccinia virus expressing gp160.

描述：（改编自申请人的摘要）积累证据表明 免疫的联合方案，其中非病毒载体（如A） 给出了DNA疫苗，其次是病毒载体，例如离甲酸病毒， 导致小鼠和非人类灵长类动物的鲁棒CTL和CD4 T细胞反应。 诱导细胞免疫对HIV的重要领域 研究了很多研究的能力，能够在粘膜下诱导CTL和体液反应 表面。但是，由于大多数暴露于HIV是通过粘膜表面发生的 成功针对艾滋病毒的预防性疫苗可能需要粘膜 成分。在这些研究中，我们正在寻求定义主要/提升策略 为了诱导高水平的粘膜免疫对艾滋病毒膜（ENV） 糖蛋白。我们建议探索使用的可能性 聚（DL-丙二醇 - 糖 - 糖苷）（PLG）微粒作为口服的车辆 用编码GP160与重组的质粒DNA疫苗接种 表达ENV基因产物以增强抗原特异性的病毒载体 粘膜和系统性免疫。这些研究中使用的重组病毒 将包括一个复制且经过重复的修饰疫苗病毒Ankara（MVA）， 与腺相关病毒（AAV）和E1/E3骨骼腺病毒（AD）载体。这 活载体将与脂质体有关，以防止胃 环境，增加的转导和体内载体传播。这 这项工作的总体目标是得出最大化免疫原性的方法 通过诱导长期保护性免疫来对HIV疫苗的安全性 粘膜和全身部位的HIV环境。此外，由于系统性 用DNA质粒或离甲酸病毒免疫不会诱导 粘膜组织中的抗原特异性免疫力， 粘膜免疫系统可能仍然天真地对口腔传递的活媒介很幼稚 疫苗接种。我们假设用PLG封装的DNA进行口服疫苗接种 表达GP160的质粒和脂质体相关的非复制病毒载体 将增加粘膜中对HIV Env的免疫反应的大小 系统性组织，并有助于克服已经存在免疫力的问题 现场向量。将追求以下具体目标：i）评估 全身和粘膜中ENV特异性细胞和体液反应的水平 在 用A）PLG封装的DNA质粒编码GP160，b）的口服疫苗接种 表达GP160的脂质体相关的重组病毒向量，c）a PLG包含的DNA质粒和脂质体相关病毒的组合 表达ENV糖蛋白的载体； ii）确定是否口服 疫苗接种克服了重组疫苗或腺病毒的障碍 因对这些病原体的免疫力而引起的免疫接种，以及是否是否 通过脂质体相关的AAV-ENV增强的多种口服免疫 GP160特异性免疫； iii）分析粘膜保护水平 针对直肠内挑战的口腔疫苗接种引起的组织 表达gp160的重组疫苗病毒。

项目成果

Enhancement of cellular and humoral immune responses to human immunodeficiency virus type 1 Gag and Pol by a G/P-92 fusion protein expressing highly immunogenic Gag p17/p24 and Pol p51 antigens.

通过表达高免疫原性 Gag p17/p24 和 Pol p51 抗原的 G/P-92 融合蛋白增强对人类免疫缺陷病毒 1 型 Gag 和 Pol 的细胞和体液免疫反应。

• 发表时间: 2001
• 期刊: Journal of human virology.
• 作者: Kmieciak,D;Bolesta,E;Naito,T;Gzyl,J;Kaneko,Y;Kozbor,D
• 通讯作者: Kozbor,D

Immunization strategies to augment oral vaccination with DNA and viral vectors expressing HIV envelope glycoprotein.

使用表达 HIV 包膜糖蛋白的 DNA 和病毒载体增强口服疫苗接种的免疫策略。

• DOI: 10.1016/s0264-410x(01)00480-7
• 发表时间: 2002
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Wierzbicki,Andrzej;Kiszka,Irena;Kaneko,Hiroshi;Kmieciak,Dariusz;Wasik,ThomasJ;Gzyl,Jaroslaw;Kaneko,Yutaro;Kozbor,Danuta
• 通讯作者: Kozbor,Danuta