Immunogenicity & efficacy of chimeric flu virus expressing Ab42 B cell epitope

免疫原性

• 批准号: 8214522
• 负责人: Michael G Agadjanyan
• 金额: $ 37.4万
• 依托单位: INSTITUTE FOR MOLECULAR MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8214522
• 关键词: 3xTg-AD mouse; AN-1792; Active Immunization; Address; Adjuvant; Affect; Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animals; Antibodies; Antibody Formation; Antigens; Asses; Attenuated; Attenuated Live Virus Vaccine; Autopsy; B-Lymphocyte Epitopes; B-Lymphocytes; Brain; Brain region; CD4 Positive T Lymphocytes; California; Cells; Clinical; Clinical Trials; Collaborations; Complementary DNA; Data; Dementia; Deposition; Development; Diagnosis; Drug Formulations; Engineering; Epitopes; Flu virus; Generations; Genes; Genetic Techniques; Goals; Health; Helper-Inducer T-Lymphocyte; Hemagglutinin; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunotherapy; Impaired cognition; Infection; Infiltration; Inflammation; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Invaded; Judgment; Language; Learning; Life; Memory; Memory impairment; Meningoencephalitis; Molecular; Monitor; Mus; Neuraminidase; Neurites; Neurofibrillary Tangles; Neurons; Neurotropism; Nude Mice; Participant; Passive Immunization; Pathology; Patients; Peptides; Pilot Projects; Plasmids; Preparation; Principal Investigator; Process; Property; Protocols documentation; Publishing; Recombinants; Research Personnel; Rosa; Safety; Senile Plaques; Site; Specificity; Staging; Stress; Sum; System; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Techniques; Testing; Text; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Toxicology; Transgenic Mice; Translations; Vaccinated; Vaccination; Vaccines; Viral; Viral Antigens; Viral Vector; Virus; Wild Type Mouse; Work; anti-influenza; attenuation; autoreactive T cell; autoreactivity; base; behavioral impairment; brain tissue; cross reactivity; design; efficacy testing; flu; immunogenicity; improved; in vivo; influenza virus strain; influenza virus vaccine; influenzavirus; killings; macrophage; memory CD4 T lymphocyte; microorganism; mouse model; neuron loss; neuropathology; novel strategies; olfactory bulb; positional cloning; pre-clinical; preclinical study; prevent; programs; protective efficacy; prototype; recombinant virus; research study; response; safety testing; tau Proteins; tau aggregation; vaccine safety; vector

DESCRIPTION (provided by applicant): We and others have demonstrated that induction of antibodies to the beta-amyloid (AB) peptide endows therapeutic effects in Alzheimer's disease both in pre-clinical and clinical settings. This approach is currently hampered by elicitation of pathological autoreactivity. In order to overcome this problem we have developed several strategies to limit pathological immunity. For example, we generated an epitope vaccine composed of small immunodominant self B cell peptide of AB42 fused with a foreign CD4+Th cell epitope and demonstrated that such vaccine induced high titers of anti-AB antibodies without generation of potentially harmful autoreactive T cells specific to AB. Importantly, these antibodies were therapeutically active, as we showed in two different mouse models of AD (APP/Tg 2576 & 3xTg-AD). After having demonstrated feasibility of selectively inducing a beneficial antibody response to AB in absence of pathological autoreactivity, we decided to expand these studies to a more clinically applicable system. In collaboration with our co-investigator, we have used the influenza virus platform for delivery of immunodominant B cell epitopes of AB42 (AB1-10) into the host. In our preliminary data we have generated a flu-AB1-10 vaccine that induces robust anti-AB and anti-influenza antibodies and reduces AB-deposits in the brains of immune 3xTg-AD mice. Thus, in the first three translational Aims of this proposal we plan to learn about (i) immunogenicity and efficacy of recombinant flu- AB1-10 vaccine in 3xTg-AD mice without AD-like pathology (Aim 1), as well as with early (Aim 2) and late (Aim 3) AD-like pathology. The last Aim 4 of this study is designed to explore immunological mechanism/s of generation of anti-AB antibodies by this vaccine and identify specificity of anti-viral memory Th cells involved in this process. Thus, at the end of this study we will learn about cellular and molecular mechanisms governing the generation of antibodies specific to both AB1-10 and influenza. The long-term goal of this proposal will be a generation of the safe and effective dual (flu-AB) vaccine that may prevent development of AD pathology in pre-symptomatic people, protecting them from the flu infection at the same time. PUBLIC HEALTH RELEVANCE: Alzheimer's Disease is the major cause of dementia in the US and is characterized by an insidious onset and progressive cognitive decline that impacts memory, language, judgment, orientation to time and place, etc. Pathologically there is an increase in the presence in amyloid plaques, neurofibrillary tangles, dystrophic neurites and a general loss of neurons. It was demonstrated that induction of antibodies to the beta-amyloid peptide endows therapeutic effects in Alzheimer's disease both in pre-clinical and clinical settings. This approach is currently hampered by elicitation of pathological autoreactive T helper cells. In order to overcome this problem we and others are developing several strategies to limit pathological immunity. In current project we are proposing to generate the safe and effective dual vaccine, based on influenza viral vector and immunodominant B cell epitope from beta-amyloid peptide that may prevent/reduce development of Alzheimer's disease pathology in pre-symptomatic people diagnosed with early-stage AD, protecting them from the flu infection at the same time.

描述（由申请人提供）：我们和其他人已经证明，β-淀粉样蛋白（AB）肽抗体的诱导在临床前和临床环境中对阿尔茨海默病具有治疗作用。目前，这种方法受到病理自身反应性诱发的阻碍。为了克服这个问题，我们开发了几种限制病理免疫的策略。例如，我们生产了一种由AB42的小免疫显性自身B细胞肽与外源CD4+Th细胞表位融合组成的表位疫苗，并证明这种疫苗可诱导高滴度的抗AB抗体，而不会产生潜在有害的自身反应性T细胞，该抗体特异性针对AB42。 AB。重要的是，这些抗体具有治疗活性，正如我们在两种不同的 AD 小鼠模型（APP/Tg 2576 和 3xTg-AD）中所显示的那样。在证明了在不存在病理自身反应性的情况下选择性诱导对 AB 的有益抗体反应的可行性后，我们决定将这些研究扩展到更临床适用的系统。我们与我们的共同研究员合作，使用流感病毒平台将 AB42 (AB1-10) 的免疫显性 B 细胞表位递送到宿主中。在我们的初步数据中，我们已经生成了一种流感 AB1-10 疫苗，该疫苗可诱导强效抗 AB 和抗流感抗体，并减少免疫 3xTg-AD 小鼠大脑中的 AB 沉积。因此，在本提案的前三个转化目标中，我们计划了解 (i) 重组流感 AB1-10 疫苗在没有 AD 样病理的 3xTg-AD 小鼠中的免疫原性和功效（目标 1），以及早期（目标 2）和晚期（目标 3）AD 样病理。本研究的最后一个目标 4 旨在探索该疫苗产生抗 AB 抗体的免疫学机制，并鉴定参与该过程的抗病毒记忆 Th 细胞的特异性。因此，在本研究结束时，我们将了解控制 AB1-10 和流感特异性抗体生成的细胞和分子机制。该提案的长期目标是开发出安全有效的双重 (flu-AB) 疫苗，可以预防出现症状的人群出现 AD 病理，同时保护他们免受流感感染。公共健康相关性：阿尔茨海默氏病是美国痴呆症的主要原因，其特点是起病隐匿、进行性认知能力下降，影响记忆、语言、判断、时间和地点定向等。从病理学角度来看，阿尔茨海默氏病的存在有所增加。淀粉样蛋白斑、神经原纤维缠结、营养不良的神经突和神经元的普遍丧失。研究表明，在临床前和临床环境中，诱导β-淀粉样肽抗体对阿尔茨海默病具有治疗作用。目前，这种方法受到病理性自身反应性 T 辅助细胞诱导的阻碍。为了克服这个问题，我们和其他人正在开发几种限制病理免疫的策略。在当前的项目中，我们建议基于流感病毒载体和 β-淀粉样肽的免疫显性 B 细胞表位生产安全有效的双重疫苗，可以预防/减少早期诊断的症状前人群阿尔茨海默病病理学的发展AD，同时保护他们免受流感感染。

项目成果

Restricted V gene usage and VH/VL pairing of mouse humoral response against the N-terminal immunodominant epitope of the amyloid ýý peptide.

限制 V 基因使用和小鼠体液反应的 VH/VL 配对针对淀粉样蛋白 α 肽的 N 末端免疫显性表位。

• 发表时间: 2010-11
• 影响因子: 3.6
• 作者: Robert, Remy;Lefranc, Marie;Ghochikyan, Anahit;Agadjanyan, Michael G;Cribbs, David H;Van Nostrand, William E;Wark, Kim L;Dolezal, Olan
• 通讯作者: Dolezal, Olan