ADJUVANT ENHANCED ANTIVIRAL IMMUNITY

佐剂增强抗病毒免疫力

基本信息

批准号：
7959088
负责人：
Jeff AC Fairman
金额：
$ 14.23万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7959088
关键词：
Adjuvant Adopted Aluminum Hydroxide Antibodies Antigen-Presenting Cells Antigens Antiviral Agents CD8-Positive T-Lymphocytes CD8B1 gene California Complex Computer Retrieval of Information on Scientific Projects Database DNA Development Dose Elderly Functional RNA Funding Goals Grant Hemagglutinin Housing Immune response Immunity Inactivated Vaccines Infant Infection Infection prevention Influenza Institution Lipids Liposomes Membrane Proteins Morbidity - disease rate Mus Neuraminidase Preparation Primates Proteins Recombinant Vaccines Research Research Personnel Resources Respiratory System Respiratory tract structure Source System T-Lymphocyte T-Lymphocyte Subsets Testing United States National Institutes of Health Vaccination Vaccine Adjuvant Vaccines Viral Vaccines Virus Virus Diseases aluminum sulfate base mortality neutralizing antibody nonhuman primate plasmid DNA pre-clinical product development research clinical testing response vaccination strategy vaccine efficacy

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Influenza A infection causes annual substantial morbidity and mortality worldwide, particularly for infants, the elderly, and the immuncompromised. Current vaccines, such as the parenterally administered trivalent inactivated vaccine (TIV) are administered either unadjuvanted or adjuvanted with aluminum hydroxide (alum). The efficacy of these vaccines is highly dependent on close matching of the hemagglutinin (HA) and neuraminidase (NA) surface proteins of the vaccine with currently circulating virus. Should neutralizing antibody fail to prevent infection of the respiratory tract, subsequent clearance of viral infection is mainly dependent on T cells, particularly cytolytic T lymphocytes (CTL) of the CD8+ T-cell subset. A unique adjuvant that is particularly promising for vaccines that induce both high levels of antibody and T-cell immunity, including CTL is being developed. The adjuvant is based on a cationic lipid carrier and non-coding DNA complex (CLDC). Inclusion of protein antigens with CLDC results in an extremely robust humoral and CD4+ and CD8+ T-cell response. The unique aspect of the CLDC adjuvant is that it functions both as a delivery system that targets associated antigens to antigen presenting cells via the liposome component and an immunostimulatory adjuvant via the plasmid DNA. The final product resulting from this proposal is the completion of pre-clinical evaluation and development of the CLDC product for use as an adjuvant in viral vaccines and specifically for influenza. The product development strategy for the CLDC adjuvant in influenza is focused on the exploitation of the near-term opportunity of adjuvanting currently approved vaccines (in the U.S. and abroad) while recognizing the potential of recombinant vaccine approaches currently being evaluated. The specific goals of this proposal are to: 1) Establish limits on adjuvant and vaccine preparation and storage; 2) Optimization of dose; 3) Comparison of the magnitude and durability of the immune response following CLDC/Ag vaccination with existing adjuvants or no adjuvants; 4) Determine mechanism of action of the adjuvant in inducing adaptive immunity in mouse and non-human primate; 5) extent of heterosubtypic protection with CLDC adjuvanted monovalent split vaccines, which will be prepared in house, or monovalent whole inactivated vaccine virus. There is significant evidence that heterosubtypic immunity may follow natural infection and, to a lesser extent, current vaccination strategies. Such immunity will likely be markedly enhanced using CLDC adjuvanted vaccines, but a formal demonstration of this in mice and non-human primates is required before vaccine strategies invoking this mechanism can be clinically tested and adopted for general application.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目及研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。甲型流感感染每年在全世界造成大量发病和死亡，特别是对于婴儿、老年人和免疫功能低下的人。目前的疫苗，例如肠胃外施用的三价灭活疫苗（TIV），要么不加佐剂，要么加氢氧化铝（明矾）佐剂。这些疫苗的功效高度依赖于疫苗的血凝素（HA）和神经氨酸酶（NA）表面蛋白与当前传播的病毒的紧密匹配。如果中和抗体无法预防呼吸道感染，随后病毒感染的清除主要依赖于 T 细胞，特别是 CD8+ T 细胞亚群的溶细胞 T 淋巴细胞 (CTL)。一种独特的佐剂特别有希望用于诱导高水平抗体和 T 细胞免疫（包括 CTL）的疫苗。该佐剂基于阳离子脂质载体和非编码 DNA 复合物 (CLDC)。将蛋白质抗原包含在 CLDC 中会产生极其强大的体液反应以及 CD4+ 和 CD8+ T 细胞反应。 CLDC佐剂的独特之处在于，它既可以作为通过脂质体成分将相关抗原靶向抗原呈递细胞的递送系统，又可以通过质粒DNA作为免疫刺激佐剂。该提案的最终产品是完成 CLDC 产品的临床前评估和开发，用作病毒疫苗（特别是流感疫苗）的佐剂。流感 CLDC 佐剂的产品开发策略侧重于利用近期机会为目前已批准的疫苗（在美国和国外）提供佐剂，同时认识到目前正在评估的重组疫苗方法的潜力。该提案的具体目标是： 1) 制定佐剂和疫苗制备和储存的限制； 2）剂量优化； 3）使用现有佐剂或不使用佐剂的CLDC/Ag疫苗接种后免疫反应的强度和持久性的比较； 4)确定佐剂在小鼠和非人灵长类动物中诱导适应性免疫的作用机制； 5) CLDC佐剂单价裂解疫苗（将在内部制备）或单价全灭活疫苗病毒的异亚型保护程度。有重要证据表明，异亚型免疫可能遵循自然感染，并且在较小程度上遵循当前的疫苗接种策略。使用 CLDC 佐剂疫苗可能会显着增强这种免疫力，但在对调用这种机制的疫苗策略进行临床测试并普遍应用之前，需要在小鼠和非人类灵长类动物中进行正式证明。