Adjuvant Enhanced Antiviral Immunity

佐剂增强抗病毒免疫力

• 批准号: 7915408
• 负责人: Jeff C Fairman
• 金额: $ 182.98万
• 依托单位: JUVARIS BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915408
• 关键词: Acute; Adjuvant; Adopted; Aluminum Hydroxide; Antibodies; Antigen-Presenting Cells; Antigens; Antiviral Agents; B-Lymphocytes; Biological Assay; Biological Response Modifier Therapy; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Charge; Chronic; Complex; DNA; Dendritic Cells; Development; Dose; Drug Formulations; Elderly; Evaluation; Functional RNA; Goals; Hemagglutinin; Housing; Human; Immune; Immune response; Immune system; Immunity; Immunization; Inactivated Vaccines; Infant; Infection; Infection prevention; Influenza; Influenza vaccination; Interleukin-12; Interleukin-15; Lipids; Liposomes; Macaca mulatta; Mediating; Membrane Proteins; Modeling; Morbidity - disease rate; Mus; Neuraminidase; Nucleoproteins; Performance; Preparation; Prophylactic treatment; Proteins; Reagent; Recombinant Vaccines; Recombinants; Relative (related person); Resistance; Respiratory System; Respiratory tract structure; Rodent; Role; System; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Technology; Testing; Toxicology; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccine Research; Vaccines; Viral; Viral Vaccines; Virus; Virus Diseases; adaptive immunity; aluminum sulfate; base; immunogenicity; influenza epidemic; influenza virus vaccine; influenzavirus; insight; mortality; mouse model; neutralizing antibody; nonhuman primate; pandemic influenza; physical property; plasmid DNA; pre-clinical; product development; research clinical testing; seasonal influenza; subcutaneous; vaccination strategy; vaccine efficacy

DESCRIPTION (provided by applicant): 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. Juvaris BioTherapeutics is developing and characterizing a unique adjuvant that is particularly promising for vaccines that induce both high levels of antibody and T-cell immunity, including CTL. 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.

描述（由申请人提供）：流感a感染会导致全球年度大量发病率和死亡率，尤其是对于婴儿，老年人和免疫进来的。当前的疫苗，例如肠胃外施用的三价灭活疫苗（TIV）被施用，或辅助氢氧化铝（校友）。这些疫苗的功效高度依赖于疫苗的疫苗与目前循环病毒的疫苗的表面蛋白的紧密匹配。如果中和抗体无法防止感染呼吸道，随后的病毒感染清除率主要取决于CD8+ T细胞子群的T细胞，尤其是T细胞，尤其是细胞溶解T淋巴细胞（CTL）。 Juvaris Biotherapeics正在开发和表征独特的佐剂，对于诱导高水平的抗体和T细胞免疫（包括CTL）的疫苗特别有希望。佐剂基于阳离子脂质载体和非编码DNA复合物（CLDC）。将蛋白质抗原纳入具有CLDC的蛋白质会导致非常健壮的体液和CD4+和CD8+ T细胞反应。 CLDC佐剂的独特方面是，它既可以用作递送系统，该输送系统通过脂质体成分将抗原与抗原呈递细胞相关，并且通过质粒DNA的免疫刺激辅助剂。该提案产生的最终产品是完成CLDC产品的临床前评估和开发，以用作病毒疫苗，专门用于流感。流感中CLDC佐剂的产品开发策略集中在目前批准的辅助疫苗（在美国和国外）的近期机会的剥削，同时认识到当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）建立辅助和疫苗准备和储存的限制； 2）优化剂量； 3）比较CLDC/Ag疫苗接种后与现有佐剂或无佐剂后免疫反应的大小和耐用性的比较； 4）确定佐剂在诱导小鼠和非人类灵长类动物的适应性免疫方面的作用机理； 5）与CLDC佐剂单价疫苗的杂型保护范围，该疫苗将在内部制备，或者是全价灭活的疫苗病毒。有大量的证据表明，异源性免疫力可能遵循自然感染，并且在较小程度上是当前的疫苗接种策略。使用CLDC辅助疫苗可能会显着增强这种免疫力，但是在小鼠和非人类灵长类动物中，需要对此进行正式证明，然后才能在临床测试并采用一般应用。