Novel Combination Adjuvant for Eliciting Systemic and Mucosal CD8 T Cell Memory

用于激发全身和粘膜 CD8 T 细胞记忆的新型组合佐剂

• 批准号: 9228321
• 负责人: Marulasiddappa Suresh
• 金额: $ 57.61万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-17 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9228321
• 关键词: Acquired Immunodeficiency Syndrome; Adjuvant; Adverse event; Agonist; Animals; Antibodies; Antibody Response; Antigen Presentation; Antigens; Attenuated Live Virus Vaccine; Attenuated Vaccines; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Carbopol; Cells; Cellular Immunity; Chickenpox; Clinical; Communicable Diseases; Consensus; Couples; Cross Presentation; Cytomegalovirus; Data; Development; Disease; Drug Industry; Early Endosome; Emulsions; Epitopes; Equilibrium; Ethers; Evolution; Genetic Engineering; Goals; HIV; Human; Immune; Immune response; Immunity; Immunization; In Vitro; Inactivated Vaccines; Individual; Infection; Influenza; Lecithin; Light; Lipid A; Liposomes; Listeria; Lung; Lysosomes; Malaria; Memory; Mucous Membrane; Mus; Polymers; Pregnancy; Process; Property; Recombinants; Research; Role; Safety; Signal Pathway; Spleen; Subunit Vaccines; System; T cell response; T-Lymphocyte; Testing; Time; Tissues; Toll-like receptors; Tuberculosis; Vaccines; Vaccinia virus; Viral; Viral Vaccines; Work; acrylic acid; aluminum sulfate; base; clinical development; crosslink; extracellular; immunogenic; immunogenicity; in vivo; influenzavirus; innovation; insight; memory CD4 T lymphocyte; microbial; multicatalytic endopeptidase complex; neutralizing antibody; novel; pathogen; programs; public health relevance; response; soy; uptake; vaccine development

 DESCRIPTION (provided by applicant): In light of the safety concerns associated with live vaccines, vaccine formulations are increasingly based on highly purified subunit antigens and/or antigens produced by recombinant DNA technology. However, the poor immunogenicity typical of such antigenic subunits necessitates the use of adjuvants to enhance the immune responses to the protective epitopes in the vaccine. Despite decades of research, very few adjuvants are licensed for use in humans. Unlike live vaccines, current inactivated/subunit vaccines formulated with the licensed adjuvants often confer shorter duration of immunity, largely induce antibody responses, require multiple immunizations to maintain protective immunity, and trigger poor cell-mediated immunity (CMI; TH1 and CD8 T cell memory). Therefore, there is a critical need to identify adjuvants that engender balanced antibody and CMI to protect against both extracellular and intracellular pathogens. Carbomers are polymers of acrylic acid cross-linked with polyalkenyl ethers, and are extensively used as bioadhesives in the pharmaceutical industry and as adjuvants in veterinary and experimental vaccines. We have identified a carbomer-class adjuvant, Adjuplex (ADJ) that elicits potent systemic and mucosal CD4 TH1 and CD8 T cell responses, like a live viral vaccine. In this proposal, as a combination adjuvant, we will leverage the CD4/CD8 T cell responses induced by ADJ to balance and potentiate the immune responses triggered by clinically tested TLR agonists, glucopyranosyl lipid A (GLA) and CpG. Based on preliminary data, we hypothesize that ADJ is an effective antigen delivery system with immune modulating properties. We further hypothesize that combining ADJ with GLA and CpG constitutes a novel adjuvant that couples the effective antigen delivery and immune modulatory properties of ADJ with the immune potentiating effects of GLA and CpG to concomitantly activate multiple innate signaling pathways. In aim 1, we will test whether the combination adjuvant augments the differentiation and persistence of systemic and mucosal tissue-resident memory CD8 T cells along with antibodies and CD4 T cells. Aim 2 will investigate whether and how the combination adjuvant enhances the process of cross presentation by human and murine DCs in vitro. Mechanisms examined will include antigen uptake and targeting to early endosomes, endosomal acidification and retention of antigen, role of lysosomes and proteasome, antigen presentation to naïve T cells and the signaling pathways engaged. In aim 3, we will determine whether and how the combination adjuvant enhances mechanisms of cross presentation in vivo. The proposed work has the potential to discover a novel combination adjuvant that will engage multiple signaling pathways in immune cells and harness the unique immune stimulating properties of individual components to engender a balanced and durable humoral and CMI response. The findings from this work will be highly significant and expected to have broad impact on the clinical development of effective vaccines against diverse pathogens.

 描述（由申请人提供）：考虑到与活疫苗相关的安全性问题，疫苗制剂越来越多地基于高度纯化的亚单位抗原和/或通过重组DNA技术产生的抗原，然而，此类抗原亚单位典型的较差免疫原性需要使用佐剂来增强对疫苗中保护性表位的免疫反应尽管经过了数十年的研究，但与目前的活疫苗不同，很少有佐剂被许可用于人类。使用许可佐剂配制的灭活/亚单位疫苗通常会产生较短的免疫持续时间，主要诱导抗体反应，需要多次免疫才能维持保护性免疫，并引发较差的细胞介导免疫（CMI；TH1和CD8 T细胞记忆）。迫切需要确定能够产生平衡抗体和 CMI 的佐剂，以抵御细胞外和细胞内病原体。 卡波姆是与聚烯基交联的丙烯酸聚合物。我们已经确定了一种卡波姆类佐剂 Adjuplex (ADJ)，它可以引发有效的全身和粘膜 CD4 TH1 和 CD8 T 细胞反应，并广泛用作制药工业中的生物粘合剂和兽医和实验疫苗中的佐剂。在此提案中，作为组合佐剂，我们将利用 ADJ 诱导的 CD4/CD8 T 细胞反应来平衡和增强所触发的免疫反应。基于初步数据，我们发现ADJ是一种具有免疫调节特性的有效抗原递送系统，我们进一步发现ADJ与GLA和CpG的结合构成了一种新型佐剂。在目标 1 中，我们将 ADJ 的有效抗原递送和免疫调节特性与 GLA 和 CpG 的免疫增强作用结合起来，同时激活多个先天信号通路。将测试组合佐剂是否增强全身和粘膜组织驻留记忆 CD8 T 细胞以及抗体和 CD4 T 细胞的分化和持久性，目标 2 将研究组合佐剂是否以及如何增强人类和小鼠的交叉呈递过程。体外检查的 DC 机制包括抗原摄取和靶向早期内体、内体酸化和抗原保留、溶酶体和蛋白酶体的作用、抗原呈递给初始 T 细胞。在目标 3 中，我们将确定组合佐剂是否以及如何增强体内交叉呈递机制。这项工作有可能发现一种新的组合佐剂，它可以参与免疫细胞中的多种信号传导途径。各个成分独特的免疫刺激特性可产生平衡且持久的体液和 CMI 反应。这项工作的结果将非常重要，预计将对针对不同病原体的有效疫苗的临床开发产生广泛影响。