Safe mucosal vaccines

安全的粘膜疫苗

• 批准号: 9112987
• 负责人: Terry D. Connell
• 金额: $ 23.93万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112987
• 关键词: Adjuvant; Adverse effects; Affinity; Antibiotic Resistance; Antigens; Avian Influenza; Bacillus anthracis; Binding; Biological Assay; Bordetella pertussis; Brain; Cells; Cholera Toxin; Clinical; Clinical Trials; Clostridium difficile; Communicable Diseases; Cryptococcus gattii; Data; Ebola virus; Effectiveness; Engineering; Enterotoxins; Enterovirus; Environment; Exhibits; Flow Cytometry; Future; Ganglioside GM1; Gangliosides; Goals; Health; Heating; Human; Human Herpesvirus 8; Image; Immune; Immune response; Immunization; Immunohistochemistry; Immunologic Receptors; Incentives; Individual; Infection; Inflammatory; Intoxication; Intranasal Administration; Invaded; Label; Laboratories; Listeria monocytogenes; Lymphocyte; Measles virus; Membrane; Methodology; Modeling; Monitor; Mucosal Immune Responses; Mucous Membrane; Mus; Mycobacterium tuberculosis; Nasal cavity; Neurons; Olfactory Nerve; Optics; Oral; Oral mucous membrane structure; Phenotype; Pilot Projects; Property; Radiolabeled; Recruitment Activity; Research; Resistance; Ricin; Route; Safety; Severe Acute Respiratory Syndrome; Sinus; Staphylococcus aureus; Stomach; Streptococcus; Surface; System; Testing; Time; Tissue Stains; Tissues; Toxic effect; Tuberculosis; Vaccines; Vagina; Work; chemokine; cytokine; experience; ganglioside receptor; gastrointestinal; humanized mouse; in vivo; in vivo imaging; member; microorganism; mouse model; mucosal vaccine; mutant; neuroinflammation; nonhuman primate; novel; olfactory bulb; pathogen; pre-clinical; pre-clinical trial; radiotracer; receptor; receptor binding; research study; respiratory; response; trafficking

 DESCRIPTION (provided by applicant): The mucosae of the oral, nasopharyngeal, gastrointestinal, respiratory, and vaginal tracts are the points of entry for most infectious microorganisms. To preclude infection by those agents, which include multiple antibiotic resistant microorganisms (e.g., Staph aureus, Strep. spp., etc.) and pathogens that are newly emerging or reemerging (e.g., Ebola virus, enterovirus, tuberculosis, Clostridium difficile, Cryptococcus gattii, SARS, avian flu, etc.), vaccines that will induce strong and protective mucosal responses are desperately needed. Unfortunately, endogenous regulatory systems that suppress immune responses to foreign antigens make it challenging to elicit strong immune responses to vaccines on the mucosae. To circumvent these suppressive systems, vaccines must be administered in the presence of mucosal adjuvants. To date, the most potent mucosal adjuvants that have been described belong to the superfamily of bacterial heat-labile enterotoxins (HLT). Recently, it was determined that LT, a prototypical HLT of the Type I HLT subfamily, when introduced via the intranasal route, has a propensity to traffic from the nasal cavity to the brain via the olfactory nerve where the HLT induces expression of inflammatory cytokines, an effect that is likely initiated by binding to its specific ganglioside receptor. This undesirable side-effect has hindered the clinical use of HLTs as mucosal adjuvants. To abrogate this undesirable side-effect and to restore the potential use of HLTs as mucosal adjuvants for clinical use, our laboratory has evaluated the immune properties of LT-IIb(T13I), a single point substitution mutant of a non-human Type II HLT that has: (i) altered affinity for its ganglioside receptors, (ii) no detectible toxicity, (iii) strong mucosal adjuvant properties, but (v) DOES NOT induce neuroinflammation. Two additional non-toxic HLTs have been engineered that exhibit similar receptor and immune properties. We HYPOTHESIZE that intranasally administered LT-IIb(T13I), LT-IIb(T14I), and LT- IIb(T13I/T14I), due to their altered receptor-binding properties, do not mobilize into the brain, or alternatively, do not induce expression of neuroinflammatory cytokines or recruit inflammatory cells into the brain. We will test that hypothesis using radioiodinated HLTs, immunohistochemistry, and In Vivo Expression Imaging (IVET). Flow cytometry will be employed to evaluate the cytokine environment and the presence or absence of inflammatory cells in the brains of mice intranasally administered mutant and wt HLTs. While we recognize the current resistance to evaluating HLTs as adjuvants in clinical trials, these pre-clinical experiments will demonstrate the safely and efficacy of this new class o mutant HLT adjuvants. At the successful completion of this proof-of-principle research, we will submit an R01 application to investigate the properties of the mutant HLTs in non-human primates, which will provide the data needed to move these valuable immune agents into clinical trials and, ultimately, into clinical use.

 描述（由适用提供）：口服，鼻咽，胃肠道，呼吸道和阴道的粘膜是大多数感染性微生物的入境点。 To preclude infection by those agents, which include multiple antibiotic resistant microorganisms (e.g., Staph aureus, Strep. spp., etc.) and pathogens that are newly emerging or reemerging (e.g., Ebola virus, enterovirus, tuberculosis, Clostridium difficile, Cryptococcus gattii, SARS, avian flu, etc.), vaccines that will迫切需要诱导强烈和受保护的粘膜反应。不幸的是，抑制对外国抗原免疫反应的内源性调节系统使得引起对粘膜上疫苗的强烈免疫反应的挑战。为了避免这些抑制系统，必须在粘膜调节器存在下进行疫苗。迄今为止，已描述为细菌热肠热肠毒素（HLT）的最有效的粘膜佐剂。最近，确定LT是I型HLT亚家族的原型HLT，当通过鼻内途径引入时，有望通过嗅觉神经系统从鼻腔传播到大脑，其中HLT HLT诱导炎症细胞因子表达的炎症，这是一种可能引起与其具体的群型受体相结合的作用，这可能引起了其特定的群囊层。这 不良的副作用阻碍了HLT作为粘膜调节器的临床使用。为了擦除这种不良的副作用，并恢复HLT作为临床用途的粘膜调节器的潜在用途，我们的实验室评估了LT-IIB（T13I）的免疫特性（T13i）的免疫特性，一种单点取代突变体，这是非人类II型HLT的单点取代突变体，该突变体具有：（II）强度（II）的（II）（II）（II）（II）（II）（II）（II）（II）（II）（I II）（II）（I II）（II）（II II）（II）（II）（I II）（II）（I II）（II）（II）（II）（I II）（II）（II）（I II）（II）（II）（I II）（II）（II）（II）（I II）（I II）（II）（II）（II）（I II）（II）（II）。辅助特性，但（v）不会诱导神经炎症。已经设计了另外两种无毒的HLT，具有相似的受体和免疫特性。我们假设在义内施用的LT​​-IIB（T13I），LT-IIB（T14I）和LT- IIB（T13I/T14I），由于其受体结合特性的改变，不会动员到大脑中，或者不另有诱导神经融合的细胞表达脑部或braiut症状的表达。我们将使用放射性固定的HLT，免疫组织化学和体内表达成像（IVET）检验该假设。将进行流式细胞仪，以评估小鼠胸内施用的突变体和WT HLT的大脑中细胞因子环境以及炎症细胞的存在或不存在。尽管我们认识到当前评估HLT作为临床试验中的调节器的阻力，但这些临床前实验将证明这种新的O类O突变HLT HLT调节器的安全和有效性。在成功完成本原则研究后，我们将提交R01申请，以调查突变HLT在非人类隐私中的特性，该申请将提供将这些有价值的免疫剂转移到临床试验中所需的数据，并最终将其用于临床使用。

项目成果

Novel Therapeutic Approach for Inhibition of HIV-1 Using Cell-Penetrating Peptide and Bacterial Toxins.

使用细胞穿透肽和细菌毒素抑制 HIV-1 的新治疗方法。

• DOI: 10.4172/2155-6113.1000737
• 发表时间: 2017
• 期刊: Journal of AIDS & clinical research
• 作者: Samuels,Steven;Alwan,Zainab;Egnin,Marceline;Jaynes,Jessie;Connell,TerryD;Bernard,GregoryC;Nashar,Toufic
• 通讯作者: Nashar,Toufic