Adjuvants for Skin Immunization: Discovery and Mechanisms

皮肤免疫佐剂：发现和机制

• 批准号: 8904594
• 负责人: IOANNA SKOUNTZOU
• 金额: $ 79.26万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904594
• 关键词: Address; Adjuvant; Animal Model; Antigen Targeting; Antigen-Presenting Cells; Antigens; Biological Assay; Biological Products; Biomedical Engineering; Cells; Chronically Ill; Clinical Research; Communicable Diseases; Dendritic Cells; Disease; Disease Outbreaks; Dose; Drug Formulations; Elderly; Encapsulated; Environment; Epidemic; Evaluation; FDA approved; Future; Goals; HIV; Health; Hospitalization; Human; Human Resources; Immune; Immune response; Immune system; Immunity; Immunization; Immunologist; Infectious Agent; Inflammatory; Influenza; Influenza vaccination; Interferons; Investigation; Kinetics; Lead; Licensing; Life; Longevity; Malaria; Mass Vaccinations; Mediator of activation protein; Metals; Methods; Modeling; Molds; Mucosal Immune Responses; Mutate; National Security; Nature; Outcome; Patients; Persons; Pharmacologic Substance; Phase I Clinical Trials; Polymers; Population; Pregnant Women; Production; Property; Recombinants; Recruitment Activity; Refrigeration; Research; Role; Safety; Self Administration; Serological; Severity of illness; Site; Skin; Subunit Vaccines; System; Technology; Training; Translations; Tuberculosis; Universities; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Viral; Virus; adaptive immunity; arm; chemokine; commercialization; cost; cytokine; design; experience; high risk; immunogenicity; improved; indexing; influenza epidemic; influenza virus vaccine; influenzavirus; interest; long term memory; lymph nodes; microlymphatic circulation; migration; mortality; nonhuman primate; novel; novel vaccines; pandemic disease; pathogen; product development; programs; respiratory; response; scale up; social; socioeconomics; targeted delivery; vaccine delivery; vaccine development; vaccine efficacy; vaccine response

DESCRIPTION (provided by applicant): It is widely recognized that despite the enormous progress in vaccine development, a large part of the population does not receive any coverage due to poor access and low socioeconomic conditions. Importantly for several life-threatening infectious diseases such as HIV, tuberculosis or malaria there are no available vaccines. Moreover bioweapon threats could include the deliberate release of an infectious agent that causes one or more of a variety of different diseases. Currently there are no safe and effective vaccines in the pipeline for many biological agents that may pose high risk to national security, due to increased person-to person transmissibility, disease severity and social disruption. For the aforementioned reasons current research focuses not only on the design of new vaccines against a broad range of diseases but also on the optimization of the existing ones, aiming to increased potency, safety, rapid distribution and possibly self-administration. Since many vaccines under investigation are either subunit or split pathogens or highly purified recombinant molecules, they lack the inherent immunostimulatory properties of the original pathogen. It is therefore important to consider the incorporation of adjuvants in the formulations and/or the design of novel delivery systems that will take advantage of the host's immune battery and enhance the vaccine immunogenicity. To address these issues we propose to deliver the vaccine in the skin and combine it with lead adjuvants. We will investigate the role of novel fused cytokines and immunomodulatory chemokines secreted in the skin following vaccine delivery that can alter the magnitude and the quality of immune responses to vaccines. We also plan to take advantage of our extensive experience with microneedles to design novel dissolving polymer microneedle formulations to encapsulate the adjuvanted vaccine while preserving the functional properties of the components. For the purpose of this study, we will use a licensed subunit influenza vaccine as a model antigen because it can benefit from the addition of adjuvants, because of the challenging nature of the virus that continuously mutates to evade host immune defenses and the availability of excellent animal models for immunogenicity, challenge and protection studies. We are motivated by our findings that influenza vaccine delivery to the skin with dissolving polymer or metal microneedle patches induces enhanced immunogenicity, as demonstrated by the longevity of immune responses compared to conventional systemic immunization in small animal models. Our preliminary studies in non-human primates with microneedles delivering unadjuvanted influenza vaccine have also demonstrated the potential of skin immunization. We hypothesize that the appropriate adjuvants will increase immunogenicity of the vaccine in the young and elderly population, as well as the breadth of immunity, which is a critical issue in case of unpredicted outbreaks from emerging strains. Finally, we expect that in the long term, adjuvanted influenza vaccination using a dissolving polymer microneedle patch will enable safe self-administration and more rapid distribution of the vaccine in the case of large epidemics or new pandemics.

描述（由申请人提供）：人们普遍认为，尽管疫苗开发取得了巨大进展，但由于获得机会少和社会经济条件差，很大一部分人口没有得到任何覆盖。重要的是，对于几种威胁生命的传染病，如艾滋病毒、结核病或疟疾，没有可用的疫苗。此外，生物武器威胁可能包括故意释放一种传染剂，造成一种或多种不同的疾病。目前，由于人与人之间的传染性、疾病的严重性和社会破坏性的增加，许多生物制剂可能对国家安全构成高风险，因此没有安全有效的疫苗正在研制中。由于上述原因，目前的研究不仅集中在针对广泛疾病的新疫苗的设计上，而且还集中在现有疫苗的优化上，旨在提高效力、安全性、快速分布和可能的自我施用。由于研究中的许多疫苗是亚单位或裂解病原体或高度纯化的重组分子，它们缺乏原始病原体的固有免疫刺激特性。因此，重要的是考虑在制剂中掺入佐剂和/或设计新的递送系统，其将利用宿主的免疫电池并增强疫苗免疫原性。为了解决这些问题，我们建议在皮肤中递送疫苗，并将其与铅佐剂联合收割机结合。我们将研究新的融合细胞因子和免疫调节趋化因子在疫苗递送后皮肤中分泌的作用，这些细胞因子和趋化因子可以改变对疫苗的免疫应答的幅度和质量。我们还计划利用我们在微针方面的丰富经验，设计新型溶解聚合物微针制剂，以封装含佐剂的疫苗，同时保留组分的功能特性。出于本研究的目的，我们将使用许可的亚单位流感疫苗作为模型抗原，因为它可以从添加佐剂中受益，因为病毒的挑战性不断突变以逃避宿主免疫防御，并且可以获得用于免疫原性、攻击和保护研究的优良动物模型。我们的动机是我们的发现，即用溶解的聚合物或金属微针贴片将流感疫苗递送至皮肤诱导增强的免疫原性，如在小动物模型中与常规全身免疫相比的免疫应答的寿命所证明的。我们在非人灵长类动物中使用微针递送无佐剂流感疫苗的初步研究也证明了皮肤免疫的潜力。我们假设，适当的佐剂将增加疫苗在年轻和老年人群中的免疫原性，以及免疫广度，这是一个关键问题，在新出现的菌株发生不可预测的爆发的情况下。最后，我们预计，从长远来看，使用溶解聚合物微针贴片的佐剂流感疫苗接种将能够在大流行或新流行的情况下安全地自我接种和更快速地分发疫苗。