Evaluation of Protective Immunity After Mucosal Vaccination Against Ebola Virus

埃博拉病毒粘膜疫苗接种后的保护性免疫评价

• 批准号: 7890555
• 负责人: Maria A Croyle
• 金额: $ 46万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7890555
• 关键词: Address; Adenoviruses; Adjuvant; Animal Model; Antigens; B-Lymphocytes; Biochemical; Biological; Bioterrorism; CD8B1 gene; Capsid; Cavia; Childhood; Clinical; Clinical Data; Communicable Diseases; Data; Development; Dose; Dose-Limiting; Drug Formulations; Ebola Vaccines; Ebola virus; Elements; Evaluation; Exposure to; Face; Filovirus; Gastrointestinal tract structure; Glycoproteins; Goals; Human; Immune response; Immune system; Immunity; Immunization; Infection; Influenza A Virus, H5N1 Subtype; Lead; Light; Memory; Methods; Modeling; Modification; Mucosal Immune Responses; Mucosal Immunity; Mus; Nature; Nose; Oral; Oral Administration; Play; Population; Protocols documentation; Recombinants; Regimen; Role; Route; Screening procedure; Serotyping; Severe Acute Respiratory Syndrome; System; T memory cell; Testing; Toxic effect; Ursidae Family; Vaccination; Vaccines; Vesicular stomatitis Indiana virus; Viral; base; cell mediated immune response; design; mucosal vaccination; nonhuman primate; pathogen; protective efficacy; respiratory; response; vaccination strategy; vaccine development; vector

DESCRIPTION (provided by applicant): World globalization and the increased threat of bioterrorism have mandated rapid evaluation of immunization strategies for a panel of agents including Ebola (EBO), SARS and H5N1 viruses for which there are limited clinical or biological data. To date, the most effective Ebola immunization protocols have involved parenteral administration of a vesicular stomatitis virus (VSV)-based vector expressing the Ebola glycoprotein (EBOGP) or administration of recombinant adenovirus serotype 5 (Ad) expressing EBOGP. Although Ad vaccine carriers have a substantial amount of clinical data to support their use, they face the problem of widespread pre-existing immunity in the human population. To date, vaccination strategies against EBO involve use of Ad as the vaccine carrier but do not address this important issue. Studies proposed have three major aims employing Ad as a model vaccine carrier and EBOGP as a model antigen. We plan to test the hypothesis that mucosal administration (oral or nasal) can circumvent pre-existing immunity against Ad and confer immunity against Ebola challenge in several animal models. Mucosal immunization against EBO and other filoviruses has not been explored, yet immunization through the respiratory and gastrointestinal tract can effectively induce both local and systemic immune responses against many pathogens. Although there is some suggestive evidence that mucosal immunity plays a significant role in protection from EBO challenge, it is not clear what the influence of both the innate and adaptive immune response and the interaction between the two bears on the efficacy of EBO immunization strategies. Studies detailed in this proposal are specifically designed to fully characterize T and B cell mediated immune responses that develop systemically and locally after mucosal immunization before and after challenge with EBO in the presence and absence of pre-existing immunity to the Ad carrier. We also propose several formulation and biochemical strategies to promote and further strengthen the immune response against EBOGP during mucosal immunization. Results from these studies will further the understanding of EBO infection and identify specific elements of the immune response necessary to confer immunity to EBO. This information will be of value in the development of immunization strategies and identify targets for anti-viral regimens. They will also lead to development of effective and attractive vaccination strategies that can be applied to other pathogens.

描述（由申请人提供）：世界全球化和生物恐怖主义威胁的增加要求对包括埃博拉（EBO）、SARS和H5N1病毒在内的一组病原体的免疫策略进行快速评价，这些病原体的临床或生物学数据有限。迄今为止，最有效的埃博拉免疫方案涉及肠胃外施用表达埃博拉糖蛋白（EBOGP）的基于水疱性口炎病毒（VSV）的载体或施用表达EBOGP的重组腺病毒血清型5（Ad）。虽然Ad疫苗载体具有大量的临床数据来支持其使用，但它们面临着在人群中广泛存在的预先存在的免疫力的问题。迄今为止，针对EBO的疫苗接种策略涉及使用Ad作为疫苗载体，但没有解决这一重要问题。提出的研究有三个主要目的，采用Ad作为模型疫苗载体和EBOGP作为模型抗原。我们计划在几种动物模型中检验粘膜给药（口服或鼻腔）可以规避预先存在的针对Ad的免疫力并赋予针对埃博拉病毒攻击的免疫力的假设。尚未探索针对EBO和其他丝状病毒的粘液素免疫，但通过呼吸道和胃肠道免疫可有效诱导针对许多病原体的局部和全身免疫应答。虽然有一些提示性的证据表明，粘膜免疫在保护EBO攻击中起着重要的作用，但先天性和适应性免疫应答的影响以及两者之间的相互作用对EBO免疫策略的效力的影响尚不清楚。本提案中详述的研究专门设计用于充分表征在存在和不存在对Ad载体的既存免疫力的情况下，在EBO激发前后粘膜免疫后全身和局部产生的T和B细胞介导的免疫应答。我们还提出了几种制剂和生化策略，以促进和进一步加强粘膜免疫过程中对EBOGP的免疫应答。这些研究的结果将进一步了解EBO感染，并确定赋予EBO免疫力所需的免疫反应的特定要素。这些信息将有助于制定免疫战略和确定抗病毒治疗方案的目标。它们还将导致开发可应用于其他病原体的有效和有吸引力的疫苗接种策略。