Evaluation of Protective Immunity After Mucosal Vaccination Against Ebola Virus

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病毒在内的一组制剂的免疫战略进行快速评估，这些病毒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包括肠外注射表达埃博拉糖蛋白（EBOGP）的水疱性口炎病毒（VSV）载体或表达EBOGP的重组血清5型腺病毒（Ad）。尽管Ad疫苗携带者有大量临床数据支持其使用，但他们面临着人群中广泛存在的预先免疫的问题。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，以Ad作为模型疫苗载体，EBOGP作为模型抗原。我们计划在几种动物模型中验证粘膜给药（口服或鼻腔）可以绕过预先存在的对Ad的免疫并赋予对埃博拉挑战的免疫的假设。针对EBO和其他丝状病毒的粘膜免疫尚未探索，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反应。虽然有一些证据表明粘膜免疫在预防EBO攻击中起着重要作用，但目前尚不清楚先天免疫和适应性免疫反应以及两者之间的相互作用对EBO免疫策略效果的影响。本提案中详细的研究是专门设计的，以充分表征T和B细胞介导的免疫反应，这些免疫反应在EBO攻击前后粘膜免疫后发生系统性和局部，存在或不存在对Ad载体的预先免疫。我们还提出了在粘膜免疫过程中促进和进一步加强EBOGP免疫应答的几种配方和生化策略。这些研究的结果将进一步了解EBO感染，并确定对EBO免疫所必需的免疫反应的特定因素。这一信息将对制定免疫战略和确定抗病毒方案的目标具有价值。它们还将导致制定可应用于其他病原体的有效和有吸引力的疫苗接种战略。

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.