An in-situ gelling nasal vaccine delivery platform

描述(由申请人提供)：鼻腔是一种容易获得和有效的疫苗接种途径，通过它不仅可以诱导全身免疫，而且可以诱导粘膜免疫。鼻腔接种易于管理，适合大规模免疫。新的和现有的疫苗有可能通过这一途径提供。总体目标是开发一种简单而广泛的鼻腔疫苗递送平台，延长抗原停留时间，增强免疫应答，提供容易的配方过程，并适用于多种不同类型的抗原。该平台商标为GelVac，基于一种独特的高分子量酸性多糖(GelSite TM聚合物)。GelSite聚合物能够原位凝胶，或在与鼻液接触时从液体变成凝胶，从而提供抗原的受控释放。 初步研究已经为GelVac平台提供了初步的概念验证，证明了GelVac平台在鼻腔内原位凝胶化，延长了鼻腔停留时间，并在鼻腔给药后提高了针对模型抗原(DT-CRM，白喉毒素突变CRM)的血清免疫球蛋白和肺免疫球蛋白A免疫反应。该提案旨在通过确定GelVac平台的基本功能特性来建立GelVac平台，该平台与其对免疫反应和保护的影响有关。具体地说，这项研究将检查和确定1)凝胶和抗原的鼻腔停留时间，2)影响抗原释放的因素，3)不同抗原的配方参数，以及4)在有或没有佐剂的情况下经鼻给药后的免疫反应和保护。该平台将使用不同类型的抗原，包括蛋白质(DT-CRM和破伤风类毒素)、多糖-蛋白质结合物(流感嗜血杆菌b多糖-蛋白质结合物)和病毒颗粒(轮状病毒和流感病毒)，证明该平台作为广泛的鼻腔疫苗递送载体的可行性。这些研究将形成该平台第二阶段开发的基础，目标是展示对人类具有重大未满足的医疗和生物防御需求的选定病原体的安全性和有效性。

DESCRIPTION (provided by applicant): The nasal cavity represents an easily accessible and effective route of vaccination by which not only systemic, but also mucosal immunity, can be induced. Nasal vaccination is easy to administer and is suitable for mass immunization. New and existing vaccines can potentially be delivered via this route. The overall goal is to develop a simple and broad nasal vaccine delivery platform that prolongs the antigen residence time, enhances immune response, provides an easy formulation process, and is suitable for many different types of antigens. This platform, trademarked as GelVac, is based on a unique high molecular weight acidic polysaccharide (GelSite TM polymer). The GelSite polymer is capable of gelling in-situ, or changing from liquid to a gel upon contact with nasal fluids, thereby providing a controlled release of the antigen. Preliminary studies have provided an initial proof-of-concept for the GelVac platform by demonstrating in situ gelling in the nasal cavity, prolonged nasal residence, and increased serum IgG and lung IgA immune response against a model antigen (DT-CRM, diphtheria toxin mutant CRM) following intranasal delivery. This proposal seeks to establish the GelVac platform by determining its basic functional properties in relation to its effect on immune response and protection. Specifically, this study will examine and determine 1) the nasal residence times of the gel and antigen, 2) factors affecting antigen release, 3) formulation parameters for different antigens, and 4) immune response and protection following intranasal delivery in the presence or absence of an adjuvant. The feasibility of this platform as a broad nasal vaccine delivery vehicle will be demonstrated using different types of antigens including proteins (DT-CRM and tetanus toxoid), polysaccharide-protein conjugate (Haemophilus influenzae b polysaccharide-protein conjugate), and viral particles (rotavirus and influenza virus). These studies will form the basis for phase II development of this platform targeting demonstration of safety and efficacy against selected pathogens that have significant unmet medical and biodefense needs in humans.