Nanocarriers for Vaccine Delivery

描述（由申请方提供）：通过使用两种不同的疫苗：灭活脊髓灰质炎病毒疫苗（IPV）和减毒口服脊髓灰质炎病毒疫苗（OPV），在根除脊髓灰质炎方面取得了实质性进展。口服脊髓灰质炎疫苗在世界大多数地区根除脊髓灰质炎是有用的，因为它给药简单，通过排泄产生群体免疫力，易于生产，成本低。不幸的是，与发达国家的儿童相比，发展中国家使用口服脊髓灰质炎疫苗往往需要多达10次免疫接种才能达到同等的免疫保护水平。一些团体建议用IPV取代OPV，作为最终根除脊髓灰质炎运动的一部分。不幸的是，IPV比OPV更昂贵，并且不诱导听觉免疫或粘膜保护。存在许多用于改善IPV和其他疫苗的免疫原性和功效的潜在方法，包括替代递送途径（例如，皮内或舌下）和使用纳米级递送系统。已经开发了许多可适用于疫苗递送的微米和纳米载体，包括脂质体、微米乳液、纳米乳液和多重乳液、聚合物纳米颗粒、树枝状聚合物和免疫刺激复合物（ISCOMS）。过去五年来，我们自己的纳米和微米级技术疫苗递送研究使我们认识到纳米载体通过不同免疫途径增强多种疫苗的免疫原性和效力的潜力。对于这个项目，我们的主要重点将是使用纳米级载体，以促进皮内和舌下传递IPV，建立在我们早期的研究结果。拟议的研究将通过利用纳米载体的新特性，解决应用纳米技术进行疫苗递送的重要问题。这些研究的结果将广泛适用于各种疫苗，并将进一步突出纳米技术在科学和医学中的重要作用。具体目标是1）优化IPV在专用纳米载体内的掺入和稳定性; 2）在鼠模型中，在皮内或舌下免疫后，评价纳米载体制剂增强血清和粘膜抗体以及针对所有三种脊髓灰质炎病毒血清型的中和抗体的产生的能力; 3）在鼠模型中评估纳米载体制剂在皮内或舌下免疫后增强对IPV分次剂量的免疫应答的能力; 4）在鼠模型中，在皮内或舌下免疫后，评估针对IPV的预先存在的抗体对配制在不同纳米载体中的IPV的免疫应答的影响，和5）评估血清和粘膜，在非人灵长类动物中，用配制在每种途径的最佳纳米载体中的IPV进行皮内或舌下免疫后的体液和细胞应答。

DESCRIPTION (provided by applicant): Substantial progress has been made towards the eradication of polio through the use of two different vaccines: the inactivated poliovirus vaccine (IPV) and the attenuated oral poliovirus vaccine (OPV). OPV has been useful in eradicating polio from most of the world, due to its simplicity of administration, development of herd immunity resulting from excretion, ease of production, and low cost. Unfortunately, use of OPV in developing countries often requires up to 10 immunizations to achieve equivalent protective levels of immunity compared to children in developed countries. A number of groups have proposed replacing OPV with IPV as part of the final polio eradication campaign. Unfortunately, IPV is more expensive than OPV and does not induce heard immunity or mucosal protection. There are number of potential approaches for improving the immunogenicity and efficacy of IPV and other vaccines, including alternate delivery routes (e.g., intradermal or sublingual) and the use of nano-scale delivery systems. A number of micro- and nano-carriers have been developed that may be appropriate for vaccine delivery, including liposomes, micro-, nano-, and multiple-emulsions, polymeric nano- particles, dendrimers, and immunostimulatory complexes (ISCOMS). Our own nano- and micro-scale technology vaccine delivery research over the last five years has led us to appreciate the potential of nano- carriers to enhance the immunogenicity and efficacy of multiple vaccines by different routes of immunization. For this project, our primary focus will be on the use of nano-scale carriers to facilitate intradermal and sublingual delivery of IPV, building upon our earlier findings. The proposed studies will address important questions in vaccine delivery by application of nano-technology through the exploitation of the novel properties of nano-carriers. The findings of these studies will be broadl applicable to a variety of vaccines and will further highlight the important role of nano-technology in science and medicine. The specific aims are 1) Optimize the incorporation and stability of IPV within specialized nano-carriers; 2) Evaluate the ability of the nano-carrier formulations to enhance production of serum and mucosal antibodies and neutralizing antibodies against all three serotypes of poliovirus following intradermal or sublingual immunization in a murine model; 3) Evaluate the ability of the nano-carrier formulations to enhance the immunologic responses to fractional doses of IPV following intradermal or sublingual immunization in a murine model; 4) Evaluate the effect of pre-existing antibodies against IPV on the immune responses to IPV formulated in the different nano-carriers following intradermal or sublingual immunization in a murine model, and 5) Evaluate serum and mucosal, humoral and cellular responses following intradermal or sublingual immunization with IPV formulated in the optimum nano-carrier for each route in non-human primates.