Nanocarriers for Vaccine Delivery

说明(申请人提供)：通过使用两种不同的疫苗：脊髓灰质炎灭活疫苗(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因其管理简单、通过排泄产生群体免疫、易于生产和成本低而在世界大部分地区被用于根除脊髓灰质炎。不幸的是，与发达国家的儿童相比，在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。一些团体提议用疫苗取代口服脊髓灰质炎疫苗，作为最终根除脊髓灰质炎运动的一部分。不幸的是，IPV比口服脊髓灰质炎疫苗更昂贵，并且不能诱导HELD免疫或粘膜保护。有许多潜在的方法可以提高IPV和其他疫苗的免疫原性和效力，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。已开发出许多适合于疫苗输送的微纳米载体，包括脂质体、微、纳米和多重乳剂、聚合物纳米颗粒、树枝状大分子和免疫刺激复合体(ISCOMS)。在过去五年中，我们自己的纳米和微米技术疫苗输送研究使我们认识到纳米载体通过不同的免疫途径提高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来促进IPV在皮内和舌下的传递，这是基于我们早期的发现。拟议的研究将通过开发纳米载体的新特性来解决应用纳米技术提供疫苗的重要问题。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。具体目的是：1)优化IPV在特定纳米载体内的掺入和稳定性；2)在小鼠模型中评价纳米载体制剂在皮内或舌下免疫后增强针对所有三种血清型脊髓灰质炎病毒的血清和粘膜抗体以及中和抗体的产生能力；3)在小鼠模型中评价纳米载体制剂在皮内或舌下免疫后增强对部分剂量IPV的免疫应答的能力；4)在小鼠皮内或舌下免疫小鼠模型中评价预先存在的抗IPV抗体对不同纳米载体中IPV免疫应答的影响；5)在非人类灵长类动物皮内或舌下免疫后，评价以最佳纳米载体制备的IPV免疫后的血清、粘膜、体液和细胞免疫应答。

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.