DNA Vaccines

该项目的最新成果对于建立DNA疫苗作为艾滋病疫苗的有效平台技术具有重要意义。我们已经证明，在恒河猴/SIV挑战模型中，DNA疫苗能够产生强大的免疫反应，能够提供对高病毒血症的保护。我们已经产生了适合临床试验的高效DNA疫苗载体，并在动物模型中提供了概念证明。该项目的一个目标仍然是为特定抗原产生最有效的表达载体。我们已经生成了一组针对HIV和SIV的优化表达载体。HIV载体是为最终的人类临床试验而开发的。同时，在人类艾滋病最忠实的模型系统中开发和研究了SIV表达载体，即SIV对恒河猴的攻击，SIV是一种与HIV密切相关的病毒，其致病机制与人类艾滋病非常相似。我们的结果表明，在没有任何其他形式的疫苗增强的情况下，优化的DNA表达载体能够保护恒河猴在高致病性SIVmac251攻击后免受高病毒血症的影响。我们已经开发出一组表达大多数HIV或SIV抗原的质粒组。这些质粒已经通过我们的CRADA合作者进入了人体临床试验。它们还被用于几项合作疫苗研究，并被证明在DNA-Prime-Virus Boost疫苗中提供了出色的引爆。我们还建议使用DNA疫苗定期增强免疫反应。这是因为人们意识到，DNA疫苗在每一次应用中都会增强现有的免疫反应，而不存在病毒载体的问题，病毒载体将免疫反应集中在疫苗载体上。为了进一步提高疫苗的效率，我们研究了不同候选抗原的内在属性。我们利用重组DNA技术来操纵表达的抗原的形式。我们已经证明，调节DNA产生的抗原的形式、稳定性和细胞命运对它们的免疫原性和产生的反应类型有深远的影响。我们进行比较研究，以开发几种抗原的最佳形式。在恒河猴身上的结果证实，表达的抗原的形式影响免疫反应的类型和大小。

Summary The recent results of this project are important for establishing DNA vaccination as a valid platform technology for AIDS vaccines. We have shown that DNA vaccination generate strong immune responses able to provide protection from high viremia in the rhesus macaque/SIV challenge model. We have generated efficient DNA vaccine vectors appropriate for clinical trials and have provided proof of concept in animal models. One goal of this project continues to be the generation of maximally efficient expression vectors for the specific antigens. We have generated a set of optimized expression vectors for HIV and SIV. HIV vectors are developed for eventual human clinical trials. In parallel, SIV expression vectors are developed and studied in the most faithful model system for human AIDS, ie., challenge of Rhesus macaques by SIV, a virus closely related to HIV, which causes very similar pathology to human AIDS. Our results show that optimized DNA expression vectors in the absence of any other form of vaccine boosting are able to protect rhesus macaque from high viremia after challenge with a highly pathogenic SIVmac251 challenge. We have developed sets of plasmids expressing the majority of HIV or SIV antigens. These plasmids have entered human clinical trials through our CRADA collaborators. They have also been used in several collaborative vaccine studies and were shown to provide excellent priming in DNA-prime-virus boost vaccinations. We have also proposed to use DNA vaccination for periodically boosting the immune response. This comes from the realization that DNA vaccination boosts existing immune responses with every application and does not have the problem of viral vectors, which focus immune response to the vaccine vector. To further improve vaccine efficiency we study the intrinsic properties of the different candidate antigens. We take advantage of the ability to manipulate the form of expressed antigen by recombinant DNA technology. We have shown that modulating the form, stability and cellular fate of the DNA-produced antigens has profound effects on their immunogenicity and the type of response generated. We perform comparative studies to develop optimal forms of several antigens. Results in rhesus macaques verified that the form of expressed antigen affects the type and magnitude of immune response.