DNA Vaccines

该项目的最新结果对于建立DNA疫苗接种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攻击模型中，DNA疫苗接种产生强大的免疫反应，能够提供对高病毒血症的保护。我们已经产生了适用于临床试验的高效DNA疫苗载体，并在动物模型中提供了概念证明。该项目的目标之一是为特定抗原生成最有效的表达载体。我们生成了一组优化的HIV和SIV表达载体。HIV载体被开发用于最终的人体临床试验。与此同时，SIV表达载体在人类艾滋病最忠实的模型系统中得到开发和研究。SIV是一种与HIV密切相关的病毒，其引起的病理与人类艾滋病非常相似。我们的研究结果表明，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免受高致病性SIVmac251攻击后的高病毒血症。我们已经开发了一套表达大多数HIV或SIV抗原的质粒。这些质粒已通过我们的CRADA合作者进入人体临床试验。它们也被用于几项合作疫苗研究，并被证明在dna -引物-病毒增强疫苗中提供了出色的引物。我们还建议使用DNA疫苗定期增强免疫反应。这是因为认识到DNA疫苗接种在每次应用中都能增强现有的免疫反应，并且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特性。我们利用重组DNA技术操纵表达抗原形式的能力。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。恒河猴的结果证实，表达抗原的形式影响免疫反应的类型和强度。

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.