DNA Vaccines

DNA疫苗

• 批准号: 8157430
• 负责人: George N. Pavlakis
• 金额: $ 195.2万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8157430
• 关键词: DNA Vaccines

Summary An important goal of this project continues to be the generation of maximally efficient expression vectors for specific antigens. Our hypothesis is that the DNA vaccine dose is suboptimal for many human applications, therefore, increased efficiency is necessary for practical human DNA vaccines. We have generated a set of optimized expression vectors for HIV and SIV. HIV vectors are developed for eventual human clinical trials. These vectors are studied in macaques for immunogenicity and ability to protect against challenge with Simian/Human Immunodeficiency Virus hybrid viruses (SHIV). 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 macaques from high viremia after challenge with a highly pathogenic SIVmac251 challenge. In addition, we have developed powerful new DNA and protein co-immunization protocols that increase the magnitude, rapidity and longevity of immune responses. 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. We study several different antigen forms to achieve optimal immune response and to address the variability of HIV strains circulating worldwide. We compare the immune response generated by either mixes of native antigens, mosaics, centralized and consensus candidates, and also antigens containing only conserved elements of HIV proteins. Such comparisons may lead to further optimization of a protective immune response. We have used our understanding of gene regulation to develop non-pathogenic strains of SIV, which are maintained in macaques for more than 10 years, yet they do not cause any disease. These animals develop a strong protective immune response and are able to resist high viremia and disease development even after challenge with wild-type SIV. We showed that these animals develop neutralizing antibodies against difficult-to-neutralize SIVmac239, and that CD8 cells contribute to the protective effect. We have also shown that these animals develop high levels of cytotoxic CD4 cells, which contribute to viral control. This macaque model is important for the further understanding of the pathogenic mechanisms leading to AIDS, the virus interactions in different tissues and the components of the immune system contributing to protection from disease development.

总结该项目的一个重要目标继续是生成特定抗原的最大有效表达向量。我们的假设是，对于许多人类应用，DNA疫苗剂量是最佳的，因此，实用的人DNA疫苗是必需的。我们为HIV和SIV生成了一组优化的表达向量。 HIV载体是针对人类临床试验开发的。这些载体在猕猴中进行了免疫原性和防止抗simian/人类免疫缺陷病毒杂种病毒（SHIV）的挑战的能力。同时，在最忠实的人类援助模型系统中开发和研究了SIV表达载体，即SIV对恒河猕猴的挑战，SIV是一种与HIV密切相关的病毒，与HIV密切相关，该病毒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促进的情况下，优化的DNA表达载体能够在挑战后能够保护恒河猕猴免受高病毒血症的影响，并具有高度致病的SIVMAC251挑战。此外，我们开发了强大的新DNA和蛋白质共免疫协议，以增加免疫反应的幅度，速度和寿命。为了进一步提高疫苗效率，我们研究了不同候选抗原的内在特性。我们利用通过重组DNA技术来操纵表达抗原形式的能力。我们已经表明，调节DNA生产抗原的形式，稳定性和细胞命运对其免疫原性和产生的反应类型具有深远的影响。我们进行比较研究以开发几种抗原的最佳形式。结果猕猴的结果证实了表达抗原的形式会影响免疫反应的类型和幅度。我们研究几种不同的抗原形式，以实现最佳的免疫反应并解决全球循环的HIV菌株的变异性。我们比较了由天然抗原，马赛克，集中式和共识的混合物以及仅包含HIV蛋白保守元素的抗原产生的免疫反应。这种比较可能会导致保护性免疫反应的进一步优化。我们已经利用对基因调节的理解来发展非致病性SIV菌株，SIV的猕猴中维持了10年以上，但不会引起任何疾病。这些动物会产生强烈的保护性免疫反应，即使在使用野生型SIV挑战之后，也能够抵抗高病毒血症和疾病的发育。我们表明，这些动物会产生对难以中和SIVMAC239的中和抗体，并且CD8细胞有助于保护作用。我们还表明，这些动物会形成高水平的细胞毒性CD4细胞，从而有助于病毒控制。这种猕猴模型对于进一步理解导致艾滋病的致病机制，不同组织中的病毒相互作用以及免疫系统的成分有助于保护疾病发育。