NOVEL HIV VACCINES

HIV-1通过性途径和肠道外途径传播，这使得针对这种病毒的成功预防性疫苗很可能需要在粘膜和全身隔室中诱导保护性免疫。此外，除了减毒活病毒疫苗外，候选HIV-1疫苗通常需要一种初增免疫策略来引起最广泛的免疫反应。需要同时诱导粘膜和全身免疫，使用初始-增强方案提供了我们的HIV-1疫苗开发计划的基本原理。该项目的长期目标是开发一种HIV-1疫苗，在粘膜和全身隔室中都能引起保护性免疫。这一目标是通过两个目标实现的。主要目的是评估口服沙门氏菌HIV-1 gp120 DNA疫苗载体在健康人类志愿者中的安全性和免疫原性。这一目标源于我们团队的长期合作，开发沙门氏菌作为HIV-1抗原的粘膜递送系统。据我们所知，这将是首次在志愿者中使用细胞内细菌粘膜传递DNA疫苗的研究。第二个目标是开发一种Env免疫原，它能产生比gp120更广泛的中和抗体，可以作为DNA疫苗和可溶性蛋白质免疫原由伤寒沙门氏菌递送。因此，我们将评估一种新的单链嵌合蛋白scgp120/Ba-L- CD4的安全性和免疫原性，该蛋白由于在gp120的共受体结合域中保守的表位组成性暴露，预计会引发广泛的中和抗体。如果该免疫原在动物临床前研究中证明是安全的，将在人类志愿者中进行评估，既可以作为可溶性亚基蛋白，也可以作为减毒沙门氏菌传递的DNA疫苗，作为编码gp120Ba-L和scgp120Ba-L-CD4的DNA疫苗的疫苗载体。项目2将基于项目1和项目2获得的临床前数据，在志愿者中开展这些免疫原的I期临床试验。这些项目将得到行政核心的支持。

The transmission of HIV-1 by both sexual and parenteral routes makes it likely that a successful preventative vaccine against this virus will need to induce protective immunity in both mucosal and systemic compartments. Moreover, aside from attenuated live virus vaccines, candidate HIV-1 vaccines usually require a prime-boost immunization strategy to elicit the broadest immune responses. The need to induce both mucosal and systemic immunity using a prime-boost protocol provides the rationale for our HIV-1 vaccine development program. The long-term objective of this program is to develop an HIV-1 vaccine that elicits protective immunity in both the mucosal and systemic compartments. This objective is pursued via two goals. The primary goal is to evaluate the safety and immunogenicity of an oral Salmonella HIV-1 gp120 DNA vaccine vector in health human volunteers. This goal stems from a long-standing collaboration of our group to develop Salmonella as a mucosal delivery system for HIV-1 antigens. To our knowledge, this will be the first study in volunteers to use an intracellular bacterium to deliver a DNA vaccine mucosally. The secondary goal is to develop an Env immunogen that elicits a broader spectrum of neutralizing antibodies than gp120 which can be delivered by Salmonella typhi as a DNA vaccine and as a soluble protein immunogen. Accordingly, we will evaluate the safety and immunogenicity of a new single chain chimeric protein, scgp120/Ba-L- CD4, that is predicted to elicit broadly neutralizing antibodies due to the constitutive exposure of conserved epitopes in the co-receptor binding domain of gp120. In this immunogen proves safe in preclinical studies in animals, it will be evaluated in human volunteers both as a soluble subunit protein and formulated as a DNA vaccine delivered by attenuated Salmonella as a vaccine vector for DNA vaccines encoding gp120Ba-L and scgp120Ba-L-CD4. Project 2 will carry out Phase I clinical trials in volunteers of these immunogens based on the preclinical data obtained in Projects 1 and 2. These projects will be supported by an Administrative Core.