NOVEL HIV VACCINES

HIV-1通过性途径和非肠道途径传播，这使得成功的预防该病毒的疫苗可能需要在粘膜和全身两个部分诱导保护性免疫。此外，除了减毒活病毒疫苗外，候选的HIV-1疫苗通常需要一种主要的增强免疫策略来引起最广泛的免疫反应。使用PRIME-BOOST方案诱导粘膜和系统免疫的需要为我们的HIV-1疫苗开发计划提供了理论基础。该计划的长期目标是开发一种在粘膜和全身两个部分都能产生保护性免疫的HIV-1疫苗。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-1gp120 DNA疫苗载体在健康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，即开发沙门氏菌作为HIV-1抗原的粘膜递送系统。据我们所知，这将是第一次在志愿者身上使用细胞内细菌通过粘膜传递DNA疫苗。第二个目标是开发一种能够诱导比gp120更广泛的中和抗体的env免疫原，gp120可以作为DNA疫苗和可溶性蛋白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/巴-L-cD4的安全性和免疫原性，由于gp120的共同受体结合域中保守的表位的结构性暴露，预计它将引起广泛的中和抗体。在动物的临床前研究中，这种免疫原被证明是安全的，它将作为一种可溶性亚单位蛋白在人类志愿者身上进行评估，并作为减毒沙门氏菌递送的DNA疫苗作为疫苗载体，用于编码gp120BA-L和scgp120BA-L-CD4的DNA疫苗。项目2将根据项目1和项目2中获得的临床前数据，在志愿者身上进行这些免疫原的第一阶段临床试验。这些项目将得到一个管理核心的支持。

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.