Novel Preventive HIV Vaccines

 描述（由申请方提供）：广泛中和抗体（bnAb）是预防HIV感染的理想成分。然而，到目前为止，还没有研究过的候选疫苗诱导了这种“圣杯”成分，尽管选定的艾滋病毒感染者在2至4年的延迟后产生了bnAb。我们假设，一个“顺序诱导”的途径参与诱导bnAbs在这些人，并提出了新的疫苗接种方法来模拟HIV诱导bnAbs作为新的预防性HIV疫苗策略的途径。我们将通过用各种结构稳定的嵌合Env gp 140蛋白（rEnvs）进行连续免疫来模拟这一过程。这些rEnv包含完全不同的菌株特异性表位谱，但共享bnAb的保守弱免疫原性表位。因此，它们不会增强毒株特异性免疫应答，但会逐渐增强针对保守决定簇的bnAb应答，模拟在长期感染后HIV感染个体中通过新兴的“新Envs”逃避毒株特异性抗体应答的bnAb引发，在此期间毒株特异性表位经历连续的抗原变异。为了增加免疫原性，将构建rEnv以包括三聚化序列以稳定其三聚体结构（cs-rEnv）。高度免疫原性的纳米颗粒，称为纳米簇，将自组装这些三聚体的cs-rEnv和用于免疫。将在豚鼠中评价广泛反应性抗体应答。 将追求两个具体目标：1）产生和纯化具有来自相同Env的保守区但来自不同亚型的Env的可变区的不同嵌合cs-rEnv，并制造由所得cs-rEnv组装的纳米簇; 2）用从不同cs-rEnv自组装的纳米簇诱导广泛反应性抗体，特别是bnAb应答的顺序免疫方案的比较，通过平行的肌内和鼻内途径在豚鼠中进行。 该提案的长期目标是制定有效的艾滋病毒疫苗战略，以实现预防性广泛中和抗体反应。该项目将提供一个概念的证据，即含有不同cs-rEnv三聚体的自组装纳米簇的顺序免疫方案是开发预防性HIV疫苗的潜在方法。

 DESCRIPTION (provided by applicant): Broadly neutralizing antibodies (bnAbs) are ideal components for preventing HIV infection. However, no vaccine candidate investigated so far has induced such "holy grail" components although selected individuals living with HIV have generated bnAbs after a 2 to 4-year delay. We hypothesize that a "sequential induction" pathway is involved in inducing bnAbs in these individuals, and propose new vaccination approaches to mimic the pathway by which HIV induces bnAbs as novel preventive HIV vaccine strategies. We will mimic this process by sequential immunizations with various structure-stabilized chimeric Env gp140 proteins (rEnvs). These rEnvs contain complete different strain-specific epitope profiles but share conserved weakly-immunogenic epitopes for bnAbs. Therefore they will not boost strain-specific immune responses but gradually boost bnAb responses against conserved determinants, mimicking the elicitation of bnAbs by the emerging "new Envs" in evading strain-specific antibody responses in HIV-infected individuals after long term infection, during which strain-specific epitopes undergo continuous antigenic variation. To increase immunogenicity, rEnvs will be constructed to include a trimerization sequence to stabilize their trimeric structures (cs-rEnvs). Highly immunogenic nanoparticles, designated as nanoclusters, will be self-assembled from these trimeric cs-rEnvs and used for immunization. Broadly reactive antibody responses will be evaluated in guinea pigs. Two specific aims will be pursued: 1) Generation and purification of different chimeric cs-rEnvs with conserved regions from the same Env but variable regions from Envs in different subtypes, and fabrication of nanoclusters assembled from the resulting cs-rEnvs; 2) Comparison of sequential-immunization regimens with nanoclusters self-assembled from different cs-rEnvs for induction of broadly reactive antibody, particularly bnAb responses, in guinea pigs by parallel intramuscular and intranasal routes. The long term goal of this proposal is to develop an effective HIV vaccine strategy to achieve preventive broadly neutralizing antibody responses. This project will provide proof of the concept that a sequential-immunization regimen with self-assembled nanoclusters containing different cs-rEnv trimers is a potential approach to develop a preventive HIV vaccine.