Addressing Intra-/Inter-Clade Diversity in HIV Vaccine Design by Immune Focusing

描述（由申请人提供）：基于ctl的疫苗或疫苗成分被认为对激发含有疾病的免疫很重要，可能对预防HIV-1感染也很重要。到目前为止，只有一种基于ctl的疫苗进入了人体试验阶段，但结果令人失望。尽管疫苗失败的原因尚不清楚，但有证据表明，免疫原性足以引发一些保护性CTL反应。我们假设缺点不在于传递系统，而在于传递的序列。抗原暴露于整个蛋白质模拟感染整个病毒，这是一个自然失败的过程。我们进一步假设，针对可变表位的错误的早期免疫优势是HIV-1感染中CTL自然失败的主要机制。为了解决这个问题，我们提出了来自高度保守和高度表达的蛋白质的疫苗序列，以集中针对具有这些特性的表位的初始CTL反应。我们还提出，疫苗是多价的，以代表这些蛋白质组区域的剩余序列可变性，这是类似的分支内和分支间。因此，该疫苗代表了HIV-1在进化支之间和进化支内部的变异性，处理了一个人可能暴露的变异性，以及一个人体内可能发生的变异性（逃逸突变）。鉴于Ad5在STEP试验中表现出免疫原性，该策略仍然是一种可行的人类候选疫苗，疫苗序列将使用dna引物和重组Ad5增强剂进行递送。我们的目标是1)创建免疫聚焦疫苗结构，传递HIV-1蛋白质组的保守和高表达区域，并代表HIV-1进化枝间和进化枝内的变异性；2)在恒河猴标准DNA-prime和rAd5-boost疫苗接种策略中确认载体的免疫原性；3)在恒河猴中使用交叉初强化疫苗来测试我们构建的疫苗的免疫聚焦能力；4)在感染SHIV 89.6P的恒河猴体内测试我们构建的Env疫苗的免疫聚焦能力。

DESCRIPTION (provided by applicant): A CTL-based vaccine or vaccine component is considered important for eliciting immunity that contains disease, and perhaps for preventing infection with HIV-1. Thus far, only one CTL-based vaccine has reached advanced human trials, but the results were disappointing. Although it is unclear why the vaccine failed, evidence suggests that immunogenicity was adequate to elicit some protective CTL responses. We hypothesize that the shortcoming was not the delivery system, but rather the sequences being delivered. Antigenic exposure to whole proteins mimics infection with whole virus, which is a naturally failing process. We further hypothesize that misguided early immunodominance against variable epitopes is the central mechanism for natural failure of CTL in HIV-1 infection. To address this issue, we propose vaccine sequences that come from highly conserved and highly expressed proteins, to focus initial CTL responses against epitopes with these properties. We also propose that the vaccine be polyvalent to represent the remaining sequence variability in these proteome regions, which is similar intra-clade and inter-clade. Thus the vaccine represents the variability of HIV-1 both across and within clades, dealing with variability to which a person could be exposed, as well as variability that can develop within a person (escape mutation). The vaccine sequences will be delivered using DNA-prime and recombinant Ad5 boost, given that Ad5 appeared immunogenic in the STEP trial and this strategy remains a viable vaccine candidate in humans. We aim 1) to create immune-focusing vaccine constructs that deliver conserved and highly expressed regions of the HIV-1 proteome and represent inter-and intra-clade variability of HIV-1; 2) to confirm the immunogenicity of our vectors in a standard DNA-prime and rAd5-boost vaccination strategy in rhesus macaques; 3) to test the immune-focusing abilities of our vaccine constructs in rhesus macaques using crossover prime-boost vaccination; and 4) to test the immune-focusing abilities of our Env vaccine construct in rhesus macaques using SHIV 89.6P infection. PUBLIC HEALTH RELEVANCE: The need for an effective HIV-1 vaccine needs little introduction. While treatment regimens have advanced enormously in efficacy and reduced side effects, lifelong treatment remains an impractical global solution due to expense, long term toxicities, poor healthcare infrastructure in developing countries, and increasing drug resistance. Historically, effective vaccines have been the best approach to dealing with global epidemics.