Development of a Vaccine for HIVAIDS: Humoral Immunity

HIV/艾滋病疫苗的开发：体液免疫

• 批准号: 8157605
• 负责人: Marjorie Robert-Guroff
• 金额: $ 178.96万
• 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/8157605
• 关键词: Avidity; Cellular Immunity; Characteristics; Chronic; Epithelial Cells; Future; Goals; HIV; Humoral Immunities; Immunity; Immunoglobulin Genes; Microarray Analysis; Recombinants; Vaccinated; env Gene Products; improved; preclinical study; prevent; rectal; transmission process; vaccine development

We have shown that immunization with live, replication-competent Ad-HIV or Ad-SIV envelope recombinant vaccines not only elicits cellular immunity, but also primes strong antibody responses that develop following administration of booster immunizations with envelope protein. These antibodies display a variety of functional activities. The most desirable for an HIV/AIDS vaccine is neutralizing activity that is able to prevent infection following exposure to the virus. We have shown in pre-clinical studies that our prime/boost vaccine approach results in neutralizing antibodies that can confer apparent sterilizing immunity following challenge of rhesus macaques with an HIV/SIV chimeric SHIV virus. HIV/SIV infection is initially manifested as small foci of infected cells. Within 2 to 6 days, virus spreads from these foci to draining lymph nodes, subsequently leading to systemic infection. In addition to neutralization, our vaccine approach elicits antibodies that possess other functional activities that although not able to block infection, may contribute to control of the initial viral burden by limiting the spread of virus from these foci of infection. Such activities include antibody dependent cellular cytotoxicity (ADCC), and antibody dependent cell-mediated viral inhibition (ADCVI). Our recent studies, again in the rhesus macaque model, demonstrate that these non-neutralizing antibody activities are correlated with lower viral burdens. Since HIV is transmitted mainly at rectal/genital mucosal sites, a key goal of HIV vaccine development is to elicit mucosal immunity. The Ad-recombinant prime/protein boost strategy induces antibodies in mucosal secretions which we have shown can inhibit transcytosis of SIV across an epithelial cell barrier, suggesting another mechanism which may contribute to protection. In fact, we have recently shown that transcytosis inhibition by such vaccine-induced mucosal antibodies is also correlated with reduced chronic viremia following challenge, suggesting this activity may help prevent cell-to-cell spread of the virus. In comprehensive studies aimed at fully characterizing vaccine-elicited antibodies, we have examined their avidity to determine whether this characteristic plays a role in protective efficacy. We have discovered that antibody avidity is correlated with functional antibody activities, indicating that antibody maturation is an important property of vaccine-elicited antibodies. Further, we have developed methodology to investigate memory B cells. The ability of vaccines to elicit long lasting memory B cells is a critical property if immunization is to provide long-lasting, and potentially life-long protection. We have shown that our repliction-competent Ad-recombinant prime/envelope boost approach elicits memory B cells, correlated not only with antibody-dependent cellular cytotoxicity, antibody-dependent cell-mediated viral inhibition, and transcytosis inhibition, but also with better protection. Elite-controller macaques initially vaccinated more than 8 years ago, were shown to control plasma viremia to undetectable levels by potent, multifunctional antibydy responses, as well as cellular immunity. The role of humoral immunity in this elite control was substantiated by microarray analysis showing expression of immunoglobulin genes in the intestine following a heterologous viral challenge. Overall, our recent studies continue to demonstrate that our vaccine strategy induces long-lasting, high-titered antibodies with a spectrum of activities both in serum and mucosal secretions, which together contribute to strong protection against viral challenge in non-human primate models. These findings have advanced the approach toward phase I clinical trials.

我们已经表明，免疫活的，复制能力的Ad-HIV或Ad-SIV包膜重组疫苗不仅增强细胞免疫，但也引发了强烈的抗体反应，加强免疫与包膜蛋白管理后发展。这些抗体显示出多种功能活性。HIV/AIDS疫苗最需要的是中和活性，能够在暴露于病毒后预防感染。我们已经在临床前研究中表明，我们的初免/加强疫苗方法产生中和抗体，其可以在用HIV/SIV嵌合SHIV病毒攻击恒河猴后赋予明显的杀菌免疫力。HIV/SIV感染最初表现为感染细胞的小病灶。在2至6天内，病毒从这些病灶扩散到引流淋巴结，随后导致全身感染。除了中和之外，我们的疫苗方法还能激发具有其他功能活性的抗体，这些抗体虽然不能阻断感染，但可能有助于通过限制病毒从这些感染灶的传播来控制初始病毒负荷。这些活性包括抗体依赖性细胞毒性（ADCC）和抗体依赖性细胞介导的病毒抑制（ADCVI）。我们最近的研究，再次在恒河猴模型中，证明这些非中和抗体活性与较低的病毒负荷相关。由于HIV主要在直肠/生殖器粘膜部位传播，HIV疫苗开发的一个关键目标是引起粘膜免疫。Ad重组初免/蛋白加强策略诱导粘膜分泌物中的抗体，我们已经证明这些抗体可以抑制SIV穿过上皮细胞屏障的转胞吞作用，这表明可能有助于保护的另一种机制。事实上，我们最近已经表明，这种疫苗诱导的粘膜抗体的转胞吞抑制也与攻击后慢性病毒血症的减少相关，表明这种活性可能有助于防止病毒的细胞间传播。在旨在全面表征疫苗引发的抗体的综合研究中，我们检查了它们的亲合力，以确定该特征是否在保护效力中起作用。我们已经发现抗体亲合力与功能性抗体活性相关，表明抗体成熟是疫苗引发的抗体的重要性质。此外，我们还开发了研究记忆B细胞的方法。如果免疫是为了提供持久的和潜在的终身保护，那么疫苗引发持久记忆B细胞的能力是关键的性质。我们已经表明，我们的复制能力的Ad重组初免/包膜加强方法激发记忆B细胞，不仅与抗体依赖性细胞毒性，抗体依赖性细胞介导的病毒抑制和转胞吞抑制相关，而且与更好的保护相关。精英控制猕猴最初接种疫苗超过8年前，显示出控制血浆病毒血症到检测不到的水平，有效的，多功能的抗体反应，以及细胞免疫。通过微阵列分析证实了体液免疫在该精英对照中的作用，微阵列分析显示在异源病毒攻击后肠中免疫球蛋白基因的表达。总体而言，我们最近的研究继续证明，我们的疫苗策略诱导了持久的、高滴度的抗体，这些抗体在血清和粘膜分泌物中具有一系列活性，它们共同有助于在非人灵长类动物模型中对病毒攻击提供强有力的保护。这些发现推进了I期临床试验的方法。