Development of a Vaccine for HIVAIDS: Humoral Immunity

用活的、复制能力强的Ad-HIV或Ad-SIV包膜重组疫苗免疫，可在接种包膜蛋白加强免疫后产生较强的抗体反应。这些抗体表现出多种功能活性。艾滋病毒/艾滋病疫苗最可取的是中和活性，能够防止接触病毒后的感染。我们已经在恒河猴模型中诱导出了这样的抗体，该模型在HIV/SIV嵌合Shiv病毒攻击后产生了明显的绝育免疫。我们的疫苗方案还诱导了具有其他功能活性的抗体，这些抗体是由Fc受体承载细胞如NK细胞介导的。HIV/SIV感染最初表现为感染细胞的小病灶。在2到6天内，病毒从这些细胞灶扩散到引流的淋巴结，随后导致全身感染。这些额外的功能活性可以通过限制病毒从这些感染源传播来帮助控制最初的病毒负担。这些活性包括抗体依赖的细胞毒性(ADCC)和抗体依赖的细胞介导的病毒抑制(ADCVI)。我们最近的研究表明，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，因此HIV疫苗开发的一个关键目标是诱导粘膜免疫。重组腺病毒载体/蛋白增强策略在粘膜分泌物中诱导抗体，可抑制SIV跨越上皮细胞屏障的跨细胞作用，提示另一种可能有助于保护的机制。我们已经证明，疫苗激发的病毒特异性黏膜IgA抗体与感染SIV后的延迟感染相关。接种疫苗的目的是培养免疫记忆。我们已经开发了一种方法来研究分泌抗体的记忆B细胞。如果免疫要提供持久的、可能是终身的保护，疫苗诱导长期记忆B细胞的能力是一个关键属性。我们全面研究了SIV感染恒河猴在治疗和治疗性免疫过程中血液和组织中记忆B细胞的动态变化。所获得的知识将有助于我们进一步设计和评估疫苗策略。我们已经证明，抗体反应的质量和病毒暴露后的记忆反应水平是影响保护性结果的关键特征。总体而言，我们最近的研究继续表明，我们的疫苗策略诱导了在血清和粘膜分泌物中具有一系列活性的持久、高滴度抗体，这些抗体共同有助于在非人类灵长类动物模型中针对病毒挑战提供强大的保护。这些发现推进了艾滋病毒/艾滋病疫苗第一阶段临床试验的方法。

Immunization with live, replication-competent Ad-HIV or Ad-SIV envelope recombinant vaccines 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 elicited such antibodies in the rhesus macaque model that conferred apparent sterilizing immunity following challenge with an HIV/SIV chimeric SHIV virus. Our vaccine regimen also elicits antibodies with other functional activities mediated by Fc-receptor bearing cells such as NK cells. HIV/SIV infection is initially manifested as small foci of infected cells. Within 2 to 6 days, virus spreads from these cell foci to draining lymph nodes, subsequently leading to systemic infection. These additional functional activities can help 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 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 can inhibit transcytosis of SIV across an epithelial cell barrier, suggesting another mechanism which may contribute to protection. We have shown that vaccine-elicited viral-specific mucosal IgA antibodies are correlated with delayed infection following challenge with infectious SIV. The goal of vaccination is to develop immune memory. We have developed methodology to investigate memory B cells, which secrete antibodies. 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 comprehensively investigated the dynamics of memory B cells in blood and tissues of SIV-infected rhesus macaques during treatment and therapeutic immunization. The knowledge gained will facilitate our further design and evaluation of vaccine strategies. We have shown that the quality of the antibody response and the level of anamnestic response following viral exposure are key features that impact a protective outcome. 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 of the HIV/AIDS vaccine.