Development of a Vaccine for HIVAIDS: Humoral Immunity

用活的、有复制能力的Ad-HIV或Ad-SIV包膜重组疫苗进行免疫接种引发了强的抗体应答，所述强的抗体应答在用包膜蛋白进行加强免疫接种后发展。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。我们已经在恒河猴模型中引发了这样的抗体，其在用HIV/SIV嵌合SHIV病毒攻击后赋予明显的杀菌免疫。我们的疫苗方案还激发具有由Fc受体承载细胞（如NK细胞）介导的其他功能活性的抗体。HIV/SIV感染最初表现为感染细胞的小病灶。在2至6天内，病毒从这些细胞病灶扩散到引流淋巴结，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灶的传播来帮助控制初始病毒负荷。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，HIV疫苗开发的一个关键目标是引起粘膜免疫。腺病毒重组初免/蛋白加强策略诱导粘膜分泌物中的抗体，其可以抑制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。我们已经表明，疫苗引起的病毒特异性粘膜伊加抗体与感染性SIV攻击后的延迟感染相关。接种疫苗的目的是发展免疫记忆。我们已经开发了研究分泌抗体的记忆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。我们已经全面调查了记忆B细胞在SIV感染恒河猴的血液和组织中的治疗和治疗性免疫过程中的动态。所获得的知识将有助于我们进一步设计和评估疫苗战略。我们已经表明，抗体应答的质量和病毒暴露后的回忆应答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HIV/AIDS疫苗I期临床试验的方法。

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.