HIV-Specific B Cell Repertoire in Humans Following Cross-Clade Immunization

描述(由申请人提供)：开发一种能够广泛中和艾滋病毒疫苗毒株的疫苗方案仍然是一个重要但难以实现的目标。可以通过使用活载体疫苗、亚单位蛋白疫苗和其他方法来提高艾滋病毒特异性抗体，但尚未在人类疫苗试验中证明对艾滋病毒初级分离株产生显著的中和广度。最近由HIV疫苗试验网络(HVTN 049)进行的一项试验，志愿者获得了来自诺华的DNA启动子和重组、三聚体、V2缺失的B分支包膜蛋白产品作为助推剂，这是一个很好的例子，该试验对同源且容易中和的SF162毒株产生了高水平的中和，但对二级分离株产生了很小的中和广度。这将有助于设计未来的试验和免疫原，以了解接种者的B细胞反应与艾滋病毒感染亚群中确实出现显着中和广度的B细胞反应如何比较。本申请的主要目的是将最先进的B细胞库和单抗技术应用于分析参加HVTN 088的人类志愿者的反应，其中HVTN 049的参与者正在接受C分支三聚体蛋白的加强免疫。这项研究将确定疫苗反应中涉及的B细胞亚群，抗体可变基因片段中存在的亲和力成熟程度，产生的CDR3环的长度，以及与未启动的疫苗接受者相比，几年前接种了B分支蛋白的疫苗接受者的靶向中和表位。将从选定的接受者中产生单抗，以进一步确定存在的广度的性质，并检验通过接种疫苗可以引起交叉中和单抗反应的假设。这些数据将提供重要的新信息，为设计旨在诱导广谱中和抗体的艾滋病毒疫苗方案提供信息。

DESCRIPTION (provided by applicant): The development of a vaccine regimen capable of eliciting broad neutralization of HIV vaccine strains remains an important but elusive goal. HIV-specific antibodies can be raised through the use of live vector vaccines, subunit protein vaccines, and other approaches, but the generation of significant breadth of neutralization against primary isolates of HIV has not yet been demonstrated in a human vaccine trial. A recent trial performed by the HIV Vaccine Trials Network (HVTN 049), in which volunteers received a DNA prime and a recombinant, trimeric, V2-deleted, clade B envelope protein product from Novartis as a boost, is a good example of a trial that generated high levels of neutralization against the homologous and easily-neutralized SF162 strain but yielded very little breadth against Tier 2 isolates. It will be helpful in designing future trials and immunogens to understand how the B cell response in vaccinees compares to that seen in the subpopulation of HIV-infected individuals who do develop significant neutralization breadth. The major goal of the present application is to apply state-of-the-art B cell repertoire and monoclonal antibody technologies to the analysis of responses of human volunteers enrolled in HVTN 088, in which HVTN 049 participants are receiving booster immunizations with a clade C trimeric protein. This study will define the B cell subsets involved in the vaccine response, the degree of affinity maturation present in antibody variable gene segments, the length of the CDR3 loops generated, and the neutralization epitopes targeted in vaccine recipients who have been primed with the clade B protein years before in comparison with those who are unprimed. Monoclonal antibodies will be generated from selected recipients to further define the nature of breadth present and to test the hypothesis that cross-neutralizing monoclonal responses can be elicited through vaccination. These data will provide important new information that will inform the design of HIV vaccine regimens designed to elicit broadly- neutralizing antibodies.