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HIV疫苗株的疫苗方案仍然是一个重要但难以实现的目标。可通过使用活载体疫苗、亚单位蛋白疫苗和其他方法提高艾滋病毒特异性抗体，但尚未在人体疫苗试验中证明对艾滋病毒初级分离株产生广泛的中和作用。最近由HIV疫苗试验网络（HVTN 049）进行的一项试验是一个很好的例子，在该试验中，志愿者接受了来自诺华公司的DNA引物和重组三聚体、v2缺失的B支包膜蛋白产品作为促进，该试验对同源且易于中和的SF162菌株产生了高水平的中和，但对Tier 2分离株产生的广度很小。这将有助于设计未来的试验和免疫原，以了解疫苗接种者的B细胞反应如何与hiv感染个体亚群中的B细胞反应进行比较，后者确实具有显著的中和广度。目前应用的主要目标是应用最先进的B细胞库和单克隆抗体技术来分析HVTN 088志愿者的反应，其中HVTN 049参与者接受了C支三聚体蛋白的增强免疫。这项研究将确定参与疫苗应答的B细胞亚群，抗体可变基因片段中存在的亲和成熟程度，产生的CDR3环的长度，以及与未启动的疫苗接种者相比，在几年前接种了进化支B蛋白的疫苗接种者中靶向的中和表位。将从选定的受者中产生单克隆抗体，以进一步确定存在广度的性质，并测试交叉中和单克隆反应可以通过接种引起的假设。这些数据将提供重要的新信息，为设计HIV疫苗方案提供信息，以诱导广泛中和的抗体。

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. PUBLIC HEALTH RELEVANCE: This study will provide new information about how antibody responses that inhibit or neutralize HIV are generated in people who receive an HIV vaccine, as compared with HIV-infected individuals. Knowledge gained from this study will help in the design of new HIV vaccines, and will tell us whether a delayed booster vaccination with a different subtype or clade can produce antibodies to a number of different subtypes of HIV.