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

描述（由申请方提供）：开发能够引起HIV疫苗株广泛中和的疫苗方案仍然是一个重要但难以实现的目标。HIV特异性抗体可以通过使用活载体疫苗、亚单位蛋白疫苗和其他方法来产生，但是针对HIV的原代分离株的显著中和宽度的产生尚未在人类疫苗试验中得到证实。HIV疫苗试验网络（HVTN 049）最近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DNA初免和来自诺华公司的重组、三聚体、V2缺失、进化枝B包膜蛋白产品作为加强，该试验产生了对同源和容易中和的SF 162菌株的高水平中和，但对2级分离株的中和幅度很小。了解接种者的B细胞应答与HIV感染者亚群中出现显著中和宽度的应答相比如何，将有助于设计未来的试验和免疫原。本申请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在HVTN 088中登记的人类志愿者的应答，其中HVTN 049参与者正在接受进化枝C三聚体蛋白的加强免疫。本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力成熟程度、产生的CDR 3环的长度以及与未引发的疫苗接受者相比，在多年前已用进化枝B蛋白引发的疫苗接受者中靶向的中和表位。将从选定的受体中产生单克隆抗体，以进一步确定存在的宽度的性质，并检验可通过接种引起交叉中和单克隆应答的假设。这些数据将提供重要的新信息，将告知设计的艾滋病毒疫苗方案，旨在引起广泛中和抗体。 公共卫生相关性：这项研究将提供新的信息，说明与HIV感染者相比，接受HIV疫苗的人如何产生抑制或中和HIV的抗体反应。从这项研究中获得的知识将有助于设计新的艾滋病毒疫苗，并将告诉我们是否延迟加强接种不同亚型或进化枝可以产生抗体的艾滋病毒的一些不同亚型。

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.