Development of a vaccine strategy using antibody-complexed antigens

 描述（由申请人提供）：全球迫切需要开发针对HIV-1的保护性疫苗。虽然中和抗体（nAb）可以提供有效的预防HIV-1的获得，引发那些广泛的反应，对许多抗原性不同的HIV-1分离株一直是一个重大的挑战，它仍然是艾滋病疫苗开发的关键障碍。这项探索性R21申请的主要目的是探索一种新的疫苗策略，以引发针对HIV-1 gp 120的CD 4结合位点（CD 4 BS）的强抗体应答，最终目标是诱导广泛中和抗体（bnAbs）。这将通过使用与具有确定表位的特异性单克隆抗体（mAb）复合的抗原来实现，以掩蔽诱导非中和抗体的免疫原性表位并将免疫应答集中于CD 4 BS。该应用背后的基本原理是，当抗原与Ab结合时，其免疫原性可以改变。此外，它如何改变取决于Ab结合的位置。目前，gp 120上的B细胞表位与Ab改变体液应答的能力之间的功能关系尚未完全阐明。更好地理解这种关系可以为开发更有效的疫苗策略提供新的见解。待测试的具体假设是：（1）通过使用与完全相同的表位结合的mAb掩蔽表位，可以避免或最小化非中和性或菌株特异性中和性Ab的诱导;和（2）阻断高度免疫原性的非/菌株特异性中和性表位，同时使CD 4 BS完全暴露，将迫使免疫系统将Ab应答集中于其;这将导致更高水平的CD 4 BSAb，其中一些可以是广泛中和的。本研究的主要创新点和优势在于：（1）在兔体内评价HIV-1抗原免疫原性方面有丰富的经验;（2）有大量的兔单克隆抗体库，可以在兔体内进行实验; (3)初步数据表明免疫掩蔽可以抑制Ab应答的原理证明：（4）使用多种mAb掩蔽所有（或大多数）非/菌株特异性中和表位，同时允许VRC 01结合;和（5）使用低pH敏感性mAb，其将在溶酶体中释放抗原以进行有效的抗原加工。成功完成拟议的实验将是研制保护性艾滋病疫苗的一个重要里程碑。

 DESCRIPTION (provided by applicant): There is a global urgency to develop a protective vaccine against HIV-1. Although neutralizing Abs (nAbs) can provide effective prophylaxis against HIV-1 acquisition, eliciting those that are broadly reactive against many antigenically diverse HIV-1 isolates has been a major challenge and it remains a critical roadblock for AIDS vaccine development. The primary objective of this exploratory R21 application is to explore a novel vaccine strategy to elicit strong Ab responses against the CD4 binding site (CD4BS) of HIV-1 gp120 with an eventual goal of inducing broadly neutralizing Abs (bnAbs). This will be accomplished by using antigens complexed with specific monoclonal Abs (mAbs) with defined epitopes to mask immunogenic epitopes that induce non-neutralizing Abs and focus immune responses towards the CD4BS. The underlying principle behind this application is that the immunogenicity of antigens can be altered when they are bound to Abs. Furthermore, how it is altered is determined by where the Abs bind. At present, the functional relationship between B cell epitopes on gp120 and Ab's ability to alter humoral responses has not been fully delineated. Better understanding of this relationship could provide new insights towards developing more effective vaccine strategies. The specific hypotheses to be tested are: (1) the induction of non-neutralizing or strain-specific neutralizing Abs can be avoided or minimized by masking the epitopes using mAbs that bind to the very same epitopes; and (2) blocking highly immunogenic non-/strain-specific neutralizing epitopes, while leaving the CD4BS fully exposed, would force the immune system to focus Ab responses towards it; this would result in greater levels of CD4BS Abs, some of which could be broadly neutralizing. The major innovations/strengths of our proposal are: (1) extensive experience in evaluating immunogenicity of HIV-1 antigens in rabbits; (2) a large library of rabbit mAbs, which will allow us to test the hypotheses in rabbits; (3) preliminary data demonstrating proof-of-principle that immune-masking can suppress Ab responses^ (4) the usage of multiple mAbs to mask all (or most) non-/strain-specific neutralizing epitopes, while allowing VRC01 to bind; and (5) the usage of low-pH sensitive mAbs that will release antigens in lysosomes for efficient antigen processing. Successful completion of proposed experiments would represent a major milestone towards development of a protective AIDS vaccine.