Development of a vaccine strategy using antibody-complexed antigens

使用抗体复合抗原开发疫苗策略

• 批准号: 9161293
• 负责人: Michael W Cho
• 金额: $ 22.04万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-10 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9161293
• 关键词: AIDS Vaccines; AIDS vaccine development; Acquired Immunodeficiency Syndrome; Affect; Affinity; Antibodies; Antibody Response; Antigen-Antibody Complex; Antigens; B-Lymphocyte Epitopes; Binding; Binding Sites; Biochemical; Cessation of life; Cloning; Complex; Cover-up; Data; Development; Engineering; Enhancing Antibodies; Epitopes; Evaluation; Future; Glycoproteins; Goals; HIV Envelope Protein gp120; HIV-1; HIV-1 vaccine; Hybridomas; Immune; Immune response; Immune system; Immunization; Infection; Left; Libraries; Lysosomes; Masks; Methodology; Modeling; Oryctolagus cuniculus; Positioning Attribute; Property; Prophylactic treatment; Testing; V3 Loop; Vaccines; Variant; Virus; antigen binding; antigen processing; experience; immunogenic; immunogenicity; innovation; insight; killings; nonhuman primate; novel vaccines; pandemic disease; public health relevance; research study; response; vaccine development

 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.

 描述(申请人提供)：全球迫切需要开发一种针对HIV-1的保护性疫苗。虽然中和抗体可以有效地预防HIV-1感染，但诱导出对许多抗原性不同的HIV-1毒株具有广泛反应的抗体一直是一个重大挑战，它仍然是艾滋病疫苗开发的关键障碍。这一探索性的R21应用的主要目的是探索一种新的疫苗策略，以诱导针对HIV-1 gp120的CD4结合位点(CD4BS)的强大抗体反应，最终目标是诱导广谱中和抗体(BNAbs)。这将通过使用与特定的具有特定表位的单抗(MAbs)络合的抗原来掩蔽诱导非中和Abs的免疫原性表位，并将免疫反应集中在CD4BS上。这一应用背后的基本原理是，当抗原与抗体结合时，其免疫原性可以改变。此外，它的改变方式取决于抗体结合的位置。目前，gp120上的B细胞表位与抗体改变体液反应能力之间的功能关系尚未完全阐明。更好地了解这种关系可以为开发更有效的疫苗战略提供新的见解。要测试的具体假设是：(1)通过使用与非常相同的表位结合的单抗掩蔽表位，可以避免或最大限度地减少非中和或菌株特异性中和抗体的诱导；以及(2)阻断高免疫原性的非/菌株特异性中和表位，同时使CD4BS完全暴露，将迫使免疫系统将抗体反应集中在它身上；这将导致更多的CD4BS抗体水平，其中一些可能是广泛的中和。我们建议的主要创新/优点是：(1)在评估HIV-1抗原在兔子身上的免疫原性方面有丰富的经验；(2)大量的兔单抗资料库，这将使我们能够在兔子身上测试假说； (3)初步数据表明，免疫掩蔽可以抑制抗体反应的原理证明；(4)使用多个单抗来掩蔽所有(或大多数)非/毒株特异性中和表位，同时允许VRC01结合；以及(5)使用低pH敏感的单抗，它将在溶酶体中释放抗原，以进行有效的抗原处理。拟议实验的成功完成将是开发保护性艾滋病疫苗的一个重要里程碑。