Expediting elicitation of HIV-1 bnAbs with membrane Env vaccines

使用膜包膜疫苗加速 HIV-1 bnAb 的诱导

• 批准号: 10568994
• 负责人: MICHAEL B ZWICK
• 金额: $ 89.12万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-09 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10568994
• 关键词: AIDS vaccine development; Address; Adenovirus Vector; Adjuvant; Affinity; Animal Model; Antibodies; Antibody Response; Antibody Specificity; Antigens; B-Lymphocytes; B-cell receptor repertoire sequencing; Binding; Binding Sites; Biochemical; Blocking Antibodies; Cell Separation; Cells; Clinic; Consensus; Data; Directed Molecular Evolution; Elements; Engineering; Epitopes; Evolution; Excision; Genetic; Genomics; Genotype; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; HIV-1 vaccine; Helper-Inducer T-Lymphocyte; Heterogeneity; Heterozygote; Homologous Gene; Human; Immune Sera; Immune system; Immunization; Immunize; Joints; Keyhole Limpet Hemocyanin; Knock-in; Knock-in Mouse; Link; Liposomes; Membrane; Modeling; Modification; Molecular Conformation; Mus; Oryctolagus cuniculus; Ovum; Pathway interactions; Peptides; Phenotype; Polysaccharides; Positioning Attribute; Production; Regimen; Reporting; Reproducibility; Scheme; Serum; Site; Solubility; Specificity; Surface; System; T-Lymphocyte; Testing; Transmembrane Domain; Vaccine Design; Vaccines; Variant; Virion; Virus; anergy; base; design; follow-up; glycosylation; immunogenicity; improved; mouse model; neutralizing antibody; next generation sequencing; novel; particle; recruit; response; single-cell RNA sequencing; vaccination outcome; vaccination strategy; vaccine candidate; vaccine delivery; vaccine development; vaccine platform; vaccine strategy; vector vaccine

Project Summary / Abstract A primary goal in HIV/AIDS vaccine development is to elicit broadly neutralizing antibodies (bnAbs) against the HIV-1 envelope glycoprotein spike that is anchored in the membrane (m-Env). To date, experimental vaccines have elicited mostly narrow, weak or non-neutralizing antibodies, typically using soluble Env (s-Env) molecules. Here, we will use membrane Env liposome (MEL) vaccines that incorporate well-ordered and stabilized m-Env trimers into liposomes via the transmembrane domain. MELs thus present a relevant conformation of Env in a multivalent manner and contain important epitopes of the membrane proximal external region (MPER) that are missing from s-Env vaccines. The creation of MELs has been made feasible by recent improvements to m-Env production by creation of high Env producer cells. Meanwhile, B cell anergy is common among HIV-1 bnAb lineages but is not well addressed by traditional vaccines. Preliminary data show initial promise of MELs in eliciting nAb responses in human CD4BS bnAb CH103 UCA heterozygous dKI (HC+LC KI) mice in which ‘on-target’ anergy prone B cells had responded poorly to s-Env vaccines. In Aim 1, we will build on these findings by using consensus Env MELs, and mixed Env MELs, combined with selective removal of N-glycan at position 197 to increase accessibility to the CD4 binding site in order to expedite elicitation of cross-neutralizing antibodies in the prime. This will be followed by sequential boosting with MELs. The ‘Booster MELs’ will be consensus Envs, or those selected in part based on specific binding by antecedent serum antibodies from prior immunization, with the intent to drive affinity maturation of B cells against conserved elements of the target site. In an effort to further broaden nAb responses, we will use an approach described recently that elicits bnAbs to the fusion peptide (FP) in multiple species including mice. In this approach, a prime-boost regimen in CH103 UCA het dKI mice consisting of an FP-KLH prime and MEL boosts is designed to “co-elicit” CD4BS bnAbs and FP bnAbs. In Aim 2, we will test a similar sequential MEL immunization strategy designed to elicit MPER-directed bnAbs in 2F5 KI mice, whose B-cells are also under more significant anergy controls. Hence, we will use strong universal T helper cell epitopes as a strategy to further help break B cell anergy to maximize bnAb responses. This will involve “pre-priming” with universal Th epitopes using a lentiviral vaccine vector (LVV). Finally, in Aim 3, down-selected m-Env vaccine candidates eliciting the best nAb responses, and ideally comprising practical regimens that elicit nAbs to CD4BS, FP and MPER with the least boosts, will be used to immunize in fully polyclonal systems, i.e. rabbits and humanized Ig locus KI (Trianni) mice. The creation of m-Env-based vaccine schemes able to elicit cross-neutralizing antibodies against key vaccine targets, particularly in humanized polyclonal Ig KI mice, should have a significant impact on HIV-1 vaccine development.

项目摘要 /摘要 艾滋病毒/艾滋病疫苗开发的主要目标是引起针对HIV-1的广泛中和抗体（BNAB） 包膜糖蛋白尖峰锚定在膜（M-ENV）中。迄今为止，实验疫苗主要引起 通常使用固体Env（S-ENV）分子窄，弱或非中和抗体。在这里，我们将使用膜 ENV脂质体（MEL）疫苗，通过通过该固定有序的和稳定的M-ENV三聚体通过该疫苗进行脂质体 跨膜结构域。因此，梅尔斯以多种方式呈现了Env的相关构象，并包含重要的 S-ENV疫苗缺少的膜近端外部区域（MPER）的表位。梅尔斯的创造 通过创建高环境生产者细胞对M-ENV生产的最新改进，使其可行。同时， B细胞消极在HIV-1 BNAB谱系中很常见，但传统疫苗无法很好地解决。初步数据 在人CD4BS BNAB CH103 UCA杂合DKI中显示MEL的初始诺言（HC+LC） ki）小鼠“靶向”易于反感的B细胞对S-ENV疫苗的反应不佳。在AIM 1中，我们将基础 这些发现通过使用共识env mels和混合env mels结合选择性去除n-glycan 位置197，以增加对CD4结合位点的可访问性，以加快跨中和抗体的启发 在素数。随后将使用Mels进行顺序提升。 “助推器”将是共识环境，或者 那些基于先前免疫的先前血清抗体的特异性结合而部分选择的。 驱动B细胞与目标位点构成元素的亲和力成熟。为了进一步扩大NAB 响应，我们将使用最近描述的方法，即在多种物种中引起融合肽（FP）的bnabs 包括老鼠。在这种方法中，CH103 UCA HET DKI小鼠中的Prime-bumost方案，由FP-KLH Prime和 Mel Boots设计为“共同使用” CD4BS BNAB和FP BNAB。在AIM 2中，我们将测试类似的顺序MEL 免疫策略旨在引起2f5 ki小鼠的MPER指导的BNAB，其B细胞也在更多 明显的无反对控制。因此，我们将使用强大的通用T辅助细胞表位作为进一步破坏B的策略 细胞消极，以最大化BNAB反应。这将涉及使用慢病毒的通用表位“预涂抹” 疫苗载体（LVV）。最后，在AIM 3中，下降的M-ENV疫苗候选者会引起最佳的NAB响应，并 理想情况下，将使用最少提升的CD4B，FP和MPER的NABS完成实用方案 在完全多克隆系统中进行免疫，即兔子和人源化Ig基因座Ki（Trianni）小鼠。基于M-ENV的创建 疫苗方案可以引起针对关键疫苗靶标的跨中和抗体，特别是在人源化多克隆中 IG Ki小鼠应对HIV-1疫苗的开发产生重大影响。