HIV-1 Q23.17 Env: Engineering a novel immunogen to elicit broadly neutralizing antibodies
HIV-1 Q23.17 Env:设计一种新型免疫原以引发广泛中和抗体
基本信息
- 批准号:10624301
- 负责人:
- 金额:$ 116.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-23 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAffinityAmino Acid SubstitutionAnimal ModelAnimalsAntibodiesAntibody ResponseAntibody-mediated protectionAntigensApicalAutologousB-LymphocytesBindingBinding SitesBiologicalChemicalsChronicClinical TrialsDataDevelopmentEngineeringEpitopesEventExhibitsFrequenciesGrantHIV-1HIV-1 vaccineHumanImmunogeneticsImmunologicsKnock-in MouseLaboratoriesMacaca mulattaMature B-LymphocyteModelingMolecularMonkeysMutagenesisMutationPathway interactionsPatternPeptidesPolysaccharidesPrevalencePrimatesRegimenReproducibilityReverse engineeringRhesusScienceScientific Advances and AccomplishmentsStructureTestingTimeTranslatingVaccinationVaccine DesignVaccine ResearchVaccinesVariantViralVirusdesignimmunogenicityinnovationinsertion/deletion mutationnanoparticle deliveryneutralizing antibodynovelpre-clinicalresponsesimian human immunodeficiency virustransmission processvaccine trialvaccinology
项目摘要
PROJECT SUMMARY
In humans, neutralizing antibodies elicited by HIV-1 coevolve with viral Envs in distinctive patterns, in some
cases acquiring substantial breadth. We found that primary HIV-1 Envs, when expressed by simian-human
immunodeficiency viruses (SHIVs) in 22 rhesus macaques (RMs), elicited patterns of Env-Ab coevolution
strikingly similar to those in humans (Science 371:eabd2638, 2021). This included conserved immunogenetic,
structural and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions and
deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a
208-strain panel, revealed a V2-apex mode of recognition like that of human bNAbs PGT145 and PCT64. We
subsequently expanded this study to include 150 RMs infected by SHIVs bearing any of 15 different primary
HIV-1 Envs; 24 (16%) of these animals developed bNAbs targeting conserved V2 apex, V3 glycan, CD4bs or
fusion peptide epitopes. The V2 apex was the most common bNAb epitope targeted in RMs. We concluded that
Env-Ab coevolution in RMs recapitulates developmental features of human bNAbs and may serve to guide and
accelerate HIV-1 immunogen design for humans. From these preclinical data, we identified HIV-1 Q23.17 Env
as the immunogen that most consistently elicited V2 apex bNAbs. Here, we propose to elucidate the Env-Ab
coevolutionary pathways by which HIV-1 Q23.17 Env selectively primes, boosts and affinity-matures V2 apex
bNAb responses and to translate these findings into an all-SOSIP Env trimer vaccine regimen consisting of a
germline-targeted Q23.17 Env prime followed by boosts with lineage-designed Q23.17 Env “imunotypes”
capable of affinity-maturing B cells to achieve breadth. Specific aims are: (i) to decipher molecular pathways of
Env-Ab coevolution in SHIV.Q23.17 infected RMs that lead to the development of V2 apex bNAbs, including the
identification of inferred germline bNAb precursors and lineage intermediates and corresponding Env
immunotypes that bind to them; (ii) to use mammalian display saturation mutagenesis to generate Q23.17 Env
variants that exhibit enhanced binding affinity to multiple rhesus germline V2 apex bNAb B cell precursors and
to engineer these Envs as nanoparticle-delivered SOSIP trimers; (iii) to test the immunogenicity of germline-
targeted and lineage-designed Q23.17 Env SOSIP trimers in V2 apex bNAb UCA knockin mice and outbred
RMs and to advance the most promising combinations to a proof-of-concept preclinical vaccine trial in RMs; and
(iv) to conduct an appropriately powered preclinical vaccine trial in 28 RMs to test the hypothesis that reverse-
engineered, B lineage-designed Q23.17 SOSIP Env trimers can prime, boost and affinity mature V2 apex bNAb
responses in RMs to an extent that is superior to conventional SOSIP Env immunogens and that protects RMs
from heterologous virus challenge. The significance of these studies could be far-reaching: if we can demonstrate
consistent induction of bNAbs using germline-targeted, lineage-designed Q23.17 Env SOSIPs in RMs, it would
represent a new beachhead for HIV-1 vaccine research that could be translated rapidly into human clinical trials.
项目概要
在人类中,HIV-1 引发的中和抗体与病毒包膜以独特的模式共同进化,在某些情况下
案件的范围相当广泛。我们发现,当由猿猴表达时,初级 HIV-1 Envs
22 只恒河猴 (RM) 体内的免疫缺陷病毒 (SHIV) 引发了 Env-Ab 协同进化模式
与人类惊人相似(Science 371:eabd2638,2021)。这包括保守的免疫遗传学,
用于表位识别和精确的 Env-氨基酸取代、插入和
删除导致病毒持续存在。一种恒河猴抗体的结构,能够中和 49%
208 菌株面板揭示了类似于人类 bNAb PGT145 和 PCT64 的 V2-apex 识别模式。我们
随后扩大了这项研究,纳入了 150 名被 SHIV 感染的 RM,这些人携带 15 种不同的原发性
HIV-1 环境;其中 24 只 (16%) 动物开发出针对保守 V2 顶点、V3 聚糖、CD4b 或
融合肽表位。 V2 顶端是 RM 中最常见的 bNAb 靶向表位。我们的结论是
RM 中的 Env-Ab 协同进化概括了人类 bNAb 的发育特征,可能有助于指导和
加速人类 HIV-1 免疫原的设计。从这些临床前数据中,我们确定了 HIV-1 Q23.17 Env
作为最一致地引发 V2 尖 bNAb 的免疫原。在这里,我们建议阐明 Env-Ab
HIV-1 Q23.17 Env 选择性启动、增强和亲和力成熟 V2 顶点的共同进化途径
bNAb 反应并将这些发现转化为全 SOSIP Env 三聚体疫苗方案,其中包括
针对种系的 Q23.17 Env Prime,随后通过谱系设计的 Q23.17 Env“免疫型”进行增强
能够使 B 细胞亲和力成熟以实现广度。具体目标是:(i)破译分子途径
SHIV.Q23.17 感染 RM 中的 Env-Ab 协同进化导致 V2 顶端 bNAb 的发育,包括
推断种系 bNAb 前体和谱系中间体以及相应 Env 的鉴定
与其结合的免疫型; (ii)使用哺乳动物展示饱和诱变来生成Q23.17 Env
对多种恒河猴种系 V2 apex bNAb B 细胞前体表现出增强的结合亲和力的变体
将这些 Env 设计为纳米粒子传递的 SOSIP 三聚体; (iii) 测试种系的免疫原性-
V2 apex bNAb UCA 敲入小鼠和远交中的靶向和谱系设计 Q23.17 Env SOSIP 三聚体
RM 并推动最有希望的组合在 RM 中进行概念验证临床前疫苗试验;和
(iv) 在 28 个 RM 中进行适当有力的临床前疫苗试验,以检验逆转的假设
工程化、B 谱系设计的 Q23.17 SOSIP Env 三聚体可以引发、增强和亲和力成熟 V2 apex bNAb
RM 中的反应程度优于传统的 SOSIP Env 免疫原并保护 RM
来自异源病毒的挑战。这些研究的意义可能是深远的:如果我们能够证明
在 RM 中使用种系靶向、谱系设计的 Q23.17 Env SOSIP 一致诱导 bNAb,它将
代表了 HIV-1 疫苗研究的新滩头堡,可以迅速转化为人体临床试验。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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GEORGE M SHAW其他文献
GEORGE M SHAW的其他文献
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{{ truncateString('GEORGE M SHAW', 18)}}的其他基金
Reverse Vaccinology in SHIV Infected Macaques as a Molecular Guide for HIV-1 Vaccine Design
SHIV 感染猕猴的逆向疫苗学作为 HIV-1 疫苗设计的分子指南
- 批准号:
10577775 - 财政年份:2021
- 资助金额:
$ 116.18万 - 项目类别:
Reverse Vaccinology in SHIV Infected Macaques as a Molecular Guide for HIV-1 Vaccine Design
SHIV 感染猕猴的逆向疫苗学作为 HIV-1 疫苗设计的分子指南
- 批准号:
10370383 - 财政年份:2021
- 资助金额:
$ 116.18万 - 项目类别:
HIV-1 Q23.17 Env: Engineering a novel immunogen to elicit broadly neutralizing antibodies
HIV-1 Q23.17 Env:设计一种新型免疫原以引发广泛中和抗体
- 批准号:
10437032 - 财政年份:2021
- 资助金额:
$ 116.18万 - 项目类别:
HIV-1 Q23.17 Env: Engineering a novel immunogen to elicit broadly neutralizing antibodies
HIV-1 Q23.17 Env:设计一种新型免疫原以引发广泛中和抗体
- 批准号:
10326691 - 财政年份:2021
- 资助金额:
$ 116.18万 - 项目类别:
Reverse Vaccinology in SHIV Infected Macaques as a Molecular Guide for HIV-1 Vaccine Design
SHIV 感染猕猴的逆向疫苗学作为 HIV-1 疫苗设计的分子指南
- 批准号:
10224528 - 财政年份:2021
- 资助金额:
$ 116.18万 - 项目类别:
SHIV/HIV Env-Antibody Coevolution as a Guide to Iterative Vaccine Design
SHIV/HIV 包膜抗体协同进化作为迭代疫苗设计的指南
- 批准号:
9316783 - 财政年份:2017
- 资助金额:
$ 116.18万 - 项目类别:
Env-Ab coevolution in SHIV infected RMs leading to V3 glycan bNAbs
SHIV 感染 RM 中的 Env-Ab 共同进化导致 V3 聚糖 bNAb
- 批准号:
10370983 - 财政年份:2017
- 资助金额:
$ 116.18万 - 项目类别:
SHIV/HIV Env-Antibody Coevolution as a Guide to Iterative Vaccine Design
SHIV/HIV 包膜抗体协同进化作为迭代疫苗设计的指南
- 批准号:
10117167 - 财政年份:2017
- 资助金额:
$ 116.18万 - 项目类别:
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