Determinants of HIV broadly-neutralizing antibody precursor induction in infants
婴儿中 HIV 广泛中和抗体前体诱导的决定因素
基本信息
- 批准号:10731276
- 负责人:
- 金额:$ 158.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-01 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:AdjuvantAdultAnimalsAntibodiesAntibody-Producing CellsAutomobile DrivingB cell differentiationB-Cell Antigen ReceptorB-LymphocytesB-cell receptor repertoire sequencingBinding SitesBioinformaticsBiometryCell LineageCell secretionCellsComplexComputer AnalysisComputer ModelsCross ReactionsDataDevelopmentDoseEarly identificationEmulsionsEpitopesEventFrequenciesFutureGlycoproteinsGoalsHIVHIV InfectionsHIV envelope proteinHIV vaccineImmuneImmune responseImmune signalingImmune systemImmunityImmunizationImmunizeImmunoglobulin Somatic HypermutationImmunologyIndividualInfantInfectionInnate Immune ResponseKnowledgeLifeMacaca mulattaMature B-LymphocyteMetagenomicsMinorityModelingMolecular ProfilingNatural ImmunityPathway interactionsPlasmaRoleShapesStatistical Data InterpretationSystems BiologyTLR7 geneTestingVaccinatedVaccinationVaccine DesignVaccineeVaccinesage groupbiological systemscomputerized toolsdesigngene regulatory networkhost microbiotamicrobiomemicrobiome signaturemicrobiotaneutralizing antibodynonhuman primateprogramsresponsesexual debuttranscriptomicsvaccine candidatevaccine evaluationvaccine strategyvaccine trial
项目摘要
ABSTRACT – OVERALL
The induction of broadly neutralizing antibodies (bNAbs) against the HIV envelope glycoprotein (Env) is
considered vital for an effective HIV vaccine. Rational vaccine design applying native Env-like trimers that target
the respective germline B cell receptor have evolved as the most promising strategy. Yet, so far, bNAb precursor
yields have not exceeded 50% of vaccinees. The goal of this Program aims to identify early determinants of
bNAb precursor induction, with a focus on the role of adjuvants and host microbiota, utilizing broad and integrated
omics approaches to decipher the mechanisms associated with bNAb development. In HIV infection, plasma
bNAbs develop in a minority of adults and only after several years, whereas bNAbs in infants with HIV can be
detected as early as one year post infection. Interestingly, bNAbs isolated from infants appear to require less
somatic hypermutations to achieve similar breadth as bNAbs of adults, implying potentially different mechanisms
of bNAb development. We present preliminary data that immunization of infant rhesus macaques (RM) with
BG505 germline-targeting (GT)1.1 SOSIP trimers adjuvanted with the TLR7,8 adjuvant 3M-052 resulted in the
induction of VRC01-like CD4 binding site bNAb precursors in 3 of 5 animals, a frequency comparable to that
observed in adult RM (6 of 12). Plasma antibodies of infant RM also targeted a broader array of epitopes
compared to adult RM, indicative of greater polyreactivity. Despite additional immunizations, the remaining 2
infant RM did not develop this neutralization signature, suggesting that early events are critical in driving bNAb
development. In infants, early immunity is partially defined by the evolving microbiota. The polyreactivity of many,
although not all, bNAbs, further supports a potential role of microbiota in bNAb development We hypothesize
that the dynamic state of the infant immune system and microbiota can be exploited to optimize the induction of
bNAbs by HIV vaccines. Leveraging the infant BG505 GT1.1 SOSIP vaccine model and applying systems
biology approaches, we will identify how the developmental pathways of bNAb induction are altered by the
modulation of the vaccine prime by different adjuvants (Project 1), the microbiome (Project 2), and the
interactions between host immunity and microbiota (Biostatistics and Computational Analysis [BCA] Core).
The Projects will be supported by the Nonhuman Primate (NHP) and the B Cell Cores, with organizational and
fiscal support by the Administrative Core. In Aims 1 and 2, we will define differences in early immune
responses and molecular signatures between vaccinees who do or do not develop bNAbs in response to BG505
GT1.1 SOSIP vaccination by modulating the vaccine prime via adjuvants (Project 1) and microbiota (Project 2).
Aim 3 will develop modeling approaches that integrate immune, microbiome, and molecular signatures to predict
the development of bnAb precursors. The results of the Program will identify critical determinants in the induction
of bNAb precursors. In future studies, we will modulate these factors to optimize HIV vaccine strategies. The
newly developed computational models will facilitate vaccine screening for the potential of bNAb development.
摘要-总体
针对HIV包膜糖蛋白(Env)的广泛中和抗体(bNAb)的诱导是
被认为对有效的艾滋病毒疫苗至关重要。应用靶向的天然Env样三聚体的合理疫苗设计
相应的生殖系B细胞受体已经发展成为最有希望的策略。然而,到目前为止,
接种率未超过50%。该计划的目的是确定早期决定因素,
bNAb前体诱导,重点是佐剂和宿主微生物群的作用,利用广泛和综合的
组学方法来破译与bNAb发展相关的机制。在艾滋病毒感染中,血浆
bNAb在少数成年人中形成,并且仅在几年后形成,而感染HIV的婴儿中的bNAb可以在
在感染后一年就能检测到。有趣的是,从婴儿中分离的bNAb似乎需要更少的
体细胞超突变达到与成人bNAb相似的宽度,这意味着潜在的不同机制
bNAb的发展。我们目前的初步数据表明,免疫婴儿恒河猴(RM)与
用TLR 7,8佐剂3 M-052佐剂化的BG 505种系靶向(GT)1.1 SOSIP三聚体产生了免疫抑制剂。
在5只动物中的3只中诱导VRC 01样CD 4结合位点bNAb前体,频率与
在成人RM中观察到(6/12)。婴儿RM的血浆抗体也针对更广泛的表位
与成人RM相比,表明多反应性更高。尽管有额外的免疫接种,其余2
婴儿RM没有出现这种中和信号,表明早期事件在驱动bNAb中至关重要
发展在婴儿中,早期免疫力部分由不断发展的微生物群定义。许多人的多反应性,
虽然不是所有的bNAb,进一步支持微生物群在bNAb发育中的潜在作用。
婴儿免疫系统和微生物群的动态状态可以用来优化
bNAb通过HIV疫苗。利用婴儿BG 505 GT1.1 SOSIP疫苗模型和应用系统
通过生物学方法,我们将确定bNAb诱导的发育途径是如何被
通过不同佐剂(项目1)、微生物组(项目2)和免疫调节剂(项目3)调节疫苗初免。
宿主免疫和微生物群之间的相互作用(生物统计学和计算分析[BCA]核心)。
这些项目将得到非人类灵长类动物(NHP)和B细胞核心的支持,
行政核心的财政支持。在目标1和2中,我们将定义早期免疫的差异,
对BG 505产生或不产生bNAb的疫苗接种者之间的应答和分子特征
GT1.1通过佐剂(项目1)和微生物群(项目2)调节疫苗初免的SOSIP疫苗接种。
目标3将开发整合免疫、微生物组和分子特征的建模方法,
bnAb前体的开发。该计划的结果将确定入职的关键决定因素
bNAb前体在未来的研究中,我们将调整这些因素,以优化艾滋病毒疫苗的策略。的
新开发的计算模型将有助于疫苗筛选bNAb的发展潜力。
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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Kristina De Paris其他文献
Kristina De Paris的其他文献
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{{ truncateString('Kristina De Paris', 18)}}的其他基金
Project 1: The impact of innate immune responses on the development of broadly neutralizing antibodies by vaccination
项目 1:先天免疫反应对通过疫苗接种产生广泛中和抗体的影响
- 批准号:
10731281 - 财政年份:2023
- 资助金额:
$ 158.46万 - 项目类别:
Project 2: Microbial determinants of HIV broadly-neutralizing antibody precursor induction in infants
项目2:婴儿中HIV广泛中和抗体前体诱导的微生物决定因素
- 批准号:
10731282 - 财政年份:2023
- 资助金额:
$ 158.46万 - 项目类别:
Vaccine-induced SARS-CoV-2-specific T cell responses in patients with X-linked Agammaglobulinemia
X 连锁无丙种球蛋白血症患者中疫苗诱导的 SARS-CoV-2 特异性 T 细胞反应
- 批准号:
10593523 - 财政年份:2023
- 资助金额:
$ 158.46万 - 项目类别:
Immunogenicity and Efficacy of SARS-CoV-2 stabilized prefusion Spike protein vaccines in infant rhesus macaques
SARS-CoV-2 稳定预灌注 Spike 蛋白疫苗在幼年恒河猴中的免疫原性和功效
- 批准号:
10223634 - 财政年份:2020
- 资助金额:
$ 158.46万 - 项目类别:
Subingual-parenteral Vaccination to Prevent Oral HIV Transmission in Infants
舌下注射疫苗预防婴儿经口艾滋病毒传播
- 批准号:
10172886 - 财政年份:2018
- 资助金额:
$ 158.46万 - 项目类别:
Subingual-parenteral Vaccination to Prevent Oral HIV Transmission in Infants
舌下注射疫苗预防婴儿经口艾滋病毒传播
- 批准号:
10425465 - 财政年份:2018
- 资助金额:
$ 158.46万 - 项目类别:
The Pros and Cons of Trained Immunity Induced by Vaccines for Tuberculosis Prevention
结核病预防疫苗诱导的训练免疫的利与弊
- 批准号:
9207318 - 财政年份:2016
- 资助金额:
$ 158.46万 - 项目类别:
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