Antigenic and virological traits of HIV-1 breakthrough infections in the VRC01 antibody-mediated prevention Phase 2b trial in sub-Saharan Africa
撒哈拉以南非洲 VRC01 抗体介导的预防 2b 期试验中 HIV-1 突破性感染的抗原和病毒学特征
基本信息
- 批准号:10609096
- 负责人:
- 金额:$ 33.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-17 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AIDS preventionActive ImmunizationAddressAffectAfricaAfrica South of the SaharaAfricanAmino AcidsAncillary StudyAntibodiesAttenuatedBinding SitesBiological AssayCD4 Lymphocyte CountChimera organismClinicalClinical MarkersClinical TrialsCollaborationsCommunicable DiseasesComplexConsensusDataData Coordinating CenterEffectivenessEpidemicEventFailureFred Hutchinson Cancer Research CenterFutureGenetic DeterminismGenetic Predisposition to DiseaseGenetic VariationGenotypeGoalsHIVHIV InfectionsHIV Vaccine Trials NetworkHIV-1HIV-1 vaccineImmune EvasionImmunizationInfectionInfection preventionInfusion proceduresInstitutionInvestigationKineticsLaboratoriesMeasuresMediatingMutationNatural ResistanceOutcomeParentsPassive ImmunizationPathogenesisPeripheral Blood Mononuclear CellPhasePhenotypePredispositionPreventionPrevention approachPrevention trialPreventiveProtocols documentationResearch PersonnelResistanceSafetySamplingScienceSeminalSerumSiteSouth AfricaSouth AfricanStandardizationTestingTrainingUnderrepresented PopulationsUniversitiesUpdateVaccinesValidationViralViral Load resultVirusWomanarmbreakthrough infectioncase controlcostenv Gene Productsfitnessflexibilitygenetic predictorsgenetic resistanceimprovedin silicoinfection rateinsightmembermutantneutralizing antibodynext generationnovelpressureprogramssecondary analysistooltraittransmission processvaccine accessviral fitnessviral transmissionvirus genetics
项目摘要
PROJECT SUMMARY
Whether through active or passive immunization, broadly neutralizing antibodies (bNAbs) will likely form
a cornerstone of HIV prevention. This application proposes an ancillary study of the African component of the
antibody-mediated prevention trial (AMP) (HVTN 703/HPTN 081). The AMP study is the first proof-of-concept
trial to evaluate the safety and efficacy of a bNAb (VRC01) to block HIV acquisition. Our team is involved in the
laboratory investigations to measure serum levels associated with protection, and through sieve analysis, to
determine how predicted genotypic features correlate with prevention efficacy. The goal of this application is
to provide a deeper understanding on how HIV-1 diversity affects the amount of antibody needed to
prevent infection; and the clinical consequences of infection with VRC01-resistant viruses.
The extreme diversity of circulating HIV strains, together with the flexibility of the Envelope protein (Env)
in evading immune pressure, could threaten the effectiveness of immunization studies. Utilizing sequence data
and functional env clones from AMP breakthrough infections, the first aim will provide an up-to-date bNAb
sensitivity profile of circulating strains, providing data useful for future clinical trials. This analysis will be done
using the standardized Env-pseudotyped assay, and a subset will also be evaluated using infectious env clones
generated in PBMCs to verify these data. The parent protocol sieve analysis will predict genetic features that
affect VRC01 neutralization susceptibility and resistance, and the second aim of this application will
experimentally validate these predictions, as well as evaluate how the cognate Env of breakthrough infections
influences the impact of these mutations. This will provide experimental data on how changes in envelope affect
the amount of antibody needed for prevention of infection. Lastly, VRC01 escape mutations have been
associated with reduced viral fitness and we will compare fitness of VRC01-resistant and sensitive viruses and
determine how this affects key clinical markers such as HIV viral load and CD4 counts.
The HVTN 703/HPTN 081 trial provides a unique opportunity to define the impact of diversity on bNAb
efficacy in a sub-Saharan Africa setting where new prevention approaches are still urgently needed. This study
will be led by investigators at the University of Cape Town and the Fred Hutchinson Cancer Research Center,
in collaboration with the National Institute for Communicable Diseases, and includes a training partnership with
North-West University in Mahikeng, South Africa. Information generated in this proposal will support the next
phase of combination passive immunization trials and will provide seminal data to understand the prevention
efficacy of VRC01.
项目摘要
无论是通过主动免疫还是被动免疫,
艾滋病预防的基石。本申请书提出了一项对《联合国宪章》非洲部分的辅助研究,
抗体介导的预防试验(AMP)(HVTN 703/HPTN 081)。AMP研究是第一个概念验证
一项评估bNAb(VRC 01)阻断HIV感染的安全性和有效性的试验。我们的团队参与了
实验室研究,以测量与保护相关的血清水平,并通过筛选分析,
确定预测的基因型特征如何与预防效果相关。这个应用程序的目标是
更深入地了解HIV-1多样性如何影响所需的抗体数量,
预防感染;以及感染耐VRC 01病毒的临床后果。
传播的HIV病毒株的极端多样性,以及包膜蛋白(Env)的灵活性
逃避免疫压力,可能威胁免疫研究的有效性。利用序列数据
和AMP突破感染的功能性env克隆,第一个目标将提供最新的bNAb
循环菌株的敏感性特征,为未来的临床试验提供有用的数据。这项分析将在
使用标准化的Env假型化试验,也将使用感染性Env克隆评价一个子集
在PBMC中产生以验证这些数据。亲本方案筛选分析将预测遗传特征,
影响VRC 01的中和敏感性和抗性,本申请的第二个目的将
实验验证这些预测,以及评估如何同源Env的突破性感染,
影响这些突变的影响。这将提供实验数据,说明信封的变化如何影响
预防感染所需的抗体量。最后,VRC 01逃逸突变已经被证实是一种基因突变。
与降低的病毒适应性相关,我们将比较VRC 01抗性和敏感病毒的适应性,
确定这如何影响关键的临床标志物,如HIV病毒载量和CD 4计数。
HVTN 703/HPTN 081试验为确定多样性对bNAb的影响提供了独特的机会
在撒哈拉以南非洲,仍然迫切需要新的预防方法。本研究
将由开普敦大学和弗雷德哈钦森癌症研究中心的研究人员领导,
与国家传染病研究所合作,包括与
西北大学在Mahikeng,南非。本提案中生成的信息将支持下一个
联合被动免疫试验阶段,并将提供开创性的数据,以了解预防
VRC 01的功效。
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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Peter B. Gilbert其他文献
Practice of Epidemiology Estimating the Efficacy of Preexposure Prophylaxis for HIV Prevention Among Participants With a Threshold Level of Drug Concentration
流行病学实践评估药物浓度阈值水平的参与者中暴露前预防对艾滋病毒预防的功效
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
James Y. Dai;Peter B. Gilbert;James P. Hughes;Elizabeth R. Brown - 通讯作者:
Elizabeth R. Brown
A comparative analysis of abandoned street children and formerly abandoned street children in La Paz, Bolivia
玻利维亚拉巴斯被遗弃街头儿童与曾经被遗弃街头儿童的比较分析
- DOI:
- 发表时间:
2004 - 期刊:
- 影响因子:5.2
- 作者:
C;P. Barreda;V. Mendoza;L. Guzmán;Peter B. Gilbert - 通讯作者:
Peter B. Gilbert
1 - Viral Kinetic Correlates of Cytomegalovirus Disease and Death after Hematopoietic Cell Transplant
- DOI:
10.1016/j.bbmt.2017.12.006 - 发表时间:
2018-03-01 - 期刊:
- 影响因子:
- 作者:
Elizabeth R. Duke;Peter B. Gilbert;Terry L. Stevens-Ayers;Jonathan L. Golob;Nicole Cossrow;Morgan A. Marks;Hong Wan;T. Christopher Mast;Meei-Li W. Huang;Keith R. Jerome;Lawrence Corey;Joshua T. Schiffer;Michael J. Boeckh - 通讯作者:
Michael J. Boeckh
Efficient nonparametric estimation of the covariate-adjusted threshold-response function, a support-restricted stochastic intervention
协变量调整阈值响应函数的有效非参数估计,支持限制随机干预
- DOI:
- 发表时间:
2021 - 期刊:
- 影响因子:0
- 作者:
L. Laan;Wenbo Zhang;Peter B. Gilbert - 通讯作者:
Peter B. Gilbert
Neutralizing antibody correlate of protection against severe-critical COVID-19 in the ENSEMBLE single-dose Ad26.COV2.S vaccine efficacy trial
在 ENSEMBLE 单剂量 Ad26.COV2.S 疫苗效力试验中与预防严重/危重 COVID-19 相关的中和抗体
- DOI:
10.1038/s41467-024-53727-y - 发表时间:
2024-11-12 - 期刊:
- 影响因子:15.700
- 作者:
Lindsay N. Carpp;Ollivier Hyrien;Youyi Fong;David Benkeser;Sanne Roels;Daniel J. Stieh;Ilse Van Dromme;Griet A. Van Roey;Avi Kenny;Ying Huang;Marco Carone;Adrian B. McDermott;Christopher R. Houchens;Karen Martins;Lakshmi Jayashankar;Flora Castellino;Obrimpong Amoa-Awua;Manjula Basappa;Britta Flach;Bob C. Lin;Christopher Moore;Mursal Naisan;Muhammed Naqvi;Sandeep Narpala;Sarah O’Connell;Allen Mueller;Leo Serebryannyy;Mike Castro;Jennifer Wang;Christos J. Petropoulos;Alex Luedtke;Yiwen Lu;Chenchen Yu;Michal Juraska;Nima S. Hejazi;Daniel N. Wolfe;Jerald Sadoff;Glenda E. Gray;Beatriz Grinsztejn;Paul A. Goepfert;Linda-Gail Bekker;Aditya H. Gaur;Valdilea G. Veloso;April K. Randhawa;Michele P. Andrasik;Jenny Hendriks;Carla Truyers;An Vandebosch;Frank Struyf;Hanneke Schuitemaker;Macaya Douoguih;James G. Kublin;Lawrence Corey;Kathleen M. Neuzil;Dean Follmann;Richard A. Koup;Ruben O. Donis;Peter B. Gilbert - 通讯作者:
Peter B. Gilbert
Peter B. Gilbert的其他文献
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{{ truncateString('Peter B. Gilbert', 18)}}的其他基金
CoVPN 5001 - A prospective study of acute immune responses to SARS-CoV-2 infection
CoVPN 5001 - 对 SARS-CoV-2 感染的急性免疫反应的前瞻性研究
- 批准号:
10581432 - 财政年份:2022
- 资助金额:
$ 33.34万 - 项目类别:
HVTN 405/HPTN 1901 Characterizing SARS-CoV-2-specific immunity in convalescent individuals
HVTN 405/HPTN 1901 表征恢复期个体的 SARS-CoV-2 特异性免疫力
- 批准号:
10570787 - 财政年份:2022
- 资助金额:
$ 33.34万 - 项目类别:
CoVPN 3006: A randomized controlled study to assess SARS-CoV-2 infection, viral shedding, and subsequent potential transmission in university students immunized with Moderna COVID-19 Vaccine
CoVPN 3006:一项随机对照研究,旨在评估接种 Moderna COVID-19 疫苗的大学生中的 SARS-CoV-2 感染、病毒脱落以及随后的潜在传播
- 批准号:
10375264 - 财政年份:2021
- 资助金额:
$ 33.34万 - 项目类别:
CoVPN 5001 A prospective study of acute immune responses to SARS-CoV-2 infection SDMC
CoVPN 5001 对 SARS-CoV-2 感染的急性免疫反应的前瞻性研究 SDMC
- 批准号:
10319288 - 财政年份:2021
- 资助金额:
$ 33.34万 - 项目类别:
CoVPN 3003 A Phase 3 Study to Assess the Efficacy and Safety of Ad26.COV2.S for the Prevention of SARS-CoV-2-mediated COVID-19 in Adults Aged 18 Years and Older SDMC
CoVPN 3003 评估 Ad26.COV2.S 在 18 岁及以上成人中预防 SARS-CoV-2 介导的 COVID-19 的功效和安全性的 3 期研究 SDMC
- 批准号:
10320660 - 财政年份:2020
- 资助金额:
$ 33.34万 - 项目类别:
CoVPN 3001 A Phase 3, Randomized, Stratified, Observer-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine SDMC
CoVPN 3001 评估 mRNA-1273 SARS-CoV-2 疫苗 SDMC 的功效、安全性和免疫原性的 3 期、随机、分层、观察者盲法、安慰剂对照研究
- 批准号:
10217912 - 财政年份:2020
- 资助金额:
$ 33.34万 - 项目类别:
HVTN 405/HPTN 1901 Characterizing SARS-CoV-2-specific immunity in convalescent individuals
HVTN 405/HPTN 1901 表征恢复期个体的 SARS-CoV-2 特异性免疫力
- 批准号:
10166307 - 财政年份:2020
- 资助金额:
$ 33.34万 - 项目类别:
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