SHIV Env-antibody coevolution as a molecular guide to HIV-1 V3 glycan targeted vaccine design
SHIV Env-抗体协同进化作为 HIV-1 V3 聚糖靶向疫苗设计的分子指南
基本信息
- 批准号:10631866
- 负责人:
- 金额:$ 410.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-03-07 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffinityAmino Acid SubstitutionAnimalsAntibodiesAntibody AffinityAntibody ResponseAntigen ReceptorsAntigensApicalAutologousAwardB cell differentiationB-Cell Antigen ReceptorB-LymphocytesBindingBinding SitesBioinformaticsBiologicalBiophysicsCell LineageChemicalsChronicDevelopmentEpitopesEventExposure toFoundationsGenesGerm CellsGoalsGrantHIV-1HIV-1 vaccineHumanHumoral ImmunitiesImmunizationImmunogeneticsImmunologicsInfectionKnock-in MouseLaboratoriesMacaca mulattaMannoseMemory B-LymphocyteModelingMolecularMonkeysMonoclonal AntibodiesMusMutagenesisPathway interactionsPatternPeptidesPlasma CellsPolysaccharidesPrevalencePrimatesProcessRegimenReproducibilityResearchResearch Project GrantsRoleScienceScientific Advances and AccomplishmentsSpecificityStructure of germinal center of lymph nodeTestingTimeVaccinationVaccine DesignVaccine ResearchVaccinesViralVirusVirus Diseasesclinically relevantdesignenv Gene Productsinsertion/deletion mutationneutralizing antibodynovelresponsesimian human immunodeficiency virusstatisticstransmission processvaccine effectiveness
项目摘要
PROJECT SUMMARY
The development of an effective HIV-1 vaccine has proven to be a daunting scientific challenge. Despite decades
of research, there are no examples of immunogens that consistently elicit potent broadly neutralizing antibodies
(bNAbs). Our scientific premise is that there are three principal obstacles to inducing bNAbs in primates and
humans that prior vaccine approaches have largely failed to overcome. These are: i) efficient and consistent
priming of multiple HIV-1 bNAb precursor B cells; ii) immunofocused boosting of B cell responses targeting
conserved bNAb epitopes and away from off-target epitopes; and iii) affinity-guided maturation of B cell lineages
to select for enhanced neutralization breadth and potency. Here, we address each of these requirements. This
application is a competitive renewal of an existing HIVRAD award where we hypothesized that a major roadblock
to rational HIV-1 vaccine design is the lack of a suitable primate model in which bNAbs can be commonly induced
and the molecular, biological and immunological mechanisms responsible for such responses studied in a
reproducible and iterative fashion. Overcoming this roadblock was one of the major goals of that grant, and over
the past five years we have made substantial progress in reaching this milestone. We did this by developing a
novel design strategy for creating simian-human immunodeficiency viruses (SHIV) that bear clinically-relevant
primary HIV-1 Envs and that replicate efficiently in rhesus macaques (RMs). We next hypothesized that SHIV-
infected RMs could be used to identify HIV-1 Envs that have a propensity for eliciting bNAbs of predetermined
epitope specificity, thus allowing for a detailed and reproducible molecular characterization of the coevolutionary
pathways of Env and Ab that lead to affinity maturation and breadth. Again, we obtained strong supporting
evidence (Science 371:eabd2638, 2021). Here we propose to build on this foundation and to test the hypothesis
that elucidation of the molecular pathways of Env-Ab coevolution leading to neutralization breadth in SHIV-
infected RMs, combined with biophysical and immunological analyses of key Env-Ab lineage intermediates, can
provide a molecular “blueprint” for successful germline-targeted, B cell lineage-based immunogen design. To
test this hypothesis, we propose three highly inter-related research projects and three cores: Project 1 - Env-Ab
coevolution in SHIV infected RMs leading to V3 glycan bNAbs (Shaw); Project 2 - Optimizing humoral immunity
to HIV-1 Env proteins (Kelsoe); Project 3 - Immunogen design to elicit polyclonal bNAb responses to the V3
glycan supersite (Wiehe). These projects will be enabled by Core A – Administrative (Shaw); Core B – Viral and
antibody gene sequencing (Hahn); and Core C – Bioinformatics and statistics (Wagh). The significance of the
proposed studies is potentially far-reaching: previous studies of HIV-1 SOSIP Env trimer vaccinations have
generally elicited only autologous strain-specific Nab responses in outbred animals. If we can demonstrate
consistent induction of bNAbs using germline-targeted, lineage-based SOSIP Env trimers as immunogens in
RMs, it would represent a major scientific advance and a new beachhead for HIV-1 vaccine research.
项目总结
项目成果
期刊论文数量(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:
$ 410.48万 - 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:
10624301 - 财政年份:2021
- 资助金额:
$ 410.48万 - 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:
$ 410.48万 - 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:
$ 410.48万 - 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:
$ 410.48万 - 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:
$ 410.48万 - 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:
$ 410.48万 - 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:
$ 410.48万 - 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:
$ 410.48万 - 项目类别:
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