Immunization strategies to elicit broadly neutralizing antibodies against HCV
引发针对 HCV 的广泛中和抗体的免疫策略
基本信息
- 批准号:10211121
- 负责人:
- 金额:$ 12.95万
- 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:2020-07-06 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAnimalsAntibodiesAntibody AvidityAntibody ResponseAntigensAntiviral AgentsAreaAutomobile DrivingAwardB-LymphocytesBindingBinding SitesBiological ModelsBiologyCD81 geneChronicCollaborationsComplexDevelopmentEpidemicEpitopesExhibitsFutureGenesGenetic VariationGlycoproteinsGoalsHIV-1Hepatitis C VaccineHepatitis C virusHumanImmune responseImmunizationImmunologyIndividualInfectionLaboratoriesLengthLiver CirrhosisMacacaMalignant neoplasm of liverMediatingMentorsMentorshipMethodsModelingMolecular ConformationMusMutateOrthologous GenePhasePreventive vaccineProductionProteinsProtocols documentationPublic HealthResearchSiteSpecificityStructureTestingTrainingUnited States National Institutes of HealthVaccinatedVaccinationVaccinesVariantVirusVirus DiseasesVirus-like particleWild Type Mousebasecostdesignefficacy studyenv Gene Productsexperimental studyhepatitis C virus envelope 2 proteinin vivointerdisciplinary approachneutralizing antibodynonhuman primatenovel vaccinespreservationreceptorresponsestructural biologysuccessvaccine candidatevaccine developmentvaccine-induced antibodiesviral detection
项目摘要
PROJECT SUMMARY
Hepatitis C virus (HCV) infects over 70 million people worldwide and is a leading cause of chronic liver cirrhosis
and liver cancer. Despite the success of direct-acting antivirals, control of the HCV epidemic remains challenging
due to difficulties in early virus detection, the high cost of therapy, and possible reinfection after the successful
treatment. An effective prophylactic vaccine would help to control the epidemic, but the enormous genetic
diversity of the HCV hampers its development. Despite the high variability of the virus, 30% of HCV-infected
individuals clear the viral infection by developing broadly neutralizing antibodies (bNAbs) that bind to conserved
neutralizing epitopes of HCV glycoprotein E2. By stimulating the development of bNAbs by vaccination, the HCV
epidemic might be stopped.
We recently identified several E2 proteins from different HCV isolates that bind to germline precursors of human
bNAbs, raising the possibility of vaccine development using these variants. In this proposal, we aim to use
naturally-occurring E2 proteins to design immunogens that will elicit HCV-specific bNAbs in animal
models. To accomplish this goal, E2 protein or virus-like particle-based immunogens will be tested in wild-type
mice and non-human primates. Next, the structures of HCV-specific antibodies induced by immunization will be
determined. For this, we will sort and sequence epitope-specific B cells from vaccinated animals and express
antibodies from these sequences. Then, we will determine the structures of HCV-specific bNAbs alone or in
complex with immunogens to elucidate the determinants of broad neutralization of HCV by vaccine-induced
antibodies. The detailed analysis of the elicited antibody response will facilitate the optimization of immunogens
by enhancing their specificity and selectivity. Together, the results of these aims will lead to the identification and
characterization of novel vaccine candidates that elicit HCV-specific bNAbs, facilitating the development of an
effective HCV vaccine.
The mentoring phase of this proposal will take place in Dr. Pamela Bjorkman's laboratory at Caltech. Since there
are several critical areas of the proposed project that require additional training, Dr. Andrew Flyak has assembled
a mentorship committee comprising experts in structural biology (Dr. Pamela Bjorkman), B cell immunology (Dr.
Michel Nussenzweig), and HCV biology (Dr. Justin Bailey). By using an interdisciplinary approach developed
throughout this project and support from the mentoring committee, Dr. Flyak will begin the independent phase
of this award, answering fundamental questions that hinder the development of effective vaccines against HCV,
or other rapidly mutating viruses.
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项目总结
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
SARS-CoV-2 B cell receptor signatures in at-risk populations.
高危人群中的 SARS-CoV-2 B 细胞受体特征。
- DOI:10.1172/jci144685
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Flyak,AndrewI
- 通讯作者:Flyak,AndrewI
Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations.
- DOI:10.1016/j.immuni.2021.07.008
- 发表时间:2021-08-10
- 期刊:
- 影响因子:32.4
- 作者:Muecksch F;Weisblum Y;Barnes CO;Schmidt F;Schaefer-Babajew D;Wang Z;C Lorenzi JC;Flyak AI;DeLaitsch AT;Huey-Tubman KE;Hou S;Schiffer CA;Gaebler C;Da Silva J;Poston D;Finkin S;Cho A;Cipolla M;Oliveira TY;Millard KG;Ramos V;Gazumyan A;Rutkowska M;Caskey M;Nussenzweig MC;Bjorkman PJ;Hatziioannou T;Bieniasz PD
- 通讯作者:Bieniasz PD
Mechanisms of HCV resistance to broadly neutralizing antibodies.
- DOI:10.1016/j.coviro.2021.07.003
- 发表时间:2021-10
- 期刊:
- 影响因子:5.9
- 作者:Frumento N;Flyak AI;Bailey JR
- 通讯作者:Bailey JR
Computational identification of HCV neutralizing antibodies with a common HCDR3 disulfide bond motif in the antibody repertoires of infected individuals.
- DOI:10.1038/s41467-022-30865-9
- 发表时间:2022-06-08
- 期刊:
- 影响因子:16.6
- 作者:
- 通讯作者:
Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization.
- DOI:10.1016/j.immuni.2021.12.003
- 发表时间:2022-02-08
- 期刊:
- 影响因子:32.4
- 作者:Weber, Timm;Potthoff, Julian;Bizu, Sven;Labuhn, Maurice;Dold, Leona;Schoofs, Till;Horning, Marcel;Ercanoglu, Meryem S.;Kreer, Christoph;Gieselmann, Lutz;Vanshylla, Kanika;Langhans, Bettina;Janicki, Hanna;Stroeh, Luisa J.;Knops, Elena;Nierhoff, Dirk;Spengler, Ulrich;Kaiser, Rolf;Bjorkman, Pamela J.;Krey, Thomas;Bankwitz, Dorothea;Pfeifer, Nico;Pietschmann, Thomas;Flyak, Andrew, I;Klein, Florian
- 通讯作者:Klein, Florian
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Andrew I Flyak其他文献
Andrew I Flyak的其他文献
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{{ truncateString('Andrew I Flyak', 18)}}的其他基金
Immunization strategies to elicit broadly neutralizing antibodies against HCV
引发针对 HCV 的广泛中和抗体的免疫策略
- 批准号:
10654093 - 财政年份:2020
- 资助金额:
$ 12.95万 - 项目类别:
Immunization strategies to elicit broadly neutralizing antibodies against HCV
引发针对 HCV 的广泛中和抗体的免疫策略
- 批准号:
10681384 - 财政年份:2020
- 资助金额:
$ 12.95万 - 项目类别:
Immunization strategies to elicit broadly neutralizing antibodies against HCV
引发针对 HCV 的广泛中和抗体的免疫策略
- 批准号:
10039038 - 财政年份:2020
- 资助金额:
$ 12.95万 - 项目类别:
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