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

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. !
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。
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
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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