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Epitope-focused immunogen design based on the ebolavirus glycoprotein HR2-MPER region.
Schoeder, Clara T; Gilchuk, Pavlo; Sangha, Amandeep K; Ledwitch, Kaitlyn V; Malherbe, Delphine C; Zhang, Xuan; Binshtein, Elad; Williamson, Lauren E; Martina, Cristina E; Dong, Jinhui; Armstrong, Erica; Sutton, Rachel; Nargi, Rachel; Rodriguez, Jessica; Kuzmina, Natalia; Fiala, Brooke; King, Neil P; Bukreyev, Alexander; Crowe, James E; Meiler, Jens.
  • Schoeder CT; Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America.
  • Gilchuk P; Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
  • Sangha AK; Institute for Drug Discovery, University Leipzig Medical School, Leipzig, Germany.
  • Ledwitch KV; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Tennessee, United States of America.
  • Malherbe DC; Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America.
  • Zhang X; Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
  • Binshtein E; Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America.
  • Williamson LE; Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
  • Martina CE; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
  • Dong J; Galveston National Laboratory, Galveston, Texas, United States of America.
  • Armstrong E; Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America.
  • Sutton R; Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
  • Nargi R; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Tennessee, United States of America.
  • Rodriguez J; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Tennessee, United States of America.
  • Kuzmina N; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
  • Fiala B; Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America.
  • King NP; Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
  • Bukreyev A; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Tennessee, United States of America.
  • Crowe JE; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Tennessee, United States of America.
  • Meiler J; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Tennessee, United States of America.
PLoS Pathog ; 18(5): e1010518, 2022 05.
Article in English | MEDLINE | ID: covidwho-1902647
ABSTRACT
The three human pathogenic ebolaviruses Zaire (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) virus, cause severe disease with high fatality rates. Epitopes of ebolavirus glycoprotein (GP) recognized by antibodies with binding breadth for all three ebolaviruses are of major interest for rational vaccine design. In particular, the heptad repeat 2 -membrane-proximal external region (HR2-MPER) epitope is relatively conserved between EBOV, BDBV, and SUDV GP and targeted by human broadly-neutralizing antibodies. To study whether this epitope can serve as an immunogen for the elicitation of broadly-reactive antibody responses, protein design in Rosetta was employed to transplant the HR2-MPER epitope identified from a co-crystal structure with the known broadly-reactive monoclonal antibody (mAb) BDBV223 onto smaller scaffold proteins. From computational analysis, selected immunogen designs were produced as recombinant proteins and functionally validated, leading to the identification of a sterile alpha motif (SAM) domain displaying the BDBV-HR2-MPER epitope near its C terminus as a promising candidate. The immunogen was fused to one component of a self-assembling, two-component nanoparticle and tested for immunogenicity in rabbits. Robust titers of cross-reactive serum antibodies to BDBV and EBOV GPs and moderate titers to SUDV GP were induced following immunization. To confirm the structural composition of the immunogens, solution NMR studies were conducted and revealed structural flexibility in the C-terminal residues of the epitope. Overall, our study represents the first report on an epitope-focused immunogen design based on the structurally challenging BDBV-HR2-MPER epitope.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Hemorrhagic Fever, Ebola / Ebolavirus Type of study: Prognostic study / Randomized controlled trials Topics: Vaccines Limits: Animals Language: English Journal: PLoS Pathog Year: 2022 Document Type: Article Affiliation country: Journal.ppat.1010518

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Hemorrhagic Fever, Ebola / Ebolavirus Type of study: Prognostic study / Randomized controlled trials Topics: Vaccines Limits: Animals Language: English Journal: PLoS Pathog Year: 2022 Document Type: Article Affiliation country: Journal.ppat.1010518