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Title: Ebolavirus Glycoprotein Fc Fusion Protein Protects Guinea Pigs against Lethal Challenge

Abstract

Ebola virus (EBOV), a member of the Filoviridae that can cause severe hemorrhagic fever in humans and nonhuman primates, poses a significant threat to the public health. Currently, there are no licensed vaccines or therapeutics to prevent and treat EBOV infection. Several vaccines based on the EBOV glycoprotein (GP) are under development, including vectored, virus-like particles, and protein-based subunit vaccines. We previously demonstrated that a subunit vaccine containing the extracellular domain of the Ebola ebolavirus (EBOV) GP fused to the Fc fragment of human IgG1 (EBOVgp-Fc) protected mice against EBOV lethal challenge. Here, we show that the EBOVgp-Fc vaccine formulated with QS-21, alum, or polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose (poly-ICLC) adjuvants induced strong humoral immune responses in guinea pigs. The vaccinated animals developed anti-GP total antibody titers of approximately 105–106 and neutralizing antibody titers of approximately 103 as assessed by a BSL-2 neutralization assay based on vesicular stomatitis virus (VSV) pseudotypes. The poly-ICLC formulated EBOVgp-Fc vaccine protected all the guinea pigs against EBOV lethal challenge performed under BSL-4 conditions whereas the same vaccine formulated with QS-21 or alum only induced partial protection. Vaccination with a mucin-deletedEBOVgp-Fc construct formulated with QS-21 adjuvant did not have a significant effect in anti-GP antibody levels andmore » protection against EBOV lethal challenge compared to the full-lengthGP construct. The bulk of the humoral response induced by the EBOVgp-Fc vaccine was directed against epitopes outside the EBOV mucin region. Our findings indicate that different adjuvants can eliciting varying levels of protection against lethal EBOV challenge in guinea pigs vaccinated with EBOVgp-Fc,and suggest that levels of total anti-GP antibodies elicit by protein-based GP subunit vaccines do not correlate with protection. In conclusion, our data further support the development of Fc fusions of GP as a candidate vaccine for human use.« less

Authors:
 [1];  [2];  [3];  [1];  [2];  [1];  [4]
  1. Food and Drug Administration, Silver Spring, MD (United States)
  2. United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD (United States)
  3. United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD (United States); Univ. of New Mexico, Albuquerque, NM (United States)
  4. Rockefeller Univ., New York, NY (United States)
Publication Date:
Research Org.:
Food and Drug Administration, Silver Spring, MD (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1377872
Grant/Contract Number:  
Y1-AI-0664-01; Intramural; DTRA IAA 11005IA-3333-Basic
Resource Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 11; Journal Issue: 9; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; vaccines; guinea pigs; antibodies; immunologic adjuvants; enzyme-linked immunoassays; alumni; vesicular stomatitis virus; immune response

Citation Formats

Konduru, Krishnamurthy, Shurtleff, Amy C., Bradfute, Steven B., Nakamura, Siham, Bavari, Sina, Kaplan, Gerardo, and Tsuji, Moriya. Ebolavirus Glycoprotein Fc Fusion Protein Protects Guinea Pigs against Lethal Challenge. United States: N. p., 2016. Web. https://doi.org/10.1371/journal.pone.0162446.
Konduru, Krishnamurthy, Shurtleff, Amy C., Bradfute, Steven B., Nakamura, Siham, Bavari, Sina, Kaplan, Gerardo, & Tsuji, Moriya. Ebolavirus Glycoprotein Fc Fusion Protein Protects Guinea Pigs against Lethal Challenge. United States. https://doi.org/10.1371/journal.pone.0162446
Konduru, Krishnamurthy, Shurtleff, Amy C., Bradfute, Steven B., Nakamura, Siham, Bavari, Sina, Kaplan, Gerardo, and Tsuji, Moriya. Tue . "Ebolavirus Glycoprotein Fc Fusion Protein Protects Guinea Pigs against Lethal Challenge". United States. https://doi.org/10.1371/journal.pone.0162446. https://www.osti.gov/servlets/purl/1377872.
@article{osti_1377872,
title = {Ebolavirus Glycoprotein Fc Fusion Protein Protects Guinea Pigs against Lethal Challenge},
author = {Konduru, Krishnamurthy and Shurtleff, Amy C. and Bradfute, Steven B. and Nakamura, Siham and Bavari, Sina and Kaplan, Gerardo and Tsuji, Moriya},
abstractNote = {Ebola virus (EBOV), a member of the Filoviridae that can cause severe hemorrhagic fever in humans and nonhuman primates, poses a significant threat to the public health. Currently, there are no licensed vaccines or therapeutics to prevent and treat EBOV infection. Several vaccines based on the EBOV glycoprotein (GP) are under development, including vectored, virus-like particles, and protein-based subunit vaccines. We previously demonstrated that a subunit vaccine containing the extracellular domain of the Ebola ebolavirus (EBOV) GP fused to the Fc fragment of human IgG1 (EBOVgp-Fc) protected mice against EBOV lethal challenge. Here, we show that the EBOVgp-Fc vaccine formulated with QS-21, alum, or polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose (poly-ICLC) adjuvants induced strong humoral immune responses in guinea pigs. The vaccinated animals developed anti-GP total antibody titers of approximately 105–106 and neutralizing antibody titers of approximately 103 as assessed by a BSL-2 neutralization assay based on vesicular stomatitis virus (VSV) pseudotypes. The poly-ICLC formulated EBOVgp-Fc vaccine protected all the guinea pigs against EBOV lethal challenge performed under BSL-4 conditions whereas the same vaccine formulated with QS-21 or alum only induced partial protection. Vaccination with a mucin-deletedEBOVgp-Fc construct formulated with QS-21 adjuvant did not have a significant effect in anti-GP antibody levels and protection against EBOV lethal challenge compared to the full-lengthGP construct. The bulk of the humoral response induced by the EBOVgp-Fc vaccine was directed against epitopes outside the EBOV mucin region. Our findings indicate that different adjuvants can eliciting varying levels of protection against lethal EBOV challenge in guinea pigs vaccinated with EBOVgp-Fc,and suggest that levels of total anti-GP antibodies elicit by protein-based GP subunit vaccines do not correlate with protection. In conclusion, our data further support the development of Fc fusions of GP as a candidate vaccine for human use.},
doi = {10.1371/journal.pone.0162446},
journal = {PLoS ONE},
number = 9,
volume = 11,
place = {United States},
year = {2016},
month = {9}
}

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