Antibody-mediated protective mechanisms induced by a trivalent parainfluenza virus-vectored ebolavirus vaccine

J. Brian Kimble, Delphine Malherbe, Michelle Meyer, Bronwyn M. Gunn, Marcus M. Karim, Philipp A. Ilinykh, Mathieu Iampietro, Khaled S. Mohamed, Surendra Negi, Pavlo Gilchuk, Kai Huang, Yuri I. Wolf, Werner Braun, James E. Crowe, Galit Alter, Alexander Bukreyev

Research output: Contribution to journalArticle

Abstract

Ebolaviruses Zaire (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) cause human disease with high case fatality rates. Experimental monovalent vaccines, which all utilize the sole envelope glycoprotein (GP), do not protect against heterologous ebolaviruses. Human parainfluenza virus type 3-vectored vaccines offer benefits, including needle-free administration and induction of mucosal responses in the respiratory tract. Multiple approaches were taken to induce broad protection against the three ebolaviruses. While GP consensus-based antigens failed to elicit neutralizing antibodies, polyvalent vaccine immunization induced neutralizing responses to all three ebolaviruses and protected animals from death and disease caused by EBOV, SUDV, and BDBV. As immunization with a cocktail of antigenically related antigens can skew the responses and change the epitope hierarchy, we performed comparative analysis of antibody repertoire and Fc-mediated protective mechanisms in animals immunized with monovalent versus polyvalent vaccines. Compared to sera from Guinea pigs receiving the monovalent vaccines, sera from Guinea pigs receiving the trivalent vaccine bound and neutralized EBOV and SUDV at equivalent levels and BDBV at only a slightly reduced level. Peptide microarrays revealed a preponderance of binding to amino acids 389 to 403, 397 to 415, and 477 to 493, representing three linear epitopes in the mucin-like domain known to induce a protective antibody response. Competition binding assays with monoclonal antibodies isolated from human ebolavirus infection survivors demonstrated that the immune sera block the binding of antibodies specific for the GP glycan cap, the GP1-GP2 interface, the mucin-like domain, and the membrane-proximal external region. Thus, administration of a cocktail of three ebolavirus vaccines induces a desirable broad antibody response, without skewing of the response toward preferential recognition of a single virus.

Original languageEnglish (US)
Article numbere0184518
JournalJournal of virology
Volume93
Issue number4
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

Fingerprint

Ebolavirus
Paramyxoviridae Infections
Vaccines
Zaire Ebola virus
vaccines
Viruses
viruses
antibodies
Antibodies
Democratic Republic of the Congo
Human parainfluenza virus 3
glycoproteins
mucins
Glycoproteins
blood serum
guinea pigs
Mucins
epitopes
immunization
Antibody Formation

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Brian Kimble, J., Malherbe, D., Meyer, M., Gunn, B. M., Karim, M. M., Ilinykh, P. A., ... Bukreyev, A. (2019). Antibody-mediated protective mechanisms induced by a trivalent parainfluenza virus-vectored ebolavirus vaccine. Journal of virology, 93(4), [e0184518]. https://doi.org/10.1128/JVI.01845-18

Antibody-mediated protective mechanisms induced by a trivalent parainfluenza virus-vectored ebolavirus vaccine. / Brian Kimble, J.; Malherbe, Delphine; Meyer, Michelle; Gunn, Bronwyn M.; Karim, Marcus M.; Ilinykh, Philipp A.; Iampietro, Mathieu; Mohamed, Khaled S.; Negi, Surendra; Gilchuk, Pavlo; Huang, Kai; Wolf, Yuri I.; Braun, Werner; Crowe, James E.; Alter, Galit; Bukreyev, Alexander.

In: Journal of virology, Vol. 93, No. 4, e0184518, 01.02.2019.

Research output: Contribution to journalArticle

Brian Kimble, J, Malherbe, D, Meyer, M, Gunn, BM, Karim, MM, Ilinykh, PA, Iampietro, M, Mohamed, KS, Negi, S, Gilchuk, P, Huang, K, Wolf, YI, Braun, W, Crowe, JE, Alter, G & Bukreyev, A 2019, 'Antibody-mediated protective mechanisms induced by a trivalent parainfluenza virus-vectored ebolavirus vaccine', Journal of virology, vol. 93, no. 4, e0184518. https://doi.org/10.1128/JVI.01845-18
Brian Kimble, J. ; Malherbe, Delphine ; Meyer, Michelle ; Gunn, Bronwyn M. ; Karim, Marcus M. ; Ilinykh, Philipp A. ; Iampietro, Mathieu ; Mohamed, Khaled S. ; Negi, Surendra ; Gilchuk, Pavlo ; Huang, Kai ; Wolf, Yuri I. ; Braun, Werner ; Crowe, James E. ; Alter, Galit ; Bukreyev, Alexander. / Antibody-mediated protective mechanisms induced by a trivalent parainfluenza virus-vectored ebolavirus vaccine. In: Journal of virology. 2019 ; Vol. 93, No. 4.
@article{8eab07f8dd5a4e1ebf23eadb06a5956d,
title = "Antibody-mediated protective mechanisms induced by a trivalent parainfluenza virus-vectored ebolavirus vaccine",
abstract = "Ebolaviruses Zaire (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) cause human disease with high case fatality rates. Experimental monovalent vaccines, which all utilize the sole envelope glycoprotein (GP), do not protect against heterologous ebolaviruses. Human parainfluenza virus type 3-vectored vaccines offer benefits, including needle-free administration and induction of mucosal responses in the respiratory tract. Multiple approaches were taken to induce broad protection against the three ebolaviruses. While GP consensus-based antigens failed to elicit neutralizing antibodies, polyvalent vaccine immunization induced neutralizing responses to all three ebolaviruses and protected animals from death and disease caused by EBOV, SUDV, and BDBV. As immunization with a cocktail of antigenically related antigens can skew the responses and change the epitope hierarchy, we performed comparative analysis of antibody repertoire and Fc-mediated protective mechanisms in animals immunized with monovalent versus polyvalent vaccines. Compared to sera from Guinea pigs receiving the monovalent vaccines, sera from Guinea pigs receiving the trivalent vaccine bound and neutralized EBOV and SUDV at equivalent levels and BDBV at only a slightly reduced level. Peptide microarrays revealed a preponderance of binding to amino acids 389 to 403, 397 to 415, and 477 to 493, representing three linear epitopes in the mucin-like domain known to induce a protective antibody response. Competition binding assays with monoclonal antibodies isolated from human ebolavirus infection survivors demonstrated that the immune sera block the binding of antibodies specific for the GP glycan cap, the GP1-GP2 interface, the mucin-like domain, and the membrane-proximal external region. Thus, administration of a cocktail of three ebolavirus vaccines induces a desirable broad antibody response, without skewing of the response toward preferential recognition of a single virus.",
author = "{Brian Kimble}, J. and Delphine Malherbe and Michelle Meyer and Gunn, {Bronwyn M.} and Karim, {Marcus M.} and Ilinykh, {Philipp A.} and Mathieu Iampietro and Mohamed, {Khaled S.} and Surendra Negi and Pavlo Gilchuk and Kai Huang and Wolf, {Yuri I.} and Werner Braun and Crowe, {James E.} and Galit Alter and Alexander Bukreyev",
year = "2019",
month = "2",
day = "1",
doi = "10.1128/JVI.01845-18",
language = "English (US)",
volume = "93",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "4",

}

TY - JOUR

T1 - Antibody-mediated protective mechanisms induced by a trivalent parainfluenza virus-vectored ebolavirus vaccine

AU - Brian Kimble, J.

AU - Malherbe, Delphine

AU - Meyer, Michelle

AU - Gunn, Bronwyn M.

AU - Karim, Marcus M.

AU - Ilinykh, Philipp A.

AU - Iampietro, Mathieu

AU - Mohamed, Khaled S.

AU - Negi, Surendra

AU - Gilchuk, Pavlo

AU - Huang, Kai

AU - Wolf, Yuri I.

AU - Braun, Werner

AU - Crowe, James E.

AU - Alter, Galit

AU - Bukreyev, Alexander

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Ebolaviruses Zaire (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) cause human disease with high case fatality rates. Experimental monovalent vaccines, which all utilize the sole envelope glycoprotein (GP), do not protect against heterologous ebolaviruses. Human parainfluenza virus type 3-vectored vaccines offer benefits, including needle-free administration and induction of mucosal responses in the respiratory tract. Multiple approaches were taken to induce broad protection against the three ebolaviruses. While GP consensus-based antigens failed to elicit neutralizing antibodies, polyvalent vaccine immunization induced neutralizing responses to all three ebolaviruses and protected animals from death and disease caused by EBOV, SUDV, and BDBV. As immunization with a cocktail of antigenically related antigens can skew the responses and change the epitope hierarchy, we performed comparative analysis of antibody repertoire and Fc-mediated protective mechanisms in animals immunized with monovalent versus polyvalent vaccines. Compared to sera from Guinea pigs receiving the monovalent vaccines, sera from Guinea pigs receiving the trivalent vaccine bound and neutralized EBOV and SUDV at equivalent levels and BDBV at only a slightly reduced level. Peptide microarrays revealed a preponderance of binding to amino acids 389 to 403, 397 to 415, and 477 to 493, representing three linear epitopes in the mucin-like domain known to induce a protective antibody response. Competition binding assays with monoclonal antibodies isolated from human ebolavirus infection survivors demonstrated that the immune sera block the binding of antibodies specific for the GP glycan cap, the GP1-GP2 interface, the mucin-like domain, and the membrane-proximal external region. Thus, administration of a cocktail of three ebolavirus vaccines induces a desirable broad antibody response, without skewing of the response toward preferential recognition of a single virus.

AB - Ebolaviruses Zaire (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) cause human disease with high case fatality rates. Experimental monovalent vaccines, which all utilize the sole envelope glycoprotein (GP), do not protect against heterologous ebolaviruses. Human parainfluenza virus type 3-vectored vaccines offer benefits, including needle-free administration and induction of mucosal responses in the respiratory tract. Multiple approaches were taken to induce broad protection against the three ebolaviruses. While GP consensus-based antigens failed to elicit neutralizing antibodies, polyvalent vaccine immunization induced neutralizing responses to all three ebolaviruses and protected animals from death and disease caused by EBOV, SUDV, and BDBV. As immunization with a cocktail of antigenically related antigens can skew the responses and change the epitope hierarchy, we performed comparative analysis of antibody repertoire and Fc-mediated protective mechanisms in animals immunized with monovalent versus polyvalent vaccines. Compared to sera from Guinea pigs receiving the monovalent vaccines, sera from Guinea pigs receiving the trivalent vaccine bound and neutralized EBOV and SUDV at equivalent levels and BDBV at only a slightly reduced level. Peptide microarrays revealed a preponderance of binding to amino acids 389 to 403, 397 to 415, and 477 to 493, representing three linear epitopes in the mucin-like domain known to induce a protective antibody response. Competition binding assays with monoclonal antibodies isolated from human ebolavirus infection survivors demonstrated that the immune sera block the binding of antibodies specific for the GP glycan cap, the GP1-GP2 interface, the mucin-like domain, and the membrane-proximal external region. Thus, administration of a cocktail of three ebolavirus vaccines induces a desirable broad antibody response, without skewing of the response toward preferential recognition of a single virus.

UR - http://www.scopus.com/inward/record.url?scp=85061121005&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061121005&partnerID=8YFLogxK

U2 - 10.1128/JVI.01845-18

DO - 10.1128/JVI.01845-18

M3 - Article

VL - 93

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 4

M1 - e0184518

ER -