Immunization with DNA plasmids coding for crimean-congo hemorrhagic fever virus capsid and envelope proteins and/or virus-like particles induces protection and survival in challenged mice

Jorma Hinkula; Stéphanie Devignot; Sara Åkerström; Helen Karlberg; Eva Wattrang; Sándor Bereczky; Mehrdad Mousavi-Jazi; Christian Walter Risinger; Gunnel Lindegren; Caroline Vernersson; Janusz Paweska; Petrus Jansen van Vuren; Klas Ola Blixt; Alejandro Brun; Weber Friedemann; Ali Mirazimi

doi:10.1128/JVI.02076-16

Immunization with DNA plasmids coding for crimean-congo hemorrhagic fever virus capsid and envelope proteins and/or virus-like particles induces protection and survival in challenged mice

Jorma Hinkula, Stéphanie Devignot, Sara Åkerström, Helen Karlberg, Eva Wattrang, Sándor Bereczky, Mehrdad Mousavi-Jazi, Christian Walter Risinger, Gunnel Lindegren, Caroline Vernersson, Janusz Paweska, Petrus Jansen van Vuren, Klas Ola Blixt, Alejandro Brun, Weber Friedemann, Ali Mirazimi^*

^*Corresponding author af dette arbejde

Kemisk Institut

32 Citationer (Scopus)

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Abstract

Crimean-Congo hemorrhagic fever virus (CCHFV) is a bunyavirus causing severe hemorrhagic fever disease in humans, with high mortality rates. The requirement of a high-containment laboratory and the lack of an animal model hampered the study of the immune response and protection of vaccine candidates. Using the recently developed interferon alpha receptor knockout (IFNAR^-/-) mouse model, which replicates human disease, we investigated the immunogenicity and protection of two novel CCHFV vaccine candidates: a DNA vaccine encoding a ubiquitin-linked version of CCHFV Gc, Gn, and N and one using transcriptionally competent virus-like particles (tc-VLPs). In contrast to most studies that focus on neutralizing antibodies, we measured both humoral and cellular immune responses. We demonstrated a clear and 100% efficient preventive immunity against lethal CCHFV challenge with the DNA vaccine. Interestingly, there was no correlation with the neutralizing antibody titers alone, which were higher in the tc-VLP-vaccinated mice. However, the animals with a lower neutralizing titer, but a dominant cell-mediated Th1 response and a balanced Th2 response, resisted the CCHFV challenge. Moreover, we found that in challenged mice with a Th1 response (immunized by DNA/DNA and boosted by tc-VLPs), the immune response changed to Th2 at day 9 postchallenge. In addition, we were able to identify new linear B-cell epitope regions that are highly conserved between CCHFV strains. Altogether, our results suggest that a predominantly Th1-type immune response provides the most efficient protective immunity against CCHFV challenge. However, we cannot exclude the importance of the neutralizing antibodies as the surviving immunized mice exhibited substantial amounts of them.

Originalsprog	Engelsk
Artikelnummer	e02076-16
Tidsskrift	Journal of Virology
Vol/bind	91
Udgave nummer	10
Antal sider	19
ISSN	0022-538X
DOI	https://doi.org/10.1128/JVI.02076-16
Status	Udgivet - 2017

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10.1128/JVI.02076-16Licens: CC BY

Immunization with DNA PlasmidsForlagets udgivne version, 2,48 MBLicens: CC BY

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Hinkula, J., Devignot, S., Åkerström, S., Karlberg, H., Wattrang, E., Bereczky, S., Mousavi-Jazi, M., Risinger, C. W., Lindegren, G., Vernersson, C., Paweska, J., van Vuren, P. J., Blixt, K. O., Brun, A., Friedemann, W., & Mirazimi, A. (2017). Immunization with DNA plasmids coding for crimean-congo hemorrhagic fever virus capsid and envelope proteins and/or virus-like particles induces protection and survival in challenged mice. Journal of Virology, 91(10), [e02076-16]. https://doi.org/10.1128/JVI.02076-16

Immunization with DNA plasmids coding for crimean-congo hemorrhagic fever virus capsid and envelope proteins and/or virus-like particles induces protection and survival in challenged mice. / Hinkula, Jorma; Devignot, Stéphanie; Åkerström, Sara et al.

I: Journal of Virology, Bind 91, Nr. 10, e02076-16, 2017.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Hinkula, J, Devignot, S, Åkerström, S, Karlberg, H, Wattrang, E, Bereczky, S, Mousavi-Jazi, M, Risinger, CW, Lindegren, G, Vernersson, C, Paweska, J, van Vuren, PJ, Blixt, KO, Brun, A, Friedemann, W & Mirazimi, A 2017, 'Immunization with DNA plasmids coding for crimean-congo hemorrhagic fever virus capsid and envelope proteins and/or virus-like particles induces protection and survival in challenged mice', Journal of Virology, bind 91, nr. 10, e02076-16. https://doi.org/10.1128/JVI.02076-16

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title = "Immunization with DNA plasmids coding for crimean-congo hemorrhagic fever virus capsid and envelope proteins and/or virus-like particles induces protection and survival in challenged mice",

abstract = "Crimean-Congo hemorrhagic fever virus (CCHFV) is a bunyavirus causing severe hemorrhagic fever disease in humans, with high mortality rates. The requirement of a high-containment laboratory and the lack of an animal model hampered the study of the immune response and protection of vaccine candidates. Using the recently developed interferon alpha receptor knockout (IFNAR-/-) mouse model, which replicates human disease, we investigated the immunogenicity and protection of two novel CCHFV vaccine candidates: a DNA vaccine encoding a ubiquitin-linked version of CCHFV Gc, Gn, and N and one using transcriptionally competent virus-like particles (tc-VLPs). In contrast to most studies that focus on neutralizing antibodies, we measured both humoral and cellular immune responses. We demonstrated a clear and 100% efficient preventive immunity against lethal CCHFV challenge with the DNA vaccine. Interestingly, there was no correlation with the neutralizing antibody titers alone, which were higher in the tc-VLP-vaccinated mice. However, the animals with a lower neutralizing titer, but a dominant cell-mediated Th1 response and a balanced Th2 response, resisted the CCHFV challenge. Moreover, we found that in challenged mice with a Th1 response (immunized by DNA/DNA and boosted by tc-VLPs), the immune response changed to Th2 at day 9 postchallenge. In addition, we were able to identify new linear B-cell epitope regions that are highly conserved between CCHFV strains. Altogether, our results suggest that a predominantly Th1-type immune response provides the most efficient protective immunity against CCHFV challenge. However, we cannot exclude the importance of the neutralizing antibodies as the surviving immunized mice exhibited substantial amounts of them.",

keywords = "Crimean-Congo hemorrhagic fever virus, DNA vaccines, Neutralizing antibodies, Th1/Th2 responses, VLP",

author = "Jorma Hinkula and St{\'e}phanie Devignot and Sara {\AA}kerstr{\"o}m and Helen Karlberg and Eva Wattrang and S{\'a}ndor Bereczky and Mehrdad Mousavi-Jazi and Risinger, {Christian Walter} and Gunnel Lindegren and Caroline Vernersson and Janusz Paweska and {van Vuren}, {Petrus Jansen} and Blixt, {Klas Ola} and Alejandro Brun and Weber Friedemann and Ali Mirazimi",

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doi = "10.1128/JVI.02076-16",

language = "English",

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T1 - Immunization with DNA plasmids coding for crimean-congo hemorrhagic fever virus capsid and envelope proteins and/or virus-like particles induces protection and survival in challenged mice

AU - Hinkula, Jorma

AU - Devignot, Stéphanie

AU - Åkerström, Sara

AU - Karlberg, Helen

AU - Wattrang, Eva

AU - Bereczky, Sándor

AU - Mousavi-Jazi, Mehrdad

AU - Risinger, Christian Walter

AU - Lindegren, Gunnel

AU - Vernersson, Caroline

AU - Paweska, Janusz

AU - van Vuren, Petrus Jansen

AU - Blixt, Klas Ola

AU - Brun, Alejandro

AU - Friedemann, Weber

AU - Mirazimi, Ali

PY - 2017

Y1 - 2017

N2 - Crimean-Congo hemorrhagic fever virus (CCHFV) is a bunyavirus causing severe hemorrhagic fever disease in humans, with high mortality rates. The requirement of a high-containment laboratory and the lack of an animal model hampered the study of the immune response and protection of vaccine candidates. Using the recently developed interferon alpha receptor knockout (IFNAR-/-) mouse model, which replicates human disease, we investigated the immunogenicity and protection of two novel CCHFV vaccine candidates: a DNA vaccine encoding a ubiquitin-linked version of CCHFV Gc, Gn, and N and one using transcriptionally competent virus-like particles (tc-VLPs). In contrast to most studies that focus on neutralizing antibodies, we measured both humoral and cellular immune responses. We demonstrated a clear and 100% efficient preventive immunity against lethal CCHFV challenge with the DNA vaccine. Interestingly, there was no correlation with the neutralizing antibody titers alone, which were higher in the tc-VLP-vaccinated mice. However, the animals with a lower neutralizing titer, but a dominant cell-mediated Th1 response and a balanced Th2 response, resisted the CCHFV challenge. Moreover, we found that in challenged mice with a Th1 response (immunized by DNA/DNA and boosted by tc-VLPs), the immune response changed to Th2 at day 9 postchallenge. In addition, we were able to identify new linear B-cell epitope regions that are highly conserved between CCHFV strains. Altogether, our results suggest that a predominantly Th1-type immune response provides the most efficient protective immunity against CCHFV challenge. However, we cannot exclude the importance of the neutralizing antibodies as the surviving immunized mice exhibited substantial amounts of them.

AB - Crimean-Congo hemorrhagic fever virus (CCHFV) is a bunyavirus causing severe hemorrhagic fever disease in humans, with high mortality rates. The requirement of a high-containment laboratory and the lack of an animal model hampered the study of the immune response and protection of vaccine candidates. Using the recently developed interferon alpha receptor knockout (IFNAR-/-) mouse model, which replicates human disease, we investigated the immunogenicity and protection of two novel CCHFV vaccine candidates: a DNA vaccine encoding a ubiquitin-linked version of CCHFV Gc, Gn, and N and one using transcriptionally competent virus-like particles (tc-VLPs). In contrast to most studies that focus on neutralizing antibodies, we measured both humoral and cellular immune responses. We demonstrated a clear and 100% efficient preventive immunity against lethal CCHFV challenge with the DNA vaccine. Interestingly, there was no correlation with the neutralizing antibody titers alone, which were higher in the tc-VLP-vaccinated mice. However, the animals with a lower neutralizing titer, but a dominant cell-mediated Th1 response and a balanced Th2 response, resisted the CCHFV challenge. Moreover, we found that in challenged mice with a Th1 response (immunized by DNA/DNA and boosted by tc-VLPs), the immune response changed to Th2 at day 9 postchallenge. In addition, we were able to identify new linear B-cell epitope regions that are highly conserved between CCHFV strains. Altogether, our results suggest that a predominantly Th1-type immune response provides the most efficient protective immunity against CCHFV challenge. However, we cannot exclude the importance of the neutralizing antibodies as the surviving immunized mice exhibited substantial amounts of them.

KW - Crimean-Congo hemorrhagic fever virus

KW - DNA vaccines

KW - Neutralizing antibodies

KW - Th1/Th2 responses

KW - VLP

U2 - 10.1128/JVI.02076-16

DO - 10.1128/JVI.02076-16

M3 - Journal article

C2 - 28250124

AN - SCOPUS:85018269924

SN - 0022-538X

VL - 91

JO - Journal of Virology

JF - Journal of Virology

IS - 10

M1 - e02076-16

ER -

Immunization with DNA plasmids coding for crimean-congo hemorrhagic fever virus capsid and envelope proteins and/or virus-like particles induces protection and survival in challenged mice

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