scholarly journals Crimean-Congo Hemorrhagic Fever Virus Subunit Vaccines Induce High Levels of Neutralizing Antibodies But No Protection in STAT1 Knockout Mice

2015 ◽  
Vol 15 (12) ◽  
pp. 759-764 ◽  
Author(s):  
Jeroen Kortekaas ◽  
Rianka P.M. Vloet ◽  
Alexander J. McAuley ◽  
Xiaoli Shen ◽  
Berend Jan Bosch ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Neutralizing Antibodies ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Subunit Vaccines ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus

scholarly journals 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

2017 ◽  
Vol 91 (10) ◽  
Author(s):  
Jorma Hinkula ◽  
Stéphanie Devignot ◽  
Sara Åkerström ◽  
Helen Karlberg ◽  
Eva Wattrang ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Dna Vaccine ◽  
Neutralizing Antibodies ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Vaccine Candidates ◽  
Th1 Response ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus

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. IMPORTANCE Crimean-Congo hemorrhagic fever virus (CCHFV) is responsible for hemorrhagic diseases in humans, with a high mortality rate. There is no FDA-approved vaccine, and there are still gaps in our knowledge of the immune responses to infection. The recently developed mouse models mimic human CCHF disease and are useful to study the immunogenicity and the protection by vaccine candidates. Our study shows that mice vaccinated with a specific DNA vaccine were fully protected. Importantly, we show that neutralizing antibodies are not sufficient for protection against CCHFV challenge but that an extra Th1-specific cellular response is required. Moreover, we describe the identification of five conserved B-cell epitopes, of which only one was previously known, that could be of great importance for the development of diagnostics tools and the improvement of vaccine candidates.

scholarly journals GP38-targeting monoclonal antibodies protect adult mice against lethal Crimean-Congo hemorrhagic fever virus infection

2019 ◽  
Vol 5 (7) ◽  
pp. eaaw9535 ◽  
Author(s):  
Joseph W. Golden ◽  
Charles J. Shoemaker ◽  
Michael E. Lindquist ◽  
Xiankun Zeng ◽  
Sharon P. Daye ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Type I ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus ◽  
Adult Mice ◽  
Virus Exposure

Crimean-Congo hemorrhagic fever virus (CCHFV) is an important human pathogen. Limited evidence suggests that antibodies can protect humans against lethal CCHFV disease but the protective efficacy of antibodies has never been evaluated in adult animal models. Here, we used adult mice to investigate the protection provided against CCHFV infection by glycoprotein-targeting neutralizing and non-neutralizing monoclonal antibodies (mAbs). We identified a single non-neutralizing antibody (mAb-13G8) that protected adult type I interferon–deficient mice >90% when treatment was initiated before virus exposure and >60% when administered after virus exposure. Neutralizing antibodies known to protect neonatal mice from lethal CCHFV infection failed to confer protection regardless of immunoglobulin G subclass. The target of mAb-13G8 was identified as GP38, one of multiple proteolytically cleaved glycoproteins derived from the CCHFV glycoprotein precursor polyprotein. This study reveals GP38 as an important antibody target for limiting CCHFV pathogenesis and lays the foundation to develop immunotherapeutics against CCHFV in humans.

scholarly journals Crimean-Congo hemorrhagic fever virus infection is lethal for adult type I interferon receptor-knockout mice

2010 ◽  
Vol 91 (6) ◽  
pp. 1473-1477 ◽  
Author(s):  
S. Bereczky ◽  
G. Lindegren ◽  
H. Karlberg ◽  
S. Akerstrom ◽  
J. Klingstrom ◽  
...  
Keyword(s):  
Virus Infection ◽  
Knockout Mice ◽  
Type I Interferon ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Type I ◽  
Adult Type ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus ◽  
Interferon Receptor

scholarly journals Neutralizing Antibodies against Crimean–Congo Hemorrhagic Fever Virus Derived from a Human Survivor

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 128
Author(s):  
J. Maximilian Fels ◽  
Daniel Maurer ◽  
Ana I. Kuehne ◽  
Dafna M. Abelson ◽  
Noel T. Pauli ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Hemorrhagic Fever ◽  
Reservoir Host ◽  
Fever Virus ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus ◽  
Isolation And Characterization ◽  
Western Asia ◽  
Targeted Treatments

Crimean–Congo hemorrhagic fever virus (CCHFV) is an arbovirus belonging to the Nairoviridae family. The virus, as well as ticks of the Hyalomma genus, which serve as its reservoir host, are found in parts of Africa, western Asia, and southern Europe. Following sporadic zoonotic or human-to-human transmission, infection is characterized by fever, fatigue, vomiting, diarrhea, and in fatal cases, often hemorrhagic symptoms. There are currently no vaccines or targeted treatments available against CCHFV, leading the WHO to declare it a Blueprint priority pathogen in 2017. Here, we report the isolation and characterization of a panel of human monoclonal antibodies (mAbs) against CCHFV. Using a novel soluble Gn/Gc sorting antigen, we were able to isolate memory B cells specific for CCHFV from four convalescent donors. From each patient sample, we were able to derive several potently neutralizing antibodies with IC50 in the nanomolar range as determined by neutralization of CCHFV virus-like particles. Neutralization by candidate hits was also confirmed using authentic CCHFV. We further show that several of the most potently neutralizing mAbs possess a breadth of neutralization spanning three clades of CCHFV strains. These broadly neutralizing mAbs are currently being tested in a mouse model of CCHFV infection, with preliminary results indicating that they have protective potential.

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