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      A CCHFV DNA vaccine protects against heterologous challenge and establishes GP38 as immunorelevant in mice

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          Abstract

          Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus that causes severe hemorrhagic fever disease in humans. Currently, no licensed CCHF vaccines exist, and the protective epitopes remain unclear. Previously, we tested a DNA vaccine expressing the M-segment glycoprotein precursor gene of the laboratory CCHFV strain IbAr 10200 (CCHFV-M 10200). CCHFV-M 10200 provided >60% protection against homologous CCHFV-IbAr 10200 challenge in mice. Here, we report that increasing the dose of CCHFV-M 10200 provides complete protection from homologous CCHFV challenge in mice, and significant (80%) protection from challenge with the clinically relevant heterologous strain CCHFV-Afg09-2990. We also report complete protection from CCHFV-Afg09-2990 challenge following vaccination with a CCHFV-Afg09-2990 M-segment DNA vaccine (CCHFV-M Afg09). Finally, we show that the non-structural M-segment protein, GP38, influences CCHF vaccine immunogenicity and provides significant protection from homologous CCHFV challenge. Our results demonstrate that M-segment DNA vaccines elicit protective CCHF immunity and further illustrate the immunorelevance of GP38.

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          Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity.

          Dennis Bente, Naomi Forrester, Douglas Watts … (2013)
          Crimean-Congo hemorrhagic fever (CCHF) is the most important tick-borne viral disease of humans, causing sporadic cases or outbreaks of severe illness across a huge geographic area, from western China to the Middle East and southeastern Europe and throughout most of Africa. CCHFV is maintained in vertical and horizontal transmission cycles involving ixodid ticks and a variety of wild and domestic vertebrates, which do not show signs of illness. The virus circulates in a number of tick genera, but Hyalomma ticks are the principal source of human infection, probably because both immature and adult forms actively seek hosts for the blood meals required at each stage of maturation. CCHF occurs most frequently among agricultural workers following the bite of an infected tick, and to a lesser extent among slaughterhouse workers exposed to the blood and tissues of infected livestock and medical personnel through contact with the body fluids of infected patients. CCHFV is the most genetically diverse of the arboviruses, with nucleotide sequence differences among isolates ranging from 20% for the viral S segment to 31% for the M segment. Viruses with diverse sequences can be found within the same geographic area, while closely related viruses have been isolated in far distant regions, suggesting that widespread dispersion of CCHFV has occurred at times in the past, possibly by ticks carried on migratory birds or through the international livestock trade. Reassortment among genome segments during co-infection of ticks or vertebrates appears to have played an important role in generating diversity, and represents a potential future source of novel viruses. In this article, we first review current knowledge of CCHFV, summarizing its molecular biology, maintenance and transmission, epidemiology and geographic range. We also include an extensive discussion of CCHFV genetic diversity, including maps of the range of the virus with superimposed phylogenetic trees. We then review the features of CCHF, including the clinical syndrome, diagnosis, treatment, pathogenesis, vaccine development and laboratory animal models of CCHF. The paper ends with a discussion of the possible future geographic range of the virus. For the benefit of researchers, we include a Supplementary Table listing all published reports of CCHF cases and outbreaks in the English-language literature, plus some principal articles in other languages, with total case numbers, case fatality rates and all CCHFV strains on GenBank. Copyright © 2013 Elsevier B.V. All rights reserved.
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            Cellular localization and antigenic characterization of crimean-congo hemorrhagic fever virus glycoproteins.

            C Schmaljohn, Natalia Frias-Staheli, Jeanne McFalls … (2005)
            Crimean-Congo hemorrhagic fever virus (CCHFV), a member of the genus Nairovirus of the family Bunyaviridae, causes severe disease with high rates of mortality in humans. The CCHFV M RNA segment encodes the virus glycoproteins G(N) and G(C). To understand the processing and intracellular localization of the CCHFV glycoproteins as well as their neutralization and protection determinants, we produced and characterized monoclonal antibodies (MAbs) specific for both G(N) and G(C). Using these MAbs, we found that G(N) predominantly colocalized with a Golgi marker when expressed alone or with G(C), while G(C) was transported to the Golgi apparatus only in the presence of G(N). Both proteins remained endo-beta-N-acetylglucosaminidase H sensitive, indicating that the CCHFV glycoproteins are most likely targeted to the cis Golgi apparatus. Golgi targeting information partly resides within the G(N) ectodomain, because a soluble version of G(N) lacking its transmembrane and cytoplasmic domains also localized to the Golgi apparatus. Coexpression of soluble versions of G(N) and G(C) also resulted in localization of soluble G(C) to the Golgi apparatus, indicating that the ectodomains of these proteins are sufficient for the interactions needed for Golgi targeting. Finally, the mucin-like and P35 domains, located at the N terminus of the G(N) precursor protein and removed posttranslationally by endoproteolysis, were required for Golgi targeting of G(N) when it was expressed alone but were dispensable when G(C) was coexpressed. In neutralization assays on SW-13 cells, MAbs to G(C), but not to G(N), prevented CCHFV infection. However, only a subset of G(C) MAbs protected mice in passive-immunization experiments, while some nonneutralizing G(N) MAbs efficiently protected animals from a lethal CCHFV challenge. Thus, neutralization of CCHFV likely depends not only on the properties of the antibody, but on host cell factors as well. In addition, nonneutralizing antibody-dependent mechanisms, such as antibody-dependent cell-mediated cytotoxicity, may be involved in the in vivo protection seen with the MAbs to G(C).
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              A Novel Vaccine against Crimean-Congo Haemorrhagic Fever Protects 100% of Animals against Lethal Challenge in a Mouse Model

              Karen R. Buttigieg, Stuart Dowall, Stephen Findlay-Wilson … (2014)
              Crimean-Congo Haemorrhagic Fever (CCHF) is a severe tick-borne disease, endemic in many countries in Africa, the Middle East, Eastern Europe and Asia. Between 15–70% of reported cases are fatal. There is no approved vaccine available, and preclinical protection in vivo by an experimental vaccine has not been demonstrated previously. In the present study, the attenuated poxvirus vector, Modified Vaccinia virus Ankara, was used to develop a recombinant candidate vaccine expressing the CCHF virus glycoproteins. Cellular and humoral immunogenicity was confirmed in two mouse strains, including type I interferon receptor knockout mice, which are susceptible to CCHF disease. This vaccine protected all recipient animals from lethal disease in a challenge model adapted to represent infection via a tick bite. Histopathology and viral load analysis of protected animals confirmed that they had been exposed to challenge virus, even though they did not exhibit clinical signs. This is the first demonstration of efficacy of a CCHF vaccine.
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                Author and article information

                Contributors
                John J. Suschak:
                ORCID: http://orcid.org/0000-0002-2867-8265
                jjsuschak@gmail.com
                Aura R. Garrison:
                ORCID: http://orcid.org/0000-0003-3034-6400
                aura.r.garrison.civ@mail.mil
                Journal
                Journal ID (nlm-ta): NPJ Vaccines
                Journal ID (iso-abbrev): NPJ Vaccines
                Title: NPJ Vaccines
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2059-0105
                Publication date (Electronic): 2 March 2021
                Publication date PMC-release: 2 March 2021
                Publication date Collection: 2021
                Volume: 6
                Electronic Location Identifier: 31
                Affiliations
                [1 ]GRID grid.416900.a, ISNI 0000 0001 0666 4455, Virology Division, United States Army Medical Research Institute of Infectious Diseases, ; Fort Detrick, MD USA
                [2 ]GRID grid.416900.a, ISNI 0000 0001 0666 4455, Diagnostics Systems Division, United States Army Medical Research Institute of Infectious Diseases, ; Fort Detrick, MD USA
                [3 ]GRID grid.416900.a, ISNI 0000 0001 0666 4455, Headquarters Division, United States Army Medical Research Institute of Infectious Diseases, ; Fort Detrick, MD USA
                [4 ]GRID grid.419681.3, ISNI 0000 0001 2164 9667, Present Address: National Institute of Allergy and Infectious Diseases, Integrated Research Facility, ; Frederick, MD USA
                Author information
                http://orcid.org/0000-0002-2867-8265
                http://orcid.org/0000-0002-9709-313X
                http://orcid.org/0000-0002-9891-7727
                http://orcid.org/0000-0003-3034-6400
                Article
                Publisher ID: 293
                DOI: 10.1038/s41541-021-00293-9
                PMC ID: 7925670
                PubMed ID: 33654101
                SO-VID: 22512249-b3a3-4920-b927-4147bbd1d27a
                Copyright © © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 2 October 2020
                Date accepted : 29 January 2021
                Funding
                Funded by: Military Infectious Disease Research Program
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2021

                Keywords: infectious diseases,vaccines,virology
                Data availability:
                Keywords: infectious diseases, vaccines, virology

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