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      A Novel Vaccine against Crimean-Congo Haemorrhagic Fever Protects 100% of Animals against Lethal Challenge in a Mouse Model

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          Abstract

          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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          Crimean-Congo haemorrhagic fever

          Önder Ergönül (2006)
          Summary Crimean-Congo haemorrhagic fever (CCHF) is an often fatal viral infection described in about 30 countries, and it has the most extensive geographic distribution of the medically important tickborne viral diseases, closely approximating the known global distribution of Hyalomma spp ticks. Human beings become infected through tick bites, by crushing infected ticks, after contact with a patient with CCHF during the acute phase of infection, or by contact with blood or tissues from viraemic livestock. Clinical features commonly show a dramatic progression characterised by haemorrhage, myalgia, and fever. The levels of liver enzymes, creatinine phosphokinase, and lactate dehydrogenase are raised, and bleeding markers are prolonged. Infection of the endothelium has a major pathogenic role. Besides direct infection of the endothelium, indirect damage by viral factors or virus-mediated host-derived soluble factors that cause endothelial activations and dysfunction are thought to occur. In diagnosis, enzyme-linked immunoassay and real-time reverse transcriptase PCR are used. Early diagnosis is critical for patient therapy and prevention of potential nosocomial infections. Supportive therapy is the most essential part of case management. Recent studies suggest that ribavirin is effective against CCHF, although definitive studies are not available. Health-care workers have a serious risk of infection, particularly during care of patients with haemorrhages from the nose, mouth, gums, vagina, and injection sites. Simple barrier precautions have been reported to be effective.
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            Crimean-Congo hemorrhagic fever.

            Chris A. Whitehouse (2004)
            Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease caused by the arbovirus Crimean-Congo hemorrhagic fever virus (CCHFV), which is a member of the Nairovirus genus (family Bunyaviridae). CCHF was first recognized during a large outbreak among agricultural workers in the mid-1940s in the Crimean peninsula. The disease now occurs sporadically throughout much of Africa, Asia, and Europe and results in an approximately 30% fatality rate. After a short incubation period, CCHF is characterized by a sudden onset of high fever, chills, severe headache, dizziness, back, and abdominal pains. Additional symptoms can include nausea, vomiting, diarrhea, neuropsychiatric, and cardiovascular changes. In severe cases, hemorrhagic manifestations, ranging from petechiae to large areas of ecchymosis, develop. Numerous genera of ixodid ticks serve both as vector and reservoir for CCHFV; however, ticks in the genus Hyalomma are particularly important to the ecology of this virus. In fact, occurrence of CCHF closely approximates the known world distribution of Hyalomma spp. ticks. Therefore, exposure to these ticks represents a major risk factor for contracting disease; however, other important risk factors are known and are discussed in this review. In recent years, major advances in the molecular detection of CCHFV, particularly the use of real-time reverse transcription-polymerase chain reaction (RT-PCR), in clinical and tick samples have allowed for both rapid diagnosis of disease and molecular epidemiology studies. Treatment options for CCHF are limited. Immunotherapy and ribavirin have been tried with varying degrees of success during sporadic outbreaks of disease, but no case-controlled trials have been conducted. Consequently, there is currently no antiviral treatment for CCHF approved by the U.S. Food and Drug Administration (FDA). However, renewed interested in CCHFV, as well as increased knowledge of its basic biology, may lead to improved therapies in the future. This article reviews the history, epidemiology, ecology, clinical features, pathogenesis, diagnosis, and treatment of CCHF. In addition, recent advances in the molecular biology of CCHFV are presented, and issues related to its possible use as a bioterrorism agent are discussed.
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              Broadly neutralizing antiviral antibodies.

              Davide Corti, Antonio Lanzavecchia (2013)
              A fascinating aspect of viral evolution relates to the ability of viruses to escape the adaptive immune response. The widely held view has been that the great variability of viral glycoproteins would be an absolute obstacle to the development of antibody-based therapies or vaccines that could confer broad and long-lasting protection. In the past five years, new approaches have been developed to interrogate human memory B cells and plasma cells with high efficiency and to isolate several broadly neutralizing antiviral antibodies against highly variable pathogens such as HIV-1 and influenza virus. These antibodies not only provide new tools for prophylaxis and therapy for viral diseases but also identify conserved epitopes that may be used to design new vaccines capable of conferring broader protection.
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                Author and article information

                Contributors
                James P. Stewart: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 12 March 2014
                Volume: 9
                Issue: 3
                Electronic Location Identifier: e91516
                Affiliations
                [1]Microbiology Services Research, Public Health England, Porton Down, Wiltshire, United Kingdom
                University of Liverpool, United Kingdom
                Author notes

                Competing Interests: KRB, SDD, RH and MWC are named inventors on a pending patent application 40308GB “Crimean-Congo Haemorrhagic Fever Virus Antigenic Composition.” As declared on the competing interests section of the submission form, KRB, SDD, SFW, AM, RH and MWC are named inventors on a pending patent application 40308GB “Crimean-Congo Haemorrhagic Fever Virus Antigenic Composition”. The authors declare that no other competing interests exist. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: KRB SDD RH MWC. Performed the experiments: KRB SDD SFW AM ER. Analyzed the data: KRB SDD SFW AM ER. Wrote the paper: KRB SDD AM ER RH.

                Article
                Publisher ID: PONE-D-13-50499
                DOI: 10.1371/journal.pone.0091516
                PMC ID: 3951450
                PubMed ID: 24621656
                SO-VID: 82a2ecd7-3561-480a-9282-a2af7fdfa92c
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 30 November 2013
                Date accepted : 10 February 2014
                Page count
                Pages: 14
                Funding
                This work was funded by the Health Protection Agency (subsequently part of Public Health England) of the United Kingdom. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Immunology
                Subject: Immunity
                Subject: Immunity to Infections
                Subject: Immune Response
                Subject: Microbiology
                Subject: Virology
                Subject: Animal Models of Infection
                Subject: Emerging Viral Diseases
                Subject: Viral Vaccines
                Subject: Emerging Infectious Diseases
                Subject: Immunity
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Mouse
                Subject: Medicine
                Subject: Clinical Immunology
                Subject: Immunity
                Subject: Vaccination
                Subject: Vaccines
                Subject: Vaccine Development
                Subject: Infectious diseases
                Subject: Neglected Tropical Diseases
                Subject: Arboviral Infections
                Subject: Viral Hemorrhagic Fevers
                Subject: Viral diseases
                Subject: Crimean-Congo hemorrhagic fever
                Subject: Infectious Disease Modeling

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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