scholarly journals Nucleoside-modified mRNA vaccines protect IFNAR -/- mice against Crimean Congo hemorrhagic fever virus infection

2021 ◽  
Author(s):  
Sofia Appelberg ◽  
Lijo John ◽  
Norbert Pardi ◽  
Ákos Végvári ◽  
Sándor Bereczky ◽  
...  
Keyword(s):  
Immune Response ◽  
Global Health ◽  
Immune Responses ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Fatality Rate ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus ◽  
High Fatality Rate ◽  
The World

Crimean-Congo hemorrhagic fever (CCHF), caused by Crimean-Congo hemorrhagic fever virus (CCHFV), is on the World Health Organizations’ list of prioritized diseases and pathogens. With global distribution, high fatality rate and no approved vaccine or effective treatment, CCHF constitutes a threat against global health. In the current study, we demonstrate that vaccination with nucleoside-modified mRNA-lipid nanoparticles (mRNA-LNP), encoding for the CCHFV nucleoprotein (N) or glycoproteins (GcGn) protect IFNAR -/- mice against lethal CCHFV infection. In addition, we found that both mRNA-LNP induced strong humoral and cellular immune responses in IFNAR -/- and immunocompetent mice and that neutralizing antibodies are not necessary for protection. When evaluating immune responses induced by immunization including CCHFV Gc and Gn antigens, we found the Gc protein to be more immunogenic compared to the Gn protein. Hepatic injury is prevalent in CCHF and contributes to the severity and mortality of the disease in humans. Thus, to understand the immune response in the liver after infection and the potential effect of the vaccine, we performed a proteomic analysis on liver samples from vaccinated and control mice after CCHFV infection. Similar to observations in humans, vaccination affected the metabolic pathways. In conclusion, this study shows that a CCHFV mRNA-LNP vaccine, based on viral nucleo- or glycoproteins, mediate protection against CCHFV induced disease. Consequently, genetic immunization is an attractive approach to prevent disease caused by CCHFV and we believe we have necessary evidence to bring this vaccine platform to the next step in the development of a vaccine against CCHFV infection. Importance Crimean-Congo hemorrhagic fever virus (CCHFV) is a zoonotic pathogen causing Crimean-Congo hemorrhagic fever (CCHF), a severe fever disease. CCHFV have a wide distribution and are endemic in several areas around the world. Cases of CCHF are also being reported in new areas, indicating an expansion of the disease, which is of high concern. Dispersion of the disease, high fatality rate and no approved vaccine makes CCHF a threat to global health. The development of a vaccine is thus of great importance. Here we show 100% protection against lethal CCHFV infection in mice immunized with mRNA-LNP encoding for different CCHFV proteins. The vaccination showed both robust humoral and cellular immunity. mRNA-LNP vaccines combine the ability to induce an effective immune response, the safety of a transient carrier and the flexibility of genetic vaccines. This and our results from the current study support the development of a mRNA-LNP based vaccine against CCHFV.

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 Crimean-Congo Hemorrhagic Fever Virus (CCHFV): A Silent but Widespread Threat

2021 ◽  
Author(s):  
Paul A. Kuehnert ◽  
Christopher P. Stefan ◽  
Catherine V. Badger ◽  
Keersten M. Ricks
Keyword(s):  
One Health ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Virus Vector ◽  
Disease Spread ◽  
Fatality Rate ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus ◽  
High Fatality Rate ◽  
Endemic Areas

Abstract Purpose of Review This review is aimed at highlighting recent research and articles on the complicated relationship between virus, vector, and host and how biosurveillance at each level informs disease spread and risk. Recent Findings While human cases of CCHFV and tick identification in non-endemic areas in 2019–2020 were reported to sites such as ProMed, there is a gap in recent published literature on these and broader CCHFV surveillance efforts from the late 2010s. Summary A review of the complex aspects of CCHFV maintenance in the environment coupled with high fatality rate and lack of vaccines and therapeutics warrants the need for a One-Health approach toward detection and increased biosurveillance programs for CCHFV.

Crimean-Congo hemorrhagic fever virus delays activation of the innate immune response

2008 ◽  
Vol 80 (8) ◽  
pp. 1397-1404 ◽  
Author(s):  
Ida Andersson ◽  
Helen Karlberg ◽  
Mehrdad Mousavi-Jazi ◽  
Luis Martínez-Sobrido ◽  
Friedemann Weber ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Hemorrhagic Fever ◽  
Innate Immune ◽  
Fever Virus ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus

scholarly journals Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate Immune Responses via a Ubiquitin and ISG15 Specific Protease

Cell Reports ◽  
2017 ◽  
Vol 20 (10) ◽  
pp. 2396-2407 ◽  
Author(s):  
Florine E.M. Scholte ◽  
Marko Zivcec ◽  
John V. Dzimianski ◽  
Michelle K. Deaton ◽  
Jessica R. Spengler ◽  
...  
Keyword(s):  
Immune Responses ◽  
Hemorrhagic Fever ◽  
Innate Immune ◽  
Fever Virus ◽  
Innate Immune Responses ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus ◽  
Specific Protease

Healthy individuals’ immune response to the Bulgarian Crimean-Congo hemorrhagic fever virus vaccine

Vaccine ◽  
2012 ◽  
Vol 30 (44) ◽  
pp. 6225-6229 ◽  
Author(s):  
Mehrdad Mousavi-Jazi ◽  
Helen Karlberg ◽  
Anna Papa ◽  
Iva Christova ◽  
Ali Mirazimi
Keyword(s):  
Immune Response ◽  
Virus Vaccine ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Healthy Individuals ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus

scholarly journals The world areal of Crimean-Congo hemorrhagic fever virus

2006 ◽  
Vol 5 ◽  
pp. 79-86 ◽  
Author(s):  
S. Ye. Smirnova
Keyword(s):  
Hemorrhagic Fever ◽  
Domestic Animals ◽  
Fever Virus ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus ◽  
Immunological Status ◽  
The World ◽  
Cchf Virus

Distribution of Crimean-Congo hemorrhagic fever (CCHF) virus based on virus isolations and results of seroepidemiological surveys. The were investigated 147 cases of ill (4 countries of Europe and Asia), immunological status of population (13 countries of Europe, Asia and Africa) and domestic animals (16 countries of Europe, Asia and Africa) and infected ticks (7 countries of Eu- rope and Asia). CCHF was first recognized in Azerbaijan, Armenia, Afghanistan, Iran, India and confirmed in Russia, Ukraine, Bulgaria, Yugoslavia (Europe), Uzbekistan, Tadzhikistan, Turkmenistan, Kazakhstan (Asia) and Uganda, Senegal, Kenya (Africa).

GENETIC DIVERSITY OF THE CRIMEAN-CONGO HEMORRHAGIC FEVER VIRUSES CIRCULATING IN THE WORLD (REVIEW)

Vestnik ◽  
2021 ◽  
pp. 323-329
Author(s):  
Г.Н. Абуова ◽  
Т.В. Полукчи ◽  
Ф.А. Бердалиева ◽  
Д.С. Алиев ◽  
Л.Л. Сарыпбекова ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Migratory Birds ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus ◽  
The World ◽  
Key Factor ◽  
Host Blood ◽  
The Relationship

Вирус Конго-Крымской геморрагической лихорадки является возбудителем тяжелой клещевой, часто смертельной, Конго-Крымской геморрагической лихорадки, которая широко распространена во всем мире. Передача вируса Конго-Крымской геморрагической лихорадки к человеку происходит через укус клеща, раздавливание зараженных клещей или контакт с инфицированной кровью человека. Миграция вируса способна через клещей с животными и перелетных птиц, в связи с чем имеется возможность исследования географического распространения посредством генетического анализа. В этом обзоре мы стремимся обобщить самые последние данные о генетическом разнообразии вирусов Конго-Крымской геморрагической лихорадки, циркулирующих в мире. Временной и пространственный анализ многообразия штаммов вируса может послужить ключевым фактором для лучшего понимания связи серопозитивности и уровня летальности. The Crimean-Congo hemorrhagic fever virus is the causative agent of severe tick-borne, often fatal, zoonotic Crimean-Congo hemorrhagic fever, which is widespread throughout the world. Transmission of the Crimean-Congo hemorrhagic fever virus to humans occurs through a tick bite, crushing of infected ticks or contact with infected host blood. The migration of the virus is possible through ticks with animals and migratory birds, and therefore it is possible to study the geographical distribution through genetic analysis. In this review, we aim to summarize the latest data on the genetic diversity of the Crimean-Congo hemorrhagic fever viruses circulating in the world. The temporal and spatial analysis of the diversity of virus strains can serve as a key factor for a better understanding of the relationship between seropositivity and the mortality rate.

scholarly journals Immunogenicity of a DNA-Based Sindbis Replicon Expressing Crimean–Congo Hemorrhagic Fever Virus Nucleoprotein

Vaccines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1491
Author(s):  
Thomas Tipih ◽  
Mark Heise ◽  
Felicity Jane Burt
Keyword(s):  
Immune Response ◽  
Sindbis Virus ◽  
Cytokine Production ◽  
Antiviral Drug ◽  
Case Fatality ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Virus Vector ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus

Crimean–Congo hemorrhagic fever virus (CCHFV) infrequently causes hemorrhagic fever in humans with a case fatality rate of 30%. Currently, there is neither an internationally approved antiviral drug nor a vaccine against the virus. A replicon based on the Sindbis virus vector encoding the complete open reading frame of a CCHFV nucleoprotein from a South African isolate was prepared and investigated as a possible candidate vaccine. The transcription of CCHFV RNA and recombinant protein production by the replicon were characterized in transfected baby hamster kidney cells. A replicon encoding CCHFV nucleoprotein inserted in plasmid DNA, pSinCCHF-52S, directed transcription of CCHFV RNA in the transfected cells. NIH-III heterozygous mice immunized with pSinCCHF-52S generated CCHFV IgG specific antibodies with notably higher levels of IgG2a compared to IgG1. Splenocytes from mice immunized with pSinCCHF-52S secreted IFN-γ and IL-2, low levels of IL-6 or IL-10, and no IL-4. No specific cytokine production was registered in splenocytes of mock-immunized mice (p < 0.05). Thus, our study demonstrated the expression of CCHFV nucleoprotein by a Sindbis virus vector and its immunogenicity in mice. The spectrum of cytokine production and antibody profile indicated predominantly Th1-type of an anti-CCHFV immune response. Further studies in CCHFV-susceptible animals are necessary to determine whether the induced immune response is protective.

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