RARE DISEASE
Crimean-Congo hemorrhagic fever
Crimean-Congo hemorrhagic fever
Crimean-Congo hemorrhagic fever
Synonyms: CCHF, Congo fever, Congo hemorrhagic fever, Crimean hemorrhagic fever
Synonyms: CCHF, Congo fever, Congo hemorrhagic fever, Crimean hemorrhagic fever
Synonyms: CCHF, Congo fever, Congo hemorrhagic fever, Crimean hemorrhagic fever
Drug discovery
1
drug
With orphan designation
Overview
Crimean-Congo hemorrhagic fever (CCHF) is a tickborne Nairovirus infection causing severe viral hemorrhagic fever. Transmission occurs via Hyalomma ticks, contact with infected animal tissues, or human bodily fluids. Symptoms include sudden fever, myalgia, petechial rash, hemorrhage (days 3–5), and multiorgan failure, with a case fatality rate of 10%–40% [1][7][17]. Diagnosis relies on PCR or serology. Prevention focuses on tick avoidance, PPE in high-risk settings, and ribavirin prophylaxis for exposures [3][11][18].
Burden
Annual global incidence: ~10,000–15,000 cases, with underreporting in low-resource regions [1][4]
CFR ranges from 5% in well-resourced settings to 40% in Africa; indirect costs from livestock trade disruptions [5][9][15]
Emerging threat due to climate-related tick expansion and inadequate surveillance infrastructure [10][12]
Therapies
Supportive care: Fluid resuscitation, blood product transfusions, and organ support [3][11][18]
Ribavirin: Used off-label despite conflicting efficacy data; WHO recommends its use in high-risk exposures [3][7][19]
Infection control: Strict isolation and biocontainment protocols to prevent nosocomial transmission [16][18]
Categories: rare infectious diseases
Research Papers
501 drug discovery papers about Crimean-Congo hemorrhagic fever, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
501 drug discovery papers about Crimean-Congo hemorrhagic fever, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
oligonucleotides
2026-04-24 | Modified mRNA Encoding the Crimean-Congo Hemorrhagic Fever Virus Nucleocapsid Protein Confers Robust Protection Against Lethal Challenge in Mice.
The Crimean-Congo Hemorrhagic Fever Virus (Orthonairovirus haemorrhagiae) causes a hemorrhagic fever with mortality rates reaching up to 40%. For years, this virus has maintained its position among the top priority pathogens identified by the World Health Organization (WHO). This is due to its endemic presence across a vast region-from Africa and Spain to the Balkans, the Middle East, and throughout Asia-its potential for human-to-human transmission, and the lack of an effective and approved vaccine or treatment. Therefore, the development of an effective vaccine against CCHFV is of critical importance. Building on the success of mRNA-based vaccines during the Coronavirus Disease 2019 (COVID-19) pandemic, this study reports the development of a messenger ribonucleic acid (mRNA) vaccine candidate expressing the nucleocapsid protein (NP) of CCHFV. The CCHFV NP in vitro transcript (IVT) was designed with pseudouridine (Ψ) nucleoside modification. As part of the preclinical characterization of the IVT vaccine candidate, the biochemical and immunological properties of NP were confirmed in Huh-7 cells transfected with IVT NP-ΨmRNA. Afterwards, the efficacy of IVT NP-ΨmRNA immunization was evaluated in immunocompetent BALB/c and transiently immunosuppressed (IS) C57BL/6 mice. In CCHFV challenge studies, IS C57BL/6 mice were used. IS C57BL/6 mice were immunized intramuscularly with 2 doses of IVT NP- ΨmRNA, either naked or encapsulated in Poly(lactic-co-glycolic acid) (PLGA) nanoparticles, administered 14 days apart. High levels of CCHFV NP-specific humoral (IgM and IgG) and cellular (cytokine and lymphoproliferative) responses were demonstrated in BALB/c mice immunized with IVT NP- ΨmRNA. In challenge experiments, 100% survival was observed with both the naked and PLGA-encapsulated IVT NP-ΨmRNA immunizations. These findings demonstrate 100% survival following lethal CCHFV challenge under the experimental conditions tested in this mouse model and support the potential of NP-encoding pseudouridine-modified mRNA vaccines. Additionally, 100% survival was observed in mice immunized with inactivated CCHFV, whereas only 20% survival was detected in the unmodified IVT NP-mRNA vaccinated animals. In the protected mice, viral clearance was observed in the spleen, liver tissues, and blood on day 14 post-challenge. This study demonstrates that NP, the most abundant protein of the virus, is capable of providing significant survival benefits in the tested mouse model. Furthermore, our report represents a significant step in identifying a potential vaccine candidate and provides a solid foundation for further preclinical studies necessary to support future clinical development.
2026-01-17 | Field vaccination against CCHFV and Hyalomma tick infestation reduces multiple tick-borne infections in sheep.
Tick-borne pathogens (TBPs) are expanding globally, with their impact on public health expected to rise due to climate change. Immunizing livestock offers a cost-effective alternative or adjunct to human vaccination. We evaluated two DNA vaccines, one targeting Crimean-Congo hemorrhagic fever virus (CCHFV) and another targeting Hyalomma tick infestation. The Hyalomma-targeting vaccine was designed to disrupt tick feeding by targeting midgut proteins essential for blood digestion and survival; however, its direct role in preventing CCHFV transmission remains unconfirmed. Here, we demonstrate that two doses of the CCHFV vaccine significantly reduced the risk of CCHFV infection in naturally exposed sheep. We further investigated whether the Hyalomma vaccine provided cross-protection against Wad Medani virus (WMV) and Rickettsia conorii, two TBPs endemic to Senegal. Sheep were vaccinated intramuscularly with two doses of DNA vaccine, followed by electroporation, and monitored under natural farming conditions in an endemic region of Senegal. Natural infection with CCHFV, WMV, and R. conorii was assessed longitudinally using pathogen-specific IgG seroconversion as the primary endpoint. The Hyalomma vaccine reduced WMV acquisition, whereas its effect on R. conorii was less pronounced. These findings underscore the potential of veterinary vaccines to mitigate multiple TBPs and reinforce their established role in reducing tick-borne diseases.
2025-12-13 | A single-dose mRNA vaccine protects mice from lethal Crimean-Congo hemorrhagic fever virus infection.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus of the Orthonairovirus genus, Nairoviridae family, that causes severe febrile hemorrhagic disease in humans with a case fatality rate ranging from approximately 3-30%. This zoonotic pathogen is distributed across a broad geographic area spanning Asia, Europe, and Africa. Despite its significant public health threat and outbreak potential, no licensed vaccines are available. In this study, we developed and systematically assessed the immunogenicity and protective efficacy of mRNA vaccines encoding either CCHFV nucleoprotein (NP) or glycoprotein precursor (GPC) in mouse models. Vaccination with the NP-encoding mRNA alone provided complete protection against lethal cross-genotype CCHFV challenge. Moreover, combined vaccination with both the NP and GPC mRNAs elicited robust immune responses and conferred protection against CCHFV infection. Notably, a single-dose immunization with 2 μg mRNA-NP was sufficient to confer protection against lethal challenge. Furthermore, the passive transfer of NP-immune serum provided partial protection, supporting the role of NP-specific antibodies in mediating protection. Overall, these mRNA vaccines demonstrate protective efficacy against CCHFV, with combined antigenic protection and dose-sparing potential, highlighting their potential for outbreak preparedness and further clinical development.
2025-11-22 | Durable humoral immunity and long-term protection induced by a Crimean-Congo hemorrhagic fever virus replicon particle vaccine in mice.
A Crimean-Congo hemorrhagic fever virus replicon particle vaccine was evaluated for long-term immunity and efficacy in mice. IgG responses persisted up to 18 months, with similar titers across dosing strategies through 12 months. Protective efficacy reached ≥75% at 6 months (prime-only) and up to 12 months (prime-boost). Booster dosing enhanced antibody avidity, effector function, and improved long-term protection. These findings support durable immunity from single or boosted vaccination.
2025-09-15 | CCHFV-M based DNA vaccine is highly immunogenic in multiple species and protects against challenge in cynomolgus macaques.
Crimean-Congo hemorrhagic fever virus (CCHFV), a member of the Nairoviridae family, is the most widely distributed tick-borne virus of medical importance. There are no internationally licensed vaccines, and treatment is limited to supportive care. We previously developed a DNA vaccine expressing the full-length codon-optimized M-segment (CCHFV-MAfg09), encoding the structural and non-structural viral glycoproteins that protects mice against CCHFV when delivered by intramuscular electroporation (IM-EP). Here, the immunogenicity and protective efficacy of the vaccine delivered by IM-EP was assessed in the non-lethal CCHFV cynomolgus macaque model. The vaccine elicited a significant antibody response to two glycoproteins, the structural GC and non-structural GP38. CCHFV-MAfg09 elicited quantifiable T-cell responses directed against the glycoproteins encoded within the M-segment, with anti-GN immunity reaching significance. Upon intravenous infection with CCHFV, the vaccine protected 5/6 animals against viremia and reduced the pro-inflammatory response compared to sham vaccinated macaques. Numerous macaques also had detectable viral protein and viral RNA in several tissues 28 days post infection. In addition, we determined that an alternative delivery modality, jet injection, was immunogenic in both rabbits and mice, and conferred significant protection in mice. The simplicity and efficacy of disposable syringe needle-free injection system (NFIS) provides a pragmatic approach to advance the CCHF-M DNA vaccine into the clinic. Our M-segment based DNA vaccine elicits both cellular and humoral immunity and significant protection in mice and NHPs, demonstrating for the first time that a vaccine based on the glycoproteins alone is efficacious in the NHP model, which has not previously been shown.
antibodies
2026-07-21 | The growing public health concern of Crimean-Congo Hemorrhagic Fever Virus (CCHFV)
The growing public health concern of Crimean-Congo Hemorrhagic Fever Virus (CCHFV) Mohammad M. Sajadi and Scott D. Pegan discuss leveraging cross-reactive monoclonals and next-generation vaccines to address Crimean-Congo hemorrhagic fever virus diversity. Crimean-Congo hemorrhagic fever virus (CCHFV) is a zoonotic negative (-) sense RNA bunyavirus of the Nairoviridae family. CCHFV is widely distributed across Africa and wide swaths of Europe and Asia. It has also recently emerged, with fatal consequences, in the previously CCHFV-naïve country of Spain and has been detected in ticks in France. This underscores the virus’s propensity to continue spreading wherever its Hyalomma tick vector can gain a foothold. (1) Typical mortality rates for CCHFV range from 2-40% in hospitalized cases. (2) As additional countries are becoming at risk and the potential for significant human-to- human transmission increases, CCHFV is considered a dangerous human pathogen by the international community. It is also an NIAID prototype virus for several Nairovirus pathogens that can cause human disease of varying severity.(3)
2026-05-18 | A hyperimmune ovine antibody-based therapeutic candidate against Crimean-Congo haemorrhagic fever virus targeted to the Gn and Gc glycoproteins: high antibody levels with neutralization activity but lack of protective efficacy in a mouse model.
Crimean-Congo haemorrhagic fever virus (CCHFV) is a tick-borne pathogen that has a wide geographical range and has the potential to cause severe disease in those infected. There are no currently approved vaccines or therapeutics, so the development and assessment of new approaches are urgently required. A polyclonal antibody-based therapeutic was developed based on immunization of sheep with the major glycoprotein antigens from CCHFV. Along with purified immunoglobulin G (IgG) from hyperimmune sera, fragmentation of the F(ab')2 region was also performed. The pharmacokinetic properties were assessed in mice, and efficacy was ascertained in a live CCHFV challenge model. Candidate polyclonal antibody-based therapies were developed, demonstrating strong binding to the CCHFV envelope glycoprotein and neutralizing activity. The ovine whole IgG demonstrated stability post-delivery compared to a rapid reduction of the F(ab')2 fragment in the circulation. Efficacy testing when delivered either as a single dose before challenge or as daily dosing for 7 days starting on the day of challenge showed no demonstrable evidence of protection against infection. Despite protection observed from vaccine candidates using the CCHFV glycoprotein as an antigen and administration of convalescent sera, the ovine antibody-based therapeutics did not confer similar efficacious effects in the mouse preclinical model.
2026-03-31 | Human antibody targeting Crimean-Congo hemorrhagic fever virus glycoprotein 38 protects mice against heterologous virus challenge.
Crimean-Congo hemorrhagic fever virus (CCHFV) is an emerging arboviral and zoonotic bunyavirus. CCHFV can infect livestock, wild animals, and humans. Here, we report the isolation of a panel of mAbs from the B cells of an immune individual following a natural nosocomial infection. We determined that the panel comprised antibodies that bound to 2 glycoproteins: (a) the carboxy-terminal glycoprotein (Gc) that serves as the fusion protein and (b) the glycoprotein 38 (GP38). By antibody variable gene analysis, we identified genetic diversity in the B cell response to CCHFV within a single donor for both Gc- and GP38-specific responses. Protection against most bunyavirus-associated diseases is mediated principally by neutralizing antibodies, but here, we found that neutralization activity was not associated with protection. Gc-specific antibodies to diverse antigenic sites neutralized only weakly and did not protect against heterologous virus challenge. GP38-specific antibodies bound to 2 dominant antigenic sites on the glycoprotein. Although GP38-specific antibodies did not neutralize the virus, one mediated protection against heterologous virus challenge in an experimental model of infection in mice primarily by complement-mediated activity. These studies support the development of protective CCHFV countermeasures against GP38.
2026-03-28 | Divergent pathogenesis of two Chinese Crimean-Congo hemorrhagic fever viruses in cynomolgus macaques.
Crimean-Congo hemorrhagic fever (CCHF), a highly pathogenic tick-borne disease in humans with mortality rates ranging from 5% to 82%. Although cynomolgus macaques have been used to model infection with strains such as Hoti and Afghanistan, the pathogenic characteristics of Chinese CCHFV isolates remain insufficiently defined. We evaluated the pathogenicity of two Chinese CCHFV strains in cynomolgus macaques: BA04032 (tick-derived) and 75024 (non-lethal human clinical isolate). Animal were monitored for clinical parameters, viremia, hematologic and biochemical changes, viral RNA loads in blood, swabs, and tissues, as well as histopathological alterations. Infection with strain 75024 resulted in mild disease manifestations, whereas infection with strain BA04032 produced more severe illness characterized primarily by fever, viremia, thrombocytopenia, leukopenia, and extensive viral replication in multiple organs. Although both viruses belong to the Asian lineage, phylogenetic analyses classify them into different genotypes, which may correlate with their distinct clinical and virological outcomes in this model. These findings demonstrate that Chinese isolates exhibit distinct clinical, virological, and pathological phenotypes in cynomolgus macaques, underscoring the value of this model for recapitulating aspects of CCHF disease, for pathogenesis research, and for evaluating medical countermeasures.
2026-03-23 | Venturing into host-pathogen interaction in Crimean-Congo hemorrhagic fever to highlight terra incognita.
Crimean-Congo- Hemorrhagic Fever (CCHF) is the most widespread tick-borne disease in the world with a highly variable case fatality rate. It is caused by the CCHF virus (CCHFV). The disease, which has neither approved treatments nor vaccines, has long received very little attention until it was listed as a priority pathogen by WHO. Improving our understanding of mechanisms of host-virus interaction is essential for the development of effective therapeutic and prophylactic strategies. There is still much to be clarified to better understand how the virus interacts with its host and humans. Elucidating these mechanisms will provide insights into viral pathogenesis, immune evasion strategies, and host defense responses. As a result, this will stimulate the development of targeted interventions to mitigate disease severity and improve clinical outcomes. Better understanding of virus characteristics will also improve our surveillance capability which is critical for developing effective pandemic preparedness and outbreak response strategies. Here, we examine the existing landscape concerning the immune response and inflammatory events in CCHFV-human interaction and discuss gaps in our understanding of the disease. Such discussions allow us to highlight priority research directions for the identification of potential targets for improved mitigation approaches or specific therapeutic routes.
small molecules
2026-07-28 | Repurposing Small-molecule Inhibitors against Bunyaviruses: Advances, Mechanisms, and Therapeutic Prospects.
Bunyaviricetes, including highly pathogenic members such as Severe Fever with Thrombocytopenia Syndrome Virus, Crimean-Congo Hemorrhagic Fever Virus, and Rift Valley Fever Virus, pose significant global health threats characterized by high mortality rates and a lack of approved specific therapeutics. Drug repurposing provides pharmaceutical companies with cost-effective and expedited strategies to discover innovative treatment options for patients. Given the issue of antiviral drug resistance and the high cost of developing new antiviral drugs, drug repurposing offers enormous potential for expanding the repertoire of available therapeutics. This paper reviews the progress made in developing candidate drugs against bunyaviruses through high-throughput screening and drug repurposing methods, summarizes the mechanisms of action of candidate drugs targeting viruses and host cells, and looks ahead to future trends in the development of small-molecule antiviral drugs, with the aim of providing a reference for promoting the development of new bunyavirus drugs.
2026-07-23 | Structures and inhibition of the Crimean-Congo haemorrhagic fever virus polymerase.
Crimean-Congo haemorrhagic fever virus (CCHFV) is a tick-borne virus and causes severe, often fatal, human infections. Lacking licensed vaccines or drugs, CCHFV is a World Health Organization priority pathogen requiring urgent development of medical countermeasures1,2. The CCHFV Large (L) protein functions as the viral RNA-dependent RNA polymerase CCHFV-L, representing a promising antiviral target, and is among the largest viral polymerases in the order Bunyavirales. Here we define the cofactors required for CCHFV-L RNA synthesis in vitro, enabling capture and determination of elongating CCHFV-L-RNA complex structures. The structures show a markedly enlarged polymerase architecture, revealing that CCHFV-L RNA synthesis is accompanied by ordering of the polymerase peripheral domains. We also define how the baloxavir-derived experimental drug WXSH0208 (ref. 3) and the nucleoside analogue 2'-deoxy-2'-fluorocytidine4,5, which has nanomolar cellular potency, inhibit this polymerase through endonuclease inhibition and post-translocation chain termination, respectively. Together, these results should structurally guide rational optimization of inhibitors directed against CCHFV-L.
2026-07-15 | Structure-Guided Discovery and Biochemical Validation of Novel Small-Molecule Inhibitors Predicted to Target the CCHFV OTU Protease Y89-W99 Pocket.
Crimean-Congo hemorrhagic fever virus (CCHFV) remains a major public health threat due to its high mortality rates and the absence of approved antiviral therapies. The viral ovarian tumor (OTU) protease is a critical virulence factor that suppresses host innate immunity through its deubiquitinase activity, making it an attractive therapeutic target. In this study, we employed a structure-guided approach to identify and validate novel small-molecule inhibitors targeting the non-catalytic Y89-W99 pocket of the OTU protease. Recombinant OTU protease was successfully expressed, purified, and refolded, yielding a soluble and enzymatically active protein. Cellular assays confirmed that the enzyme retains robust deubiquitinase activity, significantly reducing global ubiquitin conjugates in mammalian cells. In silico analysis of a putative DUB inhibitor library identified several candidate inhibitors with favorable binding interactions within the Y89-W99 pocket. Biochemical validation using a fluorometric Ub-AMC assay revealed that multiple small molecules strongly inhibit OTU activity, including OTUi-10 (~93% inhibition), OTUi-13 (~87%), OTUi-1 (~85%), OTUi-4 and OTUi-11 (~81%), and OTUi-9 (~76%). Additional moderate inhibitors included OTUi-12 (~67%), OTUi-19 and OTUi-21 (~66%), and OTUi-5 (~57%). In silico drug-likeness and toxicity profiling filtered the library to four fully compliant candidates, OTUi-4, OTUi-10, OTUi-11, and OTUi-12, all free of predicted toxicity alerts. These findings suggest that the Y89-W99 pocket may be a pharmacologically relevant site worthy of further investigation and identify OTUi-10, OTUi-4, and OTUi-11 as promising preliminary hit compounds. The results also provide initial insights that may guide future optimization and mechanistic studies of OTU protease inhibitors targeting CCHFV.
2026-07-14 | Structures of the Crimean-Congo hemorrhagic fever virus RNA-dependent RNA polymerase.
Crimean-Congo hemorrhagic fever virus (CCHFV), designated by the WHO as a priority pathogen under its R&D Blueprint for emerging epidemics, poses a major global health threat, yet licensed vaccines or specific antiviral treatments are lacking. As the sole viral enzyme responsible for genome replication and transcription, the CCHFV L protein is a large, multienzymatic protein, but its exceptional size (> 450 kDa) and extensive domain architecture have hindered structural analysis. Here, we present high-resolution cryo-electron microscopy structures of the full-length CCHFV L protein in its apo state and bound to the 5' viral RNA promoter. These structures reveal the largest polymerase known among Bunyavirales and demonstrate that the apo form adopts a highly flexible conformation in which multiple functional elements remain disordered. Binding of the 5' promoter RNA triggers extensive conformational rearrangements that organize these elements into a catalytically competent active site. We define a conserved 5' hook-binding mode and identify two previously unrecognized residues (K1545 and E1637) that form a constriction at the NTP entry channel, representing newly defined regulatory motifs J and K conserved across Bunyavirales. We further characterize an expanded pendant domain unique to nairoviruses that, although not essential for promoter binding, likely modulates template movement within the internal tunnel during RNA synthesis. Our results provide the first structural framework for a nairovirus polymerase, illuminate the mechanisms of CCHFV RNA synthesis, and establish a foundation for structure-guided antiviral development against this high-priority pathogen.
2026-05-22 | Isolation of Rhizoma Paridis saponins as novel entry inhibitors of Crimean-Congo hemorrhagic fever virus.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic bunyavirus, causing Crimean-Congo hemorrhagic fever (CCHF) in humans with high morbidity and mortality. Currently, there are no licensed antiviral drugs or vaccines against CCHFV, emphasizing the critical need to develop novel antiviral agents. The entry process is the initial step during the viral life cycle, and has provided an attractive target for novel antiviral development. In the present study, we developed a high-throughput screening approach based on the CCHFV glycoprotein (Gn/Gc)-based HIV-1 pseudoviruses, in order to discover novel CCHFV entry inhibitors. As a pilot, a library consisting of 500 pre-purified fractions of traditional Chinese medicine was screened, and it was identified that multi-fractions of Rhizoma Paridis exhibited inhibitory effects against CCHFV entry. Next, bioactivity-guided isolation was performed and a range of Rhizoma Paridis saponins were characterized as potential anti-CCHFV actives. Moreover, the antiviral activities of both Rhizoma Paridis extracts and the saponin derivatives were validated by a cell-based assay using authentic viruses. Mechanistic studies further demonstrated that Rhizoma Paridis saponins act by targeting host factors. In summary, this study provides a promising new strategy for CCHF treatment that deserves further development in the future.
vaccines
2026-06-22 | Finding the Goldilocks zone: Modulating glycoprotein cleavage and fusogenicity optimizes the efficacy of a candidate Crimean-Congo hemorrhagic fever virus vaccine.
Crimean-Congo hemorrhagic fever virus (CCHFV) is the etiologic agent of a lethal hemorrhagic disease spread by ticks throughout Europe, the Middle East, Africa and Asia. The lack of approved medical countermeasures and fundamental understanding of molecular mechanisms of viral assembly and egress have thus far curtailed disease prevention. Here, we identify and characterize key residues within the viral glycoprotein through forward and reverse genetics for vesicular stomatitis virus (VSV)-based vaccine candidates that are highly protective in animal models. These residues are broadly applicable across divergent CCHFV strains and lead to greater protection in vivo against heterologous challenge. We further characterize the essential role of proteolytic processing in the maintenance of a stable fusogenic state required for effective VSV-based CCHFV vaccines. This study establishes a toolkit for better understanding orthonairovirus glycoprotein processing and vaccine development.
2026-06-04 | Crimean-Congo hemorrhagic fever virus protein GP38 from isolate M18-China confers broad immunological breadth.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne, negative-strand RNA virus that causes outbreaks of lethal hemorrhagic fever. No approved vaccines or specific antiviral treatments are available. CCHFV glycoprotein GP38 is an integral component of the pre-fusion glycoprotein entry complex, plays roles in viral pathogenesis, and is a key target of antibody-mediated protection. Herein, we investigated the hypothesis that recombinant GP38 itself could elicit protection against divergent CCHFV isolates/strains in an animal model. Accordingly, we generated GP38 immunogens from six CCHFV clades and showed that GP38 from the isolate M18-China induces a broad immunological response in mice despite its lower amino acid sequence similarity to other isolates. We identified sequences in M18-China GP38 associated with this immunological breadth and evaluated it as a vaccine candidate. Although M18-China GP38 was not protective in isolation, our findings warrant further exploration of its utility as one component of a broadly protective CCHFV vaccine.
2026-05-09 | Bioinformatics and immunoinformatic approaches for structural modeling and vaccine design of the CCHFV whole genome to develop a novel broad-spectrum multiepitope vaccine candidate.
Crimean-Congo hemorrhagic fever virus (CCHFV), the causative agent of Crimean-Congo hemorrhagic fever (CCHF), represents the most widely distributed tick-borne viral disease in humans and is currently managed only through supportive care. Consequently, considerable efforts have been directed toward the development of an effective vaccine to control this pathogen. Here, we report the first comprehensive in silico prediction of immunogenic CD8⁺ T cells, CD4⁺ T cells, and B-cell epitopes across the S, M, and L segments of CCHFV. Candidate epitopes were evaluated for conservation in mouse and human homologs of HLA alleles, as well as for antigenicity, toxicity, sequence homology, cellular topology, and binding affinity to a broad range of human leukocyte antigen (HLA) alleles. The final multiepitope vaccine construct was assembled by linking selected epitopes with an adjuvant via KK, AAY, and GPGPG linkers. Codon optimization and in silico cloning into prokaryotic and eukaryotic expression vectors confirmed high-level expression potential in Escherichia coli and human cells. Molecular docking analyses demonstrated that the vaccine-derived epitopes bind HLA molecules with affinities comparable to those of naturally processed peptides. Molecular dynamics simulations further revealed stable and robust interactions between the vaccine construct and Toll-like receptors (TLRs) throughout the simulation period, indicating the potential to elicit strong immune activation upon administration. The designed vaccine is predicted to stimulate both humoral and cellular immunity effectively. Although the construct exhibits promising immunogenicity, safety, and stability in silico, experimental validation in appropriate model systems is warranted to substantiate these findings.
2026-05-07 | Immunopathogenic insights into members of the class Bunyaviricetes: a comparative review of emerging zoonotic threats.
The class Bunyaviricetes encompasses a diverse group of vector- and rodent-borne viruses, many of which are major human pathogens causing severe and often lethal diseases worldwide. These include Lassa fever virus (Arenaviridae), hantaviruses such as Hantaan and Andes viruses (Hantaviridae), Crimean-Congo hemorrhagic fever virus (Nairoviridae), La Crosse and Oropouche viruses (Peribunyaviridae), and Rift Valley fever, severe fever with thrombocytopenia syndrome, and Toscana viruses (Phenuiviridae). Clinical syndromes range from hemorrhagic fever with multiorgan failure, vascular leak, and shock to acute encephalitis and severe respiratory distress. Despite their public health impact, safe and effective vaccines or targeted therapeutics are lacking for most bunyaviricetes diseases, leaving supportive care as the primary intervention. This review provides a comparative analysis of the immunopathogenesis of major human-pathogenic bunyaviricetes, highlighting shared and virus-specific strategies for innate immune evasion, cytokine modulation, and host cell targeting. Severe disease often arises from viral interference with key sensing pathways, such as RIG-I/MDA5 and downstream IRF and NF-κB signaling, which either suppresses interferon responses or leads to dysregulated inflammation. By integrating molecular, immunological, and clinical insights, we outline how these immune-virus interactions shape disease trajectory and severity. Understanding these mechanisms is critical for guiding the rational design of vaccines, antivirals, and immunomodulatory therapies, and for strengthening preparedness against these persistent zoonotic threats.
2026-04-01 | Skin Deep: Uncovering the Early Events of Crimean–Congo Hemorrhagic Fever Virus at the Tick–Host–Virus Interface
Crimean-Congo hemorrhagic fever virus (CCHFV) is transmitted predominantly through the bite of infected Hyalomma ticks, yet the earliest events at the vector–host–virus interface in human skin remain largely undefined. This review synthesizes current knowledge of human cutaneous structure and immunity, tick feeding biology, and salivary immunomodulation to propose how local skin responses may shape systemic outcomes of CCHFV disease. We detail the roles and permissiveness of major skin-resident and infiltrating cell types, including keratinocytes, melanocytes, Langerhans cells, dermal dendritic cells, monocytes/macrophages, fibroblasts, granulocytes, T cells, B cells, NK cells, and innate lymphoid cells, in antiviral defense and as potential early targets or carriers of CCHFV. Emphasis is placed on how tick saliva components reprogram the cutaneous microenvironment, alter interferon, complement, inflammasome, and cytokine pathways, and may enable saliva-assisted transmission and viral dissemination from the dermis. We highlight mounting evidence from other arboviruses demonstrating that the skin can act as both a barrier and a major amplifying organ, and we extrapolate testable hypotheses on how early cutaneous immune dynamics might influence CCHFV severity and hemorrhagic manifestations. Finally, we outline key knowledge gaps that, if answered, may inform the development of vaccines and therapeutics that harness cutaneous immunity to block systemic spread.
other
2026-08-05 | Pathogenicity and virulence of Crimean-Congo hemorrhagic fever virus: From enzootic maintenance to severe human disease
Crimean-Congo hemorrhagic fever (CCHF) is a severe tick-borne disease caused by Crimean-Congo hemorrhagic fever virus (CCHFV), an enveloped, negative-sense, tri-segmented RNA virus in the genus Orthonairovirus. The virus is endemic across Africa, the Middle East, Asia, and Europe, shaped by the ecology of ixodid ticks and their wildlife hosts. While infection in most vertebrates is asymptomatic, human disease ranges from mild illness to fulminant hemorrhagic fever with vascular leak, multiorgan failure, coagulopathy, and shock, with case-fatality rates up to 30% and no licensed countermeasures. This review synthesizes current understanding of CCHFV pathogenicity and virulence across its enzootic cycle. We highlight host and viral factors driving infection in ticks, intermediate hosts, and humans, including entry, immune evasion, and mechanisms underlying severe disease. We also identify key knowledge gaps and research priorities to advance understanding of CCHFV pathogenesis and inform strategies to mitigate severe disease.
2026-07-15 | Crimean-Congo hemorrhagic fever virus in the last four decades (1981-2025): global output, collaboration networks, and emerging frontiers.
Crimean-Congo Hemorrhagic Fever (CCHF) was first described in the 1930s and 40s, yet there is no study that has examined global research landscape of this important zoonosis. We undertook the first global and holistic bibliometric analysis on CCHF aimed at revealing gaps, trends and collaborative networks. We applied the SPAR-4-SLR protocol together with an expansive set of keywords to search and retrieve relevant studies from the Scopus database. Using our pre-defined inclusion criteria and removal of duplicates, a final dataset of 2540 studies were included for analysis. The dataset were analysed in Biblioshiny, VOSviewer, and R software. A total of 2,540 CCHF publications (1981-2025) were included in the final analysis. Overall, the number of studies showed a steady annual growth rate of 6.79%, with a sharp rise in outputs and citations after 2010. The correlation coefficient stood at R2 = 0.79. The research landscape was dominated by multi-authored collaborations, strong international partnerships, and a high share of original articles. Key contributors were from Iran, Turkey, the United States (USA), and Europe, with major funding driven by NIAID, NIH, and the European Commission. Funders and authors from African and other poorer regions were disproportionately lower despite the Congo (Africa) being the co-origin of the virus. Highly cited papers highlight advances in epidemiology, diagnostics, and tick-virus ecology. Frequently used keywords reflect strong focus on humans, CCHF virus, and surveillance. Core journals include Emerging Infectious Diseases, Antiviral Research, and PLoS Neglected Tropical Diseases. Keyword analysis showed a gradual transition from early basic studies to mechanistic, molecular, and One Health-oriented investigations. The CCHF research landscape is growing steadily, driven by strong international collaborations and major funding agencies. Persistent focus on surveillance and public health preparedness indicates a maturing, globally coordinated research landscape essential for controlling CCHF and protect public health.
2026-07-11 | Coagulopathy in viral haemorrhagic fevers and beyond: molecular mechanisms and targeted interventions.
Coagulopathy refers to any medical condition which affects the ability of the blood to clot. It can be caused due to genetic conditions like haemophilia, von Willebrand disease, or it can be caused through liver disease or deficiency of Vitamin K. It also involves a broad range of diseases affecting hemostasis as an unbalanced and even bidirectional relationship between thrombosis and bleeding. Coagulopathy can also be caused by thromboinflammation, as seen in VHFs like Ebola, Dengue, Marburg, Crimean-Congo Hemorrhagic Fever, Yellow Fever, and Hantavirus infection. The immune response and coagulation system are intricately linked in such cases. Infections from VHFs cause endothelial cell dysfunction through the immune response, monocytes/macrophages activation, and increased expression of tissue factor (TF), which in turn causes excessive thrombin production and fibrin formation. These conditions result in microvascular thrombosis, organ dysfunction, consumption of platelets and coagulation factors, causing a balanced but fragile state of hemostasis that could tip over towards either thrombosis or bleeding. New therapies have been developed that interfere with these processes, such as interference with the TF pathway (for instance, rNAPc2) and regulation of fibrinolysis (tranexamic acid). The recognition of the double-edged sword of coagulopathy is critical for the development of treatment strategies targeting coagulation disorders. This literature review discusses the molecular basis of immunothrombosis and endothelial dysfunction in VHFs.
2026-07-05 | The Impact of Admission Viral Load and Inflammatory Markers on Mortality and Prognosis in Crimean-Congo Hemorrhagic Fever.
This study aimed to evaluate the impact of admission viral load and biochemical parameters on mortality and disease severity in a large cohort of patients with Crimean-Congo Hemorrhagic Fever (CCHF). This retrospective cohort study included 492 adult patients diagnosed with CCHF between 2022 and 2025. Admission viral loads, laboratory parameters, and clinical findings were compared. Logistic regression and ROC analyses were performed to identify independent predictors and optimal cut-off values. The mortality rate was 9.8% (n = 48). In multivariate analysis, admission log-viral load was identified as a potent independent predictor of mortality (OR: 3.36, p < 0.001 95% CI: 2.88-8.95, p < 0.001), alongside CRP (OR: 1.02, p < 0.001). Notably, advanced age was a significant risk factor, associated with a 2.8% increased risk of mortality (OR: 1.028, p = 0.025). In a separate model for disease severity, log-viral load (OR: 1.71, p < 0.001), age (OR: 1.021, p = 0.002), and CRP (OR: 1.012, p < 0.001) were significant independent predictors of a severe clinical course. Conversely, higher fibrinogen levels (OR: 0.997, p = 0.025) were associated with reduced disease severity. A viral load cut-off of 6.69 log10 copies/mL predicted mortality with 85.4% sensitivity and a negative predictive value of 98%. Admission viral load serves as a primary early marker for both mortality and clinical severity in CCHF. While CRP reflects the host's inflammatory response, admission fibrinogen levels also provide critical prognostic information. Combined use of these markers can optimize early triage and clinical management in endemic regions.
2026-06-18 | Geographical distribution of Hyalomma marginatum Koch, 1844 in northwestern Spain from 2019 to 2024: A one health approach.
Hyalomma marginatum Koch, 1844, is a competent vector of the Crimean-Congo hemorrhagic fever virus (CCHFV) and other zoonotic pathogens, typically associated with warmer Mediterranean environments. Between 2019 and 2024, as part of the activities of the Galician Vector Surveillance Network (ReGaViVec), a passive surveillance program was carried out in the northwest of the Iberian Peninsula, involving regional Healthcare centers, livestock farms, equestrian facilities, Wildlife Rescue Centers, Veterinary clinics and private individuals. A total of 63 adult specimens were morphologically identified as H. marginatum, collected from humans (60.3%), free-range ungulates (35%), dogs (3.2%) and the environment (1.6%). The annual distribution ranged from 1.6% of the total in 2019 to 57.1% in 2024. Seasonal activity peaked in spring (54%), declined slightly in summer (44%) and was absent in winter. Most specimens (82.5%) came from areas under a Mediterranean climate and warm summers, and 66% were collected at locations less than 15 km from where the first specimen was found. Human infestations were primarily associated with agricultural activities (47.6%) and recreational walking in wooded areas (42.9%). Regarding human anatomical distribution, the most frequent attachment sites were the trunk (34.2%) and the lower extremities (21.1%). The continuing detection of H. marginatum ticks in the study area, along with changes in their spatial distribution over a 6-year period, highlights the need to implement surveillance protocols based on a 'One Health' approach to monitor the potential establishment of this vector in NW Spain, as well as the risk of some pathogens associated with it.
oligonucleotides
2026-04-24 | Modified mRNA Encoding the Crimean-Congo Hemorrhagic Fever Virus Nucleocapsid Protein Confers Robust Protection Against Lethal Challenge in Mice.
The Crimean-Congo Hemorrhagic Fever Virus (Orthonairovirus haemorrhagiae) causes a hemorrhagic fever with mortality rates reaching up to 40%. For years, this virus has maintained its position among the top priority pathogens identified by the World Health Organization (WHO). This is due to its endemic presence across a vast region-from Africa and Spain to the Balkans, the Middle East, and throughout Asia-its potential for human-to-human transmission, and the lack of an effective and approved vaccine or treatment. Therefore, the development of an effective vaccine against CCHFV is of critical importance. Building on the success of mRNA-based vaccines during the Coronavirus Disease 2019 (COVID-19) pandemic, this study reports the development of a messenger ribonucleic acid (mRNA) vaccine candidate expressing the nucleocapsid protein (NP) of CCHFV. The CCHFV NP in vitro transcript (IVT) was designed with pseudouridine (Ψ) nucleoside modification. As part of the preclinical characterization of the IVT vaccine candidate, the biochemical and immunological properties of NP were confirmed in Huh-7 cells transfected with IVT NP-ΨmRNA. Afterwards, the efficacy of IVT NP-ΨmRNA immunization was evaluated in immunocompetent BALB/c and transiently immunosuppressed (IS) C57BL/6 mice. In CCHFV challenge studies, IS C57BL/6 mice were used. IS C57BL/6 mice were immunized intramuscularly with 2 doses of IVT NP- ΨmRNA, either naked or encapsulated in Poly(lactic-co-glycolic acid) (PLGA) nanoparticles, administered 14 days apart. High levels of CCHFV NP-specific humoral (IgM and IgG) and cellular (cytokine and lymphoproliferative) responses were demonstrated in BALB/c mice immunized with IVT NP- ΨmRNA. In challenge experiments, 100% survival was observed with both the naked and PLGA-encapsulated IVT NP-ΨmRNA immunizations. These findings demonstrate 100% survival following lethal CCHFV challenge under the experimental conditions tested in this mouse model and support the potential of NP-encoding pseudouridine-modified mRNA vaccines. Additionally, 100% survival was observed in mice immunized with inactivated CCHFV, whereas only 20% survival was detected in the unmodified IVT NP-mRNA vaccinated animals. In the protected mice, viral clearance was observed in the spleen, liver tissues, and blood on day 14 post-challenge. This study demonstrates that NP, the most abundant protein of the virus, is capable of providing significant survival benefits in the tested mouse model. Furthermore, our report represents a significant step in identifying a potential vaccine candidate and provides a solid foundation for further preclinical studies necessary to support future clinical development.
2026-01-17 | Field vaccination against CCHFV and Hyalomma tick infestation reduces multiple tick-borne infections in sheep.
Tick-borne pathogens (TBPs) are expanding globally, with their impact on public health expected to rise due to climate change. Immunizing livestock offers a cost-effective alternative or adjunct to human vaccination. We evaluated two DNA vaccines, one targeting Crimean-Congo hemorrhagic fever virus (CCHFV) and another targeting Hyalomma tick infestation. The Hyalomma-targeting vaccine was designed to disrupt tick feeding by targeting midgut proteins essential for blood digestion and survival; however, its direct role in preventing CCHFV transmission remains unconfirmed. Here, we demonstrate that two doses of the CCHFV vaccine significantly reduced the risk of CCHFV infection in naturally exposed sheep. We further investigated whether the Hyalomma vaccine provided cross-protection against Wad Medani virus (WMV) and Rickettsia conorii, two TBPs endemic to Senegal. Sheep were vaccinated intramuscularly with two doses of DNA vaccine, followed by electroporation, and monitored under natural farming conditions in an endemic region of Senegal. Natural infection with CCHFV, WMV, and R. conorii was assessed longitudinally using pathogen-specific IgG seroconversion as the primary endpoint. The Hyalomma vaccine reduced WMV acquisition, whereas its effect on R. conorii was less pronounced. These findings underscore the potential of veterinary vaccines to mitigate multiple TBPs and reinforce their established role in reducing tick-borne diseases.
2025-12-13 | A single-dose mRNA vaccine protects mice from lethal Crimean-Congo hemorrhagic fever virus infection.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus of the Orthonairovirus genus, Nairoviridae family, that causes severe febrile hemorrhagic disease in humans with a case fatality rate ranging from approximately 3-30%. This zoonotic pathogen is distributed across a broad geographic area spanning Asia, Europe, and Africa. Despite its significant public health threat and outbreak potential, no licensed vaccines are available. In this study, we developed and systematically assessed the immunogenicity and protective efficacy of mRNA vaccines encoding either CCHFV nucleoprotein (NP) or glycoprotein precursor (GPC) in mouse models. Vaccination with the NP-encoding mRNA alone provided complete protection against lethal cross-genotype CCHFV challenge. Moreover, combined vaccination with both the NP and GPC mRNAs elicited robust immune responses and conferred protection against CCHFV infection. Notably, a single-dose immunization with 2 μg mRNA-NP was sufficient to confer protection against lethal challenge. Furthermore, the passive transfer of NP-immune serum provided partial protection, supporting the role of NP-specific antibodies in mediating protection. Overall, these mRNA vaccines demonstrate protective efficacy against CCHFV, with combined antigenic protection and dose-sparing potential, highlighting their potential for outbreak preparedness and further clinical development.
2025-11-22 | Durable humoral immunity and long-term protection induced by a Crimean-Congo hemorrhagic fever virus replicon particle vaccine in mice.
A Crimean-Congo hemorrhagic fever virus replicon particle vaccine was evaluated for long-term immunity and efficacy in mice. IgG responses persisted up to 18 months, with similar titers across dosing strategies through 12 months. Protective efficacy reached ≥75% at 6 months (prime-only) and up to 12 months (prime-boost). Booster dosing enhanced antibody avidity, effector function, and improved long-term protection. These findings support durable immunity from single or boosted vaccination.
2025-09-15 | CCHFV-M based DNA vaccine is highly immunogenic in multiple species and protects against challenge in cynomolgus macaques.
Crimean-Congo hemorrhagic fever virus (CCHFV), a member of the Nairoviridae family, is the most widely distributed tick-borne virus of medical importance. There are no internationally licensed vaccines, and treatment is limited to supportive care. We previously developed a DNA vaccine expressing the full-length codon-optimized M-segment (CCHFV-MAfg09), encoding the structural and non-structural viral glycoproteins that protects mice against CCHFV when delivered by intramuscular electroporation (IM-EP). Here, the immunogenicity and protective efficacy of the vaccine delivered by IM-EP was assessed in the non-lethal CCHFV cynomolgus macaque model. The vaccine elicited a significant antibody response to two glycoproteins, the structural GC and non-structural GP38. CCHFV-MAfg09 elicited quantifiable T-cell responses directed against the glycoproteins encoded within the M-segment, with anti-GN immunity reaching significance. Upon intravenous infection with CCHFV, the vaccine protected 5/6 animals against viremia and reduced the pro-inflammatory response compared to sham vaccinated macaques. Numerous macaques also had detectable viral protein and viral RNA in several tissues 28 days post infection. In addition, we determined that an alternative delivery modality, jet injection, was immunogenic in both rabbits and mice, and conferred significant protection in mice. The simplicity and efficacy of disposable syringe needle-free injection system (NFIS) provides a pragmatic approach to advance the CCHF-M DNA vaccine into the clinic. Our M-segment based DNA vaccine elicits both cellular and humoral immunity and significant protection in mice and NHPs, demonstrating for the first time that a vaccine based on the glycoproteins alone is efficacious in the NHP model, which has not previously been shown.
antibodies
2026-07-21 | The growing public health concern of Crimean-Congo Hemorrhagic Fever Virus (CCHFV)
The growing public health concern of Crimean-Congo Hemorrhagic Fever Virus (CCHFV) Mohammad M. Sajadi and Scott D. Pegan discuss leveraging cross-reactive monoclonals and next-generation vaccines to address Crimean-Congo hemorrhagic fever virus diversity. Crimean-Congo hemorrhagic fever virus (CCHFV) is a zoonotic negative (-) sense RNA bunyavirus of the Nairoviridae family. CCHFV is widely distributed across Africa and wide swaths of Europe and Asia. It has also recently emerged, with fatal consequences, in the previously CCHFV-naïve country of Spain and has been detected in ticks in France. This underscores the virus’s propensity to continue spreading wherever its Hyalomma tick vector can gain a foothold. (1) Typical mortality rates for CCHFV range from 2-40% in hospitalized cases. (2) As additional countries are becoming at risk and the potential for significant human-to- human transmission increases, CCHFV is considered a dangerous human pathogen by the international community. It is also an NIAID prototype virus for several Nairovirus pathogens that can cause human disease of varying severity.(3)
2026-05-18 | A hyperimmune ovine antibody-based therapeutic candidate against Crimean-Congo haemorrhagic fever virus targeted to the Gn and Gc glycoproteins: high antibody levels with neutralization activity but lack of protective efficacy in a mouse model.
Crimean-Congo haemorrhagic fever virus (CCHFV) is a tick-borne pathogen that has a wide geographical range and has the potential to cause severe disease in those infected. There are no currently approved vaccines or therapeutics, so the development and assessment of new approaches are urgently required. A polyclonal antibody-based therapeutic was developed based on immunization of sheep with the major glycoprotein antigens from CCHFV. Along with purified immunoglobulin G (IgG) from hyperimmune sera, fragmentation of the F(ab')2 region was also performed. The pharmacokinetic properties were assessed in mice, and efficacy was ascertained in a live CCHFV challenge model. Candidate polyclonal antibody-based therapies were developed, demonstrating strong binding to the CCHFV envelope glycoprotein and neutralizing activity. The ovine whole IgG demonstrated stability post-delivery compared to a rapid reduction of the F(ab')2 fragment in the circulation. Efficacy testing when delivered either as a single dose before challenge or as daily dosing for 7 days starting on the day of challenge showed no demonstrable evidence of protection against infection. Despite protection observed from vaccine candidates using the CCHFV glycoprotein as an antigen and administration of convalescent sera, the ovine antibody-based therapeutics did not confer similar efficacious effects in the mouse preclinical model.
2026-03-31 | Human antibody targeting Crimean-Congo hemorrhagic fever virus glycoprotein 38 protects mice against heterologous virus challenge.
Crimean-Congo hemorrhagic fever virus (CCHFV) is an emerging arboviral and zoonotic bunyavirus. CCHFV can infect livestock, wild animals, and humans. Here, we report the isolation of a panel of mAbs from the B cells of an immune individual following a natural nosocomial infection. We determined that the panel comprised antibodies that bound to 2 glycoproteins: (a) the carboxy-terminal glycoprotein (Gc) that serves as the fusion protein and (b) the glycoprotein 38 (GP38). By antibody variable gene analysis, we identified genetic diversity in the B cell response to CCHFV within a single donor for both Gc- and GP38-specific responses. Protection against most bunyavirus-associated diseases is mediated principally by neutralizing antibodies, but here, we found that neutralization activity was not associated with protection. Gc-specific antibodies to diverse antigenic sites neutralized only weakly and did not protect against heterologous virus challenge. GP38-specific antibodies bound to 2 dominant antigenic sites on the glycoprotein. Although GP38-specific antibodies did not neutralize the virus, one mediated protection against heterologous virus challenge in an experimental model of infection in mice primarily by complement-mediated activity. These studies support the development of protective CCHFV countermeasures against GP38.
2026-03-28 | Divergent pathogenesis of two Chinese Crimean-Congo hemorrhagic fever viruses in cynomolgus macaques.
Crimean-Congo hemorrhagic fever (CCHF), a highly pathogenic tick-borne disease in humans with mortality rates ranging from 5% to 82%. Although cynomolgus macaques have been used to model infection with strains such as Hoti and Afghanistan, the pathogenic characteristics of Chinese CCHFV isolates remain insufficiently defined. We evaluated the pathogenicity of two Chinese CCHFV strains in cynomolgus macaques: BA04032 (tick-derived) and 75024 (non-lethal human clinical isolate). Animal were monitored for clinical parameters, viremia, hematologic and biochemical changes, viral RNA loads in blood, swabs, and tissues, as well as histopathological alterations. Infection with strain 75024 resulted in mild disease manifestations, whereas infection with strain BA04032 produced more severe illness characterized primarily by fever, viremia, thrombocytopenia, leukopenia, and extensive viral replication in multiple organs. Although both viruses belong to the Asian lineage, phylogenetic analyses classify them into different genotypes, which may correlate with their distinct clinical and virological outcomes in this model. These findings demonstrate that Chinese isolates exhibit distinct clinical, virological, and pathological phenotypes in cynomolgus macaques, underscoring the value of this model for recapitulating aspects of CCHF disease, for pathogenesis research, and for evaluating medical countermeasures.
2026-03-23 | Venturing into host-pathogen interaction in Crimean-Congo hemorrhagic fever to highlight terra incognita.
Crimean-Congo- Hemorrhagic Fever (CCHF) is the most widespread tick-borne disease in the world with a highly variable case fatality rate. It is caused by the CCHF virus (CCHFV). The disease, which has neither approved treatments nor vaccines, has long received very little attention until it was listed as a priority pathogen by WHO. Improving our understanding of mechanisms of host-virus interaction is essential for the development of effective therapeutic and prophylactic strategies. There is still much to be clarified to better understand how the virus interacts with its host and humans. Elucidating these mechanisms will provide insights into viral pathogenesis, immune evasion strategies, and host defense responses. As a result, this will stimulate the development of targeted interventions to mitigate disease severity and improve clinical outcomes. Better understanding of virus characteristics will also improve our surveillance capability which is critical for developing effective pandemic preparedness and outbreak response strategies. Here, we examine the existing landscape concerning the immune response and inflammatory events in CCHFV-human interaction and discuss gaps in our understanding of the disease. Such discussions allow us to highlight priority research directions for the identification of potential targets for improved mitigation approaches or specific therapeutic routes.
small molecules
2026-07-28 | Repurposing Small-molecule Inhibitors against Bunyaviruses: Advances, Mechanisms, and Therapeutic Prospects.
Bunyaviricetes, including highly pathogenic members such as Severe Fever with Thrombocytopenia Syndrome Virus, Crimean-Congo Hemorrhagic Fever Virus, and Rift Valley Fever Virus, pose significant global health threats characterized by high mortality rates and a lack of approved specific therapeutics. Drug repurposing provides pharmaceutical companies with cost-effective and expedited strategies to discover innovative treatment options for patients. Given the issue of antiviral drug resistance and the high cost of developing new antiviral drugs, drug repurposing offers enormous potential for expanding the repertoire of available therapeutics. This paper reviews the progress made in developing candidate drugs against bunyaviruses through high-throughput screening and drug repurposing methods, summarizes the mechanisms of action of candidate drugs targeting viruses and host cells, and looks ahead to future trends in the development of small-molecule antiviral drugs, with the aim of providing a reference for promoting the development of new bunyavirus drugs.
2026-07-23 | Structures and inhibition of the Crimean-Congo haemorrhagic fever virus polymerase.
Crimean-Congo haemorrhagic fever virus (CCHFV) is a tick-borne virus and causes severe, often fatal, human infections. Lacking licensed vaccines or drugs, CCHFV is a World Health Organization priority pathogen requiring urgent development of medical countermeasures1,2. The CCHFV Large (L) protein functions as the viral RNA-dependent RNA polymerase CCHFV-L, representing a promising antiviral target, and is among the largest viral polymerases in the order Bunyavirales. Here we define the cofactors required for CCHFV-L RNA synthesis in vitro, enabling capture and determination of elongating CCHFV-L-RNA complex structures. The structures show a markedly enlarged polymerase architecture, revealing that CCHFV-L RNA synthesis is accompanied by ordering of the polymerase peripheral domains. We also define how the baloxavir-derived experimental drug WXSH0208 (ref. 3) and the nucleoside analogue 2'-deoxy-2'-fluorocytidine4,5, which has nanomolar cellular potency, inhibit this polymerase through endonuclease inhibition and post-translocation chain termination, respectively. Together, these results should structurally guide rational optimization of inhibitors directed against CCHFV-L.
2026-07-15 | Structure-Guided Discovery and Biochemical Validation of Novel Small-Molecule Inhibitors Predicted to Target the CCHFV OTU Protease Y89-W99 Pocket.
Crimean-Congo hemorrhagic fever virus (CCHFV) remains a major public health threat due to its high mortality rates and the absence of approved antiviral therapies. The viral ovarian tumor (OTU) protease is a critical virulence factor that suppresses host innate immunity through its deubiquitinase activity, making it an attractive therapeutic target. In this study, we employed a structure-guided approach to identify and validate novel small-molecule inhibitors targeting the non-catalytic Y89-W99 pocket of the OTU protease. Recombinant OTU protease was successfully expressed, purified, and refolded, yielding a soluble and enzymatically active protein. Cellular assays confirmed that the enzyme retains robust deubiquitinase activity, significantly reducing global ubiquitin conjugates in mammalian cells. In silico analysis of a putative DUB inhibitor library identified several candidate inhibitors with favorable binding interactions within the Y89-W99 pocket. Biochemical validation using a fluorometric Ub-AMC assay revealed that multiple small molecules strongly inhibit OTU activity, including OTUi-10 (~93% inhibition), OTUi-13 (~87%), OTUi-1 (~85%), OTUi-4 and OTUi-11 (~81%), and OTUi-9 (~76%). Additional moderate inhibitors included OTUi-12 (~67%), OTUi-19 and OTUi-21 (~66%), and OTUi-5 (~57%). In silico drug-likeness and toxicity profiling filtered the library to four fully compliant candidates, OTUi-4, OTUi-10, OTUi-11, and OTUi-12, all free of predicted toxicity alerts. These findings suggest that the Y89-W99 pocket may be a pharmacologically relevant site worthy of further investigation and identify OTUi-10, OTUi-4, and OTUi-11 as promising preliminary hit compounds. The results also provide initial insights that may guide future optimization and mechanistic studies of OTU protease inhibitors targeting CCHFV.
2026-07-14 | Structures of the Crimean-Congo hemorrhagic fever virus RNA-dependent RNA polymerase.
Crimean-Congo hemorrhagic fever virus (CCHFV), designated by the WHO as a priority pathogen under its R&D Blueprint for emerging epidemics, poses a major global health threat, yet licensed vaccines or specific antiviral treatments are lacking. As the sole viral enzyme responsible for genome replication and transcription, the CCHFV L protein is a large, multienzymatic protein, but its exceptional size (> 450 kDa) and extensive domain architecture have hindered structural analysis. Here, we present high-resolution cryo-electron microscopy structures of the full-length CCHFV L protein in its apo state and bound to the 5' viral RNA promoter. These structures reveal the largest polymerase known among Bunyavirales and demonstrate that the apo form adopts a highly flexible conformation in which multiple functional elements remain disordered. Binding of the 5' promoter RNA triggers extensive conformational rearrangements that organize these elements into a catalytically competent active site. We define a conserved 5' hook-binding mode and identify two previously unrecognized residues (K1545 and E1637) that form a constriction at the NTP entry channel, representing newly defined regulatory motifs J and K conserved across Bunyavirales. We further characterize an expanded pendant domain unique to nairoviruses that, although not essential for promoter binding, likely modulates template movement within the internal tunnel during RNA synthesis. Our results provide the first structural framework for a nairovirus polymerase, illuminate the mechanisms of CCHFV RNA synthesis, and establish a foundation for structure-guided antiviral development against this high-priority pathogen.
2026-05-22 | Isolation of Rhizoma Paridis saponins as novel entry inhibitors of Crimean-Congo hemorrhagic fever virus.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic bunyavirus, causing Crimean-Congo hemorrhagic fever (CCHF) in humans with high morbidity and mortality. Currently, there are no licensed antiviral drugs or vaccines against CCHFV, emphasizing the critical need to develop novel antiviral agents. The entry process is the initial step during the viral life cycle, and has provided an attractive target for novel antiviral development. In the present study, we developed a high-throughput screening approach based on the CCHFV glycoprotein (Gn/Gc)-based HIV-1 pseudoviruses, in order to discover novel CCHFV entry inhibitors. As a pilot, a library consisting of 500 pre-purified fractions of traditional Chinese medicine was screened, and it was identified that multi-fractions of Rhizoma Paridis exhibited inhibitory effects against CCHFV entry. Next, bioactivity-guided isolation was performed and a range of Rhizoma Paridis saponins were characterized as potential anti-CCHFV actives. Moreover, the antiviral activities of both Rhizoma Paridis extracts and the saponin derivatives were validated by a cell-based assay using authentic viruses. Mechanistic studies further demonstrated that Rhizoma Paridis saponins act by targeting host factors. In summary, this study provides a promising new strategy for CCHF treatment that deserves further development in the future.
vaccines
2026-06-22 | Finding the Goldilocks zone: Modulating glycoprotein cleavage and fusogenicity optimizes the efficacy of a candidate Crimean-Congo hemorrhagic fever virus vaccine.
Crimean-Congo hemorrhagic fever virus (CCHFV) is the etiologic agent of a lethal hemorrhagic disease spread by ticks throughout Europe, the Middle East, Africa and Asia. The lack of approved medical countermeasures and fundamental understanding of molecular mechanisms of viral assembly and egress have thus far curtailed disease prevention. Here, we identify and characterize key residues within the viral glycoprotein through forward and reverse genetics for vesicular stomatitis virus (VSV)-based vaccine candidates that are highly protective in animal models. These residues are broadly applicable across divergent CCHFV strains and lead to greater protection in vivo against heterologous challenge. We further characterize the essential role of proteolytic processing in the maintenance of a stable fusogenic state required for effective VSV-based CCHFV vaccines. This study establishes a toolkit for better understanding orthonairovirus glycoprotein processing and vaccine development.
2026-06-04 | Crimean-Congo hemorrhagic fever virus protein GP38 from isolate M18-China confers broad immunological breadth.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne, negative-strand RNA virus that causes outbreaks of lethal hemorrhagic fever. No approved vaccines or specific antiviral treatments are available. CCHFV glycoprotein GP38 is an integral component of the pre-fusion glycoprotein entry complex, plays roles in viral pathogenesis, and is a key target of antibody-mediated protection. Herein, we investigated the hypothesis that recombinant GP38 itself could elicit protection against divergent CCHFV isolates/strains in an animal model. Accordingly, we generated GP38 immunogens from six CCHFV clades and showed that GP38 from the isolate M18-China induces a broad immunological response in mice despite its lower amino acid sequence similarity to other isolates. We identified sequences in M18-China GP38 associated with this immunological breadth and evaluated it as a vaccine candidate. Although M18-China GP38 was not protective in isolation, our findings warrant further exploration of its utility as one component of a broadly protective CCHFV vaccine.
2026-05-09 | Bioinformatics and immunoinformatic approaches for structural modeling and vaccine design of the CCHFV whole genome to develop a novel broad-spectrum multiepitope vaccine candidate.
Crimean-Congo hemorrhagic fever virus (CCHFV), the causative agent of Crimean-Congo hemorrhagic fever (CCHF), represents the most widely distributed tick-borne viral disease in humans and is currently managed only through supportive care. Consequently, considerable efforts have been directed toward the development of an effective vaccine to control this pathogen. Here, we report the first comprehensive in silico prediction of immunogenic CD8⁺ T cells, CD4⁺ T cells, and B-cell epitopes across the S, M, and L segments of CCHFV. Candidate epitopes were evaluated for conservation in mouse and human homologs of HLA alleles, as well as for antigenicity, toxicity, sequence homology, cellular topology, and binding affinity to a broad range of human leukocyte antigen (HLA) alleles. The final multiepitope vaccine construct was assembled by linking selected epitopes with an adjuvant via KK, AAY, and GPGPG linkers. Codon optimization and in silico cloning into prokaryotic and eukaryotic expression vectors confirmed high-level expression potential in Escherichia coli and human cells. Molecular docking analyses demonstrated that the vaccine-derived epitopes bind HLA molecules with affinities comparable to those of naturally processed peptides. Molecular dynamics simulations further revealed stable and robust interactions between the vaccine construct and Toll-like receptors (TLRs) throughout the simulation period, indicating the potential to elicit strong immune activation upon administration. The designed vaccine is predicted to stimulate both humoral and cellular immunity effectively. Although the construct exhibits promising immunogenicity, safety, and stability in silico, experimental validation in appropriate model systems is warranted to substantiate these findings.
2026-05-07 | Immunopathogenic insights into members of the class Bunyaviricetes: a comparative review of emerging zoonotic threats.
The class Bunyaviricetes encompasses a diverse group of vector- and rodent-borne viruses, many of which are major human pathogens causing severe and often lethal diseases worldwide. These include Lassa fever virus (Arenaviridae), hantaviruses such as Hantaan and Andes viruses (Hantaviridae), Crimean-Congo hemorrhagic fever virus (Nairoviridae), La Crosse and Oropouche viruses (Peribunyaviridae), and Rift Valley fever, severe fever with thrombocytopenia syndrome, and Toscana viruses (Phenuiviridae). Clinical syndromes range from hemorrhagic fever with multiorgan failure, vascular leak, and shock to acute encephalitis and severe respiratory distress. Despite their public health impact, safe and effective vaccines or targeted therapeutics are lacking for most bunyaviricetes diseases, leaving supportive care as the primary intervention. This review provides a comparative analysis of the immunopathogenesis of major human-pathogenic bunyaviricetes, highlighting shared and virus-specific strategies for innate immune evasion, cytokine modulation, and host cell targeting. Severe disease often arises from viral interference with key sensing pathways, such as RIG-I/MDA5 and downstream IRF and NF-κB signaling, which either suppresses interferon responses or leads to dysregulated inflammation. By integrating molecular, immunological, and clinical insights, we outline how these immune-virus interactions shape disease trajectory and severity. Understanding these mechanisms is critical for guiding the rational design of vaccines, antivirals, and immunomodulatory therapies, and for strengthening preparedness against these persistent zoonotic threats.
2026-04-01 | Skin Deep: Uncovering the Early Events of Crimean–Congo Hemorrhagic Fever Virus at the Tick–Host–Virus Interface
Crimean-Congo hemorrhagic fever virus (CCHFV) is transmitted predominantly through the bite of infected Hyalomma ticks, yet the earliest events at the vector–host–virus interface in human skin remain largely undefined. This review synthesizes current knowledge of human cutaneous structure and immunity, tick feeding biology, and salivary immunomodulation to propose how local skin responses may shape systemic outcomes of CCHFV disease. We detail the roles and permissiveness of major skin-resident and infiltrating cell types, including keratinocytes, melanocytes, Langerhans cells, dermal dendritic cells, monocytes/macrophages, fibroblasts, granulocytes, T cells, B cells, NK cells, and innate lymphoid cells, in antiviral defense and as potential early targets or carriers of CCHFV. Emphasis is placed on how tick saliva components reprogram the cutaneous microenvironment, alter interferon, complement, inflammasome, and cytokine pathways, and may enable saliva-assisted transmission and viral dissemination from the dermis. We highlight mounting evidence from other arboviruses demonstrating that the skin can act as both a barrier and a major amplifying organ, and we extrapolate testable hypotheses on how early cutaneous immune dynamics might influence CCHFV severity and hemorrhagic manifestations. Finally, we outline key knowledge gaps that, if answered, may inform the development of vaccines and therapeutics that harness cutaneous immunity to block systemic spread.
other
2026-08-05 | Pathogenicity and virulence of Crimean-Congo hemorrhagic fever virus: From enzootic maintenance to severe human disease
Crimean-Congo hemorrhagic fever (CCHF) is a severe tick-borne disease caused by Crimean-Congo hemorrhagic fever virus (CCHFV), an enveloped, negative-sense, tri-segmented RNA virus in the genus Orthonairovirus. The virus is endemic across Africa, the Middle East, Asia, and Europe, shaped by the ecology of ixodid ticks and their wildlife hosts. While infection in most vertebrates is asymptomatic, human disease ranges from mild illness to fulminant hemorrhagic fever with vascular leak, multiorgan failure, coagulopathy, and shock, with case-fatality rates up to 30% and no licensed countermeasures. This review synthesizes current understanding of CCHFV pathogenicity and virulence across its enzootic cycle. We highlight host and viral factors driving infection in ticks, intermediate hosts, and humans, including entry, immune evasion, and mechanisms underlying severe disease. We also identify key knowledge gaps and research priorities to advance understanding of CCHFV pathogenesis and inform strategies to mitigate severe disease.
2026-07-15 | Crimean-Congo hemorrhagic fever virus in the last four decades (1981-2025): global output, collaboration networks, and emerging frontiers.
Crimean-Congo Hemorrhagic Fever (CCHF) was first described in the 1930s and 40s, yet there is no study that has examined global research landscape of this important zoonosis. We undertook the first global and holistic bibliometric analysis on CCHF aimed at revealing gaps, trends and collaborative networks. We applied the SPAR-4-SLR protocol together with an expansive set of keywords to search and retrieve relevant studies from the Scopus database. Using our pre-defined inclusion criteria and removal of duplicates, a final dataset of 2540 studies were included for analysis. The dataset were analysed in Biblioshiny, VOSviewer, and R software. A total of 2,540 CCHF publications (1981-2025) were included in the final analysis. Overall, the number of studies showed a steady annual growth rate of 6.79%, with a sharp rise in outputs and citations after 2010. The correlation coefficient stood at R2 = 0.79. The research landscape was dominated by multi-authored collaborations, strong international partnerships, and a high share of original articles. Key contributors were from Iran, Turkey, the United States (USA), and Europe, with major funding driven by NIAID, NIH, and the European Commission. Funders and authors from African and other poorer regions were disproportionately lower despite the Congo (Africa) being the co-origin of the virus. Highly cited papers highlight advances in epidemiology, diagnostics, and tick-virus ecology. Frequently used keywords reflect strong focus on humans, CCHF virus, and surveillance. Core journals include Emerging Infectious Diseases, Antiviral Research, and PLoS Neglected Tropical Diseases. Keyword analysis showed a gradual transition from early basic studies to mechanistic, molecular, and One Health-oriented investigations. The CCHF research landscape is growing steadily, driven by strong international collaborations and major funding agencies. Persistent focus on surveillance and public health preparedness indicates a maturing, globally coordinated research landscape essential for controlling CCHF and protect public health.
2026-07-11 | Coagulopathy in viral haemorrhagic fevers and beyond: molecular mechanisms and targeted interventions.
Coagulopathy refers to any medical condition which affects the ability of the blood to clot. It can be caused due to genetic conditions like haemophilia, von Willebrand disease, or it can be caused through liver disease or deficiency of Vitamin K. It also involves a broad range of diseases affecting hemostasis as an unbalanced and even bidirectional relationship between thrombosis and bleeding. Coagulopathy can also be caused by thromboinflammation, as seen in VHFs like Ebola, Dengue, Marburg, Crimean-Congo Hemorrhagic Fever, Yellow Fever, and Hantavirus infection. The immune response and coagulation system are intricately linked in such cases. Infections from VHFs cause endothelial cell dysfunction through the immune response, monocytes/macrophages activation, and increased expression of tissue factor (TF), which in turn causes excessive thrombin production and fibrin formation. These conditions result in microvascular thrombosis, organ dysfunction, consumption of platelets and coagulation factors, causing a balanced but fragile state of hemostasis that could tip over towards either thrombosis or bleeding. New therapies have been developed that interfere with these processes, such as interference with the TF pathway (for instance, rNAPc2) and regulation of fibrinolysis (tranexamic acid). The recognition of the double-edged sword of coagulopathy is critical for the development of treatment strategies targeting coagulation disorders. This literature review discusses the molecular basis of immunothrombosis and endothelial dysfunction in VHFs.
2026-07-05 | The Impact of Admission Viral Load and Inflammatory Markers on Mortality and Prognosis in Crimean-Congo Hemorrhagic Fever.
This study aimed to evaluate the impact of admission viral load and biochemical parameters on mortality and disease severity in a large cohort of patients with Crimean-Congo Hemorrhagic Fever (CCHF). This retrospective cohort study included 492 adult patients diagnosed with CCHF between 2022 and 2025. Admission viral loads, laboratory parameters, and clinical findings were compared. Logistic regression and ROC analyses were performed to identify independent predictors and optimal cut-off values. The mortality rate was 9.8% (n = 48). In multivariate analysis, admission log-viral load was identified as a potent independent predictor of mortality (OR: 3.36, p < 0.001 95% CI: 2.88-8.95, p < 0.001), alongside CRP (OR: 1.02, p < 0.001). Notably, advanced age was a significant risk factor, associated with a 2.8% increased risk of mortality (OR: 1.028, p = 0.025). In a separate model for disease severity, log-viral load (OR: 1.71, p < 0.001), age (OR: 1.021, p = 0.002), and CRP (OR: 1.012, p < 0.001) were significant independent predictors of a severe clinical course. Conversely, higher fibrinogen levels (OR: 0.997, p = 0.025) were associated with reduced disease severity. A viral load cut-off of 6.69 log10 copies/mL predicted mortality with 85.4% sensitivity and a negative predictive value of 98%. Admission viral load serves as a primary early marker for both mortality and clinical severity in CCHF. While CRP reflects the host's inflammatory response, admission fibrinogen levels also provide critical prognostic information. Combined use of these markers can optimize early triage and clinical management in endemic regions.
2026-06-18 | Geographical distribution of Hyalomma marginatum Koch, 1844 in northwestern Spain from 2019 to 2024: A one health approach.
Hyalomma marginatum Koch, 1844, is a competent vector of the Crimean-Congo hemorrhagic fever virus (CCHFV) and other zoonotic pathogens, typically associated with warmer Mediterranean environments. Between 2019 and 2024, as part of the activities of the Galician Vector Surveillance Network (ReGaViVec), a passive surveillance program was carried out in the northwest of the Iberian Peninsula, involving regional Healthcare centers, livestock farms, equestrian facilities, Wildlife Rescue Centers, Veterinary clinics and private individuals. A total of 63 adult specimens were morphologically identified as H. marginatum, collected from humans (60.3%), free-range ungulates (35%), dogs (3.2%) and the environment (1.6%). The annual distribution ranged from 1.6% of the total in 2019 to 57.1% in 2024. Seasonal activity peaked in spring (54%), declined slightly in summer (44%) and was absent in winter. Most specimens (82.5%) came from areas under a Mediterranean climate and warm summers, and 66% were collected at locations less than 15 km from where the first specimen was found. Human infestations were primarily associated with agricultural activities (47.6%) and recreational walking in wooded areas (42.9%). Regarding human anatomical distribution, the most frequent attachment sites were the trunk (34.2%) and the lower extremities (21.1%). The continuing detection of H. marginatum ticks in the study area, along with changes in their spatial distribution over a 6-year period, highlights the need to implement surveillance protocols based on a 'One Health' approach to monitor the potential establishment of this vector in NW Spain, as well as the risk of some pathogens associated with it.
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Drug Discovery Landscape
1 orphan drug designation for Crimean-Congo hemorrhagic fever.
1 orphan drug designation for Crimean-Congo hemorrhagic fever.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Ribavirin | small molecules | EMA | 2018-03-21 | — | Pharmadev Healthcare Ltd |
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