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
516 drug discovery papers about Crimean-Congo hemorrhagic fever, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
516 drug discovery papers about Crimean-Congo hemorrhagic fever, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-09-26 | A Global, High-Resolution Index of Risk and Exposure of Humans to Ticks, Lyme Borreliosis, and Crimean-Congo Haemorrhagic Fever.
Ticks are among the most important arthropod vectors affecting human and animal health worldwide. We present a set of globally harmonized indicators integrating hazard, exposure, and vulnerability associated with human-biting ticks and with two major tick-borne pathogens, Borrelia burgdorferi sensu lato (Lyme borreliosis), and Orthonairovirus haemorrhagiae (Crimean-Congo haemorrhagic fever virus, CCHFV). Hazard indices were derived from the distributions of confirmed vector tick species. Exposure was incorporated through rural human population density, livestock density, and the abundance of competent vertebrate reservoirs and/or amplification hosts, as applicable. Vulnerability was assessed using country-level indicators related to healthcare accessibility, socioeconomic development, and demographic dependency. The indices show spatially structured global patterns. Tick hazard is concentrated in eastern North America, Europe, Central and East Asia; Africa displays fragmented but substantial hotspots. The B. burgdorferi s.l. index is restricted to the Northern Hemisphere, following the distribution of Ixodes spp. and associated reservoir communities, with highest exposure in Europe and North America. The CCHFV index is confined to the Old World, extending from the Mediterranean region through the Middle East and Central Asia into Sub-Saharan Africa, reflecting the distribution of Hyalomma ticks and ungulates. The vulnerability indicators highlight regional patterns of high exposure and limited adaptive capacity, particularly in Sub-Saharan Africa and parts of the Middle East. Our framework provides the first global set of harmonized, high-resolution indices integrating vector ecology, reservoir communities, exposure, and vulnerability for major tick-borne diseases of humans. It offers a flexible platform for comparative epidemiology, surveillance prioritization, and public health decision-making at multiple administrative scales.
2026-08-18 | Loss of type I interferon signaling in Kupffer cells triggers viral spread and fatal liver damage in a mouse model of Crimean-Congo hemorrhagic fever.
Crimean-Congo hemorrhagic fever (CCHF), which is caused by infection with the CCHF virus (CCHFV), is the most widespread hemorrhagic infectious disease. In severe cases, liver damage is a salient manifestation. However, the detailed mechanism is not yet fully understood. To investigate the pathogenesis of CCHF-related liver damage, we infected type I interferon receptor 1 knockout (IFNAR1-/-) mice with Hazara virus (HAZV), which is a surrogate pathogen of CCHFV, as well as with the CCHFV itself. HAZV infection caused CCHF-like symptoms, including severe liver damage, alongside inflammatory responses. HAZV infection in IFNAR1-/- mice additionally lacking mitochondrial antiviral signaling protein (MAVS) induced minimal cytokine responses; however, these mice still exhibited weight loss and liver damage, albeit with a significantly delayed onset of lethal outcomes. We found that loss of liver-resident macrophage, Kupffer cells, occurred prior to viral spread in hepatocytes and liver damage in these mice. Notably, mice lacking IFNAR1 in Kupffer cells, but not mice lacking IFNAR1 in hepatocytes, also lost Kupffer cell population and exhibited lethal liver damage, following HAZV and CCHFV infection. Our findings indicate that IFNAR1 signaling in mononuclear phagocytes, especially Kupffer cells, is essential for preventing viral spread and fatal liver damage and raise the possibility that inflammatory cytokines- and viral replication-mediated Kupffer cell loss synergistically drives both processes.
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.
antibodies
2026-09-26 | TRIM21 Neutralizes Hazara Virus Using a Dual Mechanism of Nucleoprotein Caging and Ubiquitination.
Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is a tick-borne bunyavirus with widespread and growing geographic distribution that causes severe hemorrhagic fever and death. Vaccine candidates targeting the viral nucleoprotein (NP) have shown efficacy in both mouse and non-human primate models but the mechanism of protection is unclear. Here we employ the closely related Hazara virus (HAZV) to investigate how the intracellular antibody receptor TRIM21 uses anti-NP antibodies to neutralize infection. We show that TRIM21 can detect incoming NP particles within hours of infection and that this results in a potent block to infection. Electroporated-antibody-dependent neutralization assay (EDNA) experiments reveal that TRIM21 inhibits viral transcription, protein expression and genome synthesis and reduces the production of infectious virions. Mutations and domain deletions within TRIM21 reveal that neutralization requires antibody-binding by the PRYSPRY domain but is only partially dependent on the E3 ubiquitin ligase RING domain. The data suggest a dual restriction mechanism in which NP cross-linking by TRIM21 physically interferes with NP function whilst parallel ubiquitination labels the protein for degradation. This dual mechanism is similar to that used by TRIM5 against retroviruses and suggests that antiviral TRIMs may utilize their capacity for self-assembly both for catalytic activation and viral caging.
2026-09-18 | Structural and mechanistic insights into protective non-neutralizing antibodies targeting Crimean-Congo hemorrhagic fever virus nucleocapsid protein.
Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is a tick-borne virus endemic to Africa, Asia, and expanding regions within Europe. With mortality rates approaching 40%, rising incidence, and no currently approved countermeasures, CCHFV is recognized as a priority public health threat. CCHFV nucleocapsid protein (NP) has long been a key target for diagnostics. Recently, NP-specific humoral responses have also been correlated with protection conferred by protective vaccines candidates. Additionally, the first non-neutralizing monoclonal antibody (mAb) 9D5 demonstrated protective efficacy against CCHFV challenge, underscoring NP as a viable antiviral target. Here, nine anti-NP mAb were utilized to identify four antigenic sites on NP as well as localize these sites to the head or stalk domains. These mAb also revealed variable levels of in vivo protection, independent from whether the epitope site is located in the head or stalk regions. Additionally, three X-ray crystallography structures were obtained that included CCHFV NP from strain Afg09-2990 in complex with the most potent mAb (9D5). This, along with additional structures of two unbound NPs, revealed structural elements critical for mAb-9D5 broad-spectrum protective characteristics. These findings provide a path towards the rapid identification of broadly protective anti-NP mAb countermeasures.
2026-09-14 | Non-neutralizing antibody responses control acute Crimean-Congo hemorrhagic fever virus infection in naïve mice.
Crimean-Congo hemorrhagic fever virus (CCHFV) is the cause of a sometimes-severe viral hemorrhagic fever, CCHF. Severe cases of CCHF often have little-to-no CCHFV-specific antibody responses prior to death. However, it is unclear if the failure to mount an antibody response is the cause of a poor outcome or a correlate of a failed host response. Here, we used a mouse-adapted strain of CCHFV (MA-CCHFV) to investigate the requirement of humoral immunity in control of acute CCHFV infection in immunocompetent mice. We found that mice infected with MA-CCHFV develop a rapid non-neutralizing antibody response, consistent with humans infected with CCHFV. Further, we found that the absence of humoral immunity in male but not female mice resulted in near-uniform mortality. Lastly, we determined that complement but not activating Fc-receptors nor the cytoplasmic Fc-receptor tripartite motif containing protein 21 contributed to antibody-mediated control of MA-CCHFV infection. Together, our findings identify rapid humoral immune responses as a critical component of the host response to acute CCHFV infection in naive hosts.IMPORTANCECrimean-Congo hemorrhagic fever virus (CCHFV) is the cause of a serious viral hemorrhagic fever in humans. Severe disease and poor outcomes are correlated with little-to-no CCHFV-specific antibody. However, it is unknown if the lack of CCHFV-specific antibody is a direct cause or merely a correlate of a poor outcome. Here, we investigated the contribution of humoral immunity in control of acute CCHFV infection in naive immunocompetent mice. We found that mice develop a rapid, non-neutralizing antibody response that is crucial for control of the acute infection. Further, we found that loss of complement but not activating Fc receptors or the cytoplasmic Fc receptor TRIM21 worsened disease. Together, our findings suggest that lack of CCHFV-specific antibody responses may directly contribute to poor outcomes in CCHFV-infected humans.
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.
small molecules
2026-09-30 | Meta-analysis of Maternal and Fetal Outcomes of Crimean-Congo Hemorrhagic Fever during Pregnancy.
Crimean-Congo hemorrhagic fever (CCHF) during pregnancy is associated with severe maternal and fetal complications, but evidence remains limited to heterogeneous case reports. We synthesized patient-level data from published and unpublished cases identified through systematic database searches and direct collaboration with centers in CCHF-endemic areas. We harmonized patient-level clinical, laboratory, obstetric, treatment, and outcome data for 55 pregnancies. The maternal mortality rate was 28.8% (15/52), and fetal loss occurred in 57.4% (31/54) of cases. Maternal mortality rates increased with advancing gestation, reaching 31.3% in the third trimester, but fetal loss was highest (85.7%) in the first trimester. Ribavirin treatment during the third trimester was associated with lower observed maternal mortality rates (odds ratio 0.33, 95% CI 0.13-0.84; p = 0.031). Our findings highlight gestational age-specific risks of CCHF and support the need for standardized management protocols and strengthened CCHF surveillance during pregnancy in endemic regions.
2026-09-27 | Discovery of potential RdRp catalytic domain inhibitors against Crimean-Congo hemorrhagic fever virus from Andrographis paniculata via LC-MS/MS profiling and computational approaches.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic zoonotic virus associated with significant mortality and currently lacks FDA-approved therapeutic options. Owing to its endemic nature and epidemic potential, it has been included in WHO priority pathogen list under its R&D Blueprint, highlighting the urgent need for development of novel antiviral agents. The present study explores antiviral potential of phytoconstituents from Andrographis paniculata targeting viral catalytic domain of RNA-dependent RNA polymerase (RdRp). Cold Ethanolic leaf extract was prepared using ultrasonic-assisted extraction and subjected to LC-MS/MS QQQ profiling, leading to identification of 44 phytochemicals, mostly andrographolide diterpenes lactones and flavonoids. Among these, 11 major compounds were selected based on abundance and spectral reliability for computational evaluation. Molecular docking revealed strong binding affinities of bisandrographolide (- 8.212 kcal/mol), andrographiside (- 7.659 kcal/mol), 3-O-β-D-glucopyranosyl-andrographolide (- 7.653 kcal/mol), andrographidin A (- 7.540 kcal/mol) and neoandrographolide (- 7.353 kcal/mol) towards the catalytic domain of RdRp which is comparable to standard Ribavirin (- 8.314 kcal/mol). MD simulations of 100 ns were performed which demonstrated stable Andrographis paniculata ligand-RdRp complexes through consistent RMSD, RMSF, radius of gyration, hydrogen bonding, minimum distance (~ 0.25-0.30 nm) and SASA profiles, except for neoandrographolide, showed comparatively lower conformational stability. In silico ADMET analysis indicated generally acceptable pharmacokinetic and safety profiles, although some compounds exhibited low GIT absorption. Collectively, results suggest that Andrographis paniculata phytoconstituents, particularly andrographolide diterpenes lactones possess promising inhibitory potential against catalytic domain of CCHFV RdRp and may serve as lead candidates for antiviral drug development. Further mechanistic studies are needed to elucidate exact mode of RdRp catalytic domain inhibition while in vitro and in vivo validation is crucial to confirm their therapeutic potential and translational relevance.
2026-09-04 | Cryo-EM structures of CCHFV polymerase reveal a stepwise initiation stabilization pathway and a dual-site inhibition mechanism.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a high-priority pathogen with high case-fatality rates, yet approved therapeutics remain unavailable. The CCHFV L segment encodes a ∼450-kDa RNA-dependent RNA polymerase (L protein) orchestrating viral replication, but its structural mechanisms remain elusive. Here, we present high-resolution cryo-EM structures of the CCHFV L protein in apo, 5' vRNA-bound, 5'/3' promoter-bound, and inhibitor-bound states. The catalytic core exhibits the canonical architecture of the Bunyavirales order, featuring conserved motifs and coordinated promoter recognition via a 5' vRNA "hook" and a secondary 3' vRNA-binding site. Using suramin as a probe, we identified a dual-site mechanism of polymerase inhibition. Suramin competitively occludes the 5' vRNA-binding pocket through electrostatic mimicry of the RNA backbone and concurrently traps a distal linker-fingers interface, restricting the conformational dynamics required for catalysis. Collectively, these findings provide structural insights into CCHFV polymerase regulation and inhibition.
2026-08-27 | RNA synthesis and substrate analogue inhibition in the CCHFV polymerase.
The about 4,000-residue L proteins from the Nairoviridae are the largest known viral polymerases, lacking global structural information and promising nucleotide analogue inhibitors. Here we report structures of full-length Nairoviridae Crimean-Congo haemorrhagic fever virus (CCHFV) L, including a 3.0 Å resolution polymerase elongation complex that elucidates mechanisms of both early and late elongation stages. Large additions and insertions are found in all three major functional regions that contain the endonuclease RNA-dependent RNA polymerase (RdRP) and cap-binding domain of CCHFV L, extending RNA-binding paths on both sides of the RdRP active site and creating interaction networks critical for viral replication, as suggested by CCHFV minigenome assay data. Nucleotide analogues with ribose-2' modifications identical to the hepatitis C drug sofosbuvir are found to specifically and efficiently inhibit CCHFV RdRP through an immediate chain termination mechanism. Using a sofosbuvir-hepatitis C virus RdRP system as the reference, the potency of these nucleotide analogues is further demonstrated in competition assays in the presence of corresponding nucleoside triphosphates.
2026-08-23 | Diagnosis, management, and prevention of Crimean-Congo haemorrhagic fever: a Delphi-based consensus study in Türkiye.
Crimean-Congo haemorrhagic fever (CCHF) is a widely distributed viral haemorrhagic fever with expanding geographic range. As new regions encounter the disease, clinicians must make high-stakes decisions despite limited standardised management frameworks. In this multicentre, modified Delphi study, infectious diseases specialists were recruited from 19 centres in Türkiye via an open call through the professional communication channels of the Turkish Society of Clinical Microbiology and Infectious Diseases (known as KLİMİK). Eligibility was determined based on self-reported clinical experience. Eligible participants reported managing more than ten patients with CCHF as primary physicians, with no additional demographic or professional exclusion criteria applied. The Delphi process included three sequential rounds of anonymous online surveys (between Sept 26 2025, and Jan 1, 2026) and an interim structured clarification meeting (Nov 28-29, 2025), to map areas of agreement and heterogeneity across diagnosis, monitoring, therapeutics, and exposure management. Statements were analysed using Likert-scale methodology. Responses were summarised using medians, interquartile ranges, and proportions of agreement. Consensus levels were defined a priori. Of 45 ID specialists invited to participate in Round 1, 35 completed the questionnaire and were included in the analysis (78% response rate). All 35 eligible participants were invited to Round 2, and 32 (91%) completed the questionnaire. All 32 participants completed Round 3, with no attrition between Rounds 2 and 3. All participants reported experience of managing more than ten patients with CCHF; ∼85% of participants reported managing at least 50 confirmed cases. In total, 146 candidate statements were evaluated, of which 72 achieved early consensus in Round 1. Following iterative refinement, 39 of 56 statements (69.6%) met predefined consensus criteria in the final round, including eight with very high agreement and 22 with high agreement. Strong convergence was observed for early molecular testing and risk-based hospitalisation, ribavirin initiation within 4 days of symptom onset in confirmed cases, risk-adapted transfusion strategies guided by bleeding severity, and post-exposure prophylaxis after high-risk occupational exposure. Persistent heterogeneity remained regarding ribavirin initiation beyond the early symptomatic window, immunomodulatory therapies, and transfusion de-escalation strategies in selected scenarios. These findings should not be interpreted as formal guidelines. By transparently quantifying expert agreement and non-consensus, this study synthesises specialist clinical experience from a high incidence country and delineates areas of convergence and ongoing uncertainty relevant to both endemic and newly affected regions. Prospective studies are needed to validate key therapeutic and management strategies identified in this work. None.
vaccines
2026-09-12 | Dual-antigen AdV5 vaccines against Crimean-Congo hemorrhagic fever virus induce superior humoral and Th1-biased cellular immunity.
Platforms based on adenoviral vectors have proven their efficiency in developing vaccines and therefore can be considered potential candidates for immunization strategies against CCHFV. In this study, four replication-deficient recombinant human adenovirus serotype 5 (AdV5) vectors were engineered to express CCHFV antigens: a dual-antigen NP-P2A-Gc construct and monocistronic constructs for nucleoprotein (NP), glycoprotein complex precursor (GPC), and mature glycoprotein (Gc). Following GMP-compatible production and purification, vaccine candidates were evaluated in BALB/c mice (n = 4 per group) for immunogenicity and in IFNAR-/- mice (n = 4 per group) for protective efficacy using antigenically homologous or heterologous prime-boost regimens. Animals received priming immunization on day 0 and booster on day 28 followed by lethal CCHFV challenge (1000 TCID50) on day 42. Immune responses were characterized via ELISA, virus neutralization tests, cytokine profiling, ELISpot, and flow cytometry. Post-challenge survival, viral loads in target organs, and safety profiles were assessed. All AdV5 constructs successfully expressed the target antigens and induced rapid seroconversion, with 75-100% of animals exhibiting antibody responses after priming with a single dose. The dual-antigen formulations elicited the strongest Th1-polarized responses particularly nucleoprotein + Gc combinations with interferon-γ production more than 30-fold above baseline and preferential expansion of CD4+ T helper cells (60-70% of CD3+ populations). Neutralizing antibody titers varied across groups (80-160 arbitrary units in high responders) but did not directly correlate with survival outcomes. After lethal challenge, multiple vaccine formulations achieved 100% survival throughout the 10-day observation period, while only control groups showed no protection. All vaccinated animals demonstrated significant viral load reduction of two to four logs in liver and spleen tissues, with some achieving complete clearance of the virus. Furthermore, no off-target vector dissemination was detected in examined tissues confirming safety profile of the constructs. Immunization with adenovirus serotype 5 (AdV5) vectors expressing CCHFV antigens elicited potent humoral and cellular immune responses, conferring 100% protection against lethal viral challenge across the majority of evaluated formulations. Sterilizing immunity was observed in some animals, along with evidence that protection operates through multiple immune mechanisms including both neutralizing and non-neutralizing antibody-mediated pathways. These results strongly support further clinical development of AdV5-based CCHFV vaccines, with multiple formulation strategies showing high efficacy and providing flexibility for clinical advancement. GMP-compatible production methods have been successfully implemented for these candidates, supporting their advancement toward non-human primate studies and Phase I clinical trials.
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.
other
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.
proteins
2026-09-26 | A Global, High-Resolution Index of Risk and Exposure of Humans to Ticks, Lyme Borreliosis, and Crimean-Congo Haemorrhagic Fever.
Ticks are among the most important arthropod vectors affecting human and animal health worldwide. We present a set of globally harmonized indicators integrating hazard, exposure, and vulnerability associated with human-biting ticks and with two major tick-borne pathogens, Borrelia burgdorferi sensu lato (Lyme borreliosis), and Orthonairovirus haemorrhagiae (Crimean-Congo haemorrhagic fever virus, CCHFV). Hazard indices were derived from the distributions of confirmed vector tick species. Exposure was incorporated through rural human population density, livestock density, and the abundance of competent vertebrate reservoirs and/or amplification hosts, as applicable. Vulnerability was assessed using country-level indicators related to healthcare accessibility, socioeconomic development, and demographic dependency. The indices show spatially structured global patterns. Tick hazard is concentrated in eastern North America, Europe, Central and East Asia; Africa displays fragmented but substantial hotspots. The B. burgdorferi s.l. index is restricted to the Northern Hemisphere, following the distribution of Ixodes spp. and associated reservoir communities, with highest exposure in Europe and North America. The CCHFV index is confined to the Old World, extending from the Mediterranean region through the Middle East and Central Asia into Sub-Saharan Africa, reflecting the distribution of Hyalomma ticks and ungulates. The vulnerability indicators highlight regional patterns of high exposure and limited adaptive capacity, particularly in Sub-Saharan Africa and parts of the Middle East. Our framework provides the first global set of harmonized, high-resolution indices integrating vector ecology, reservoir communities, exposure, and vulnerability for major tick-borne diseases of humans. It offers a flexible platform for comparative epidemiology, surveillance prioritization, and public health decision-making at multiple administrative scales.
2026-08-18 | Loss of type I interferon signaling in Kupffer cells triggers viral spread and fatal liver damage in a mouse model of Crimean-Congo hemorrhagic fever.
Crimean-Congo hemorrhagic fever (CCHF), which is caused by infection with the CCHF virus (CCHFV), is the most widespread hemorrhagic infectious disease. In severe cases, liver damage is a salient manifestation. However, the detailed mechanism is not yet fully understood. To investigate the pathogenesis of CCHF-related liver damage, we infected type I interferon receptor 1 knockout (IFNAR1-/-) mice with Hazara virus (HAZV), which is a surrogate pathogen of CCHFV, as well as with the CCHFV itself. HAZV infection caused CCHF-like symptoms, including severe liver damage, alongside inflammatory responses. HAZV infection in IFNAR1-/- mice additionally lacking mitochondrial antiviral signaling protein (MAVS) induced minimal cytokine responses; however, these mice still exhibited weight loss and liver damage, albeit with a significantly delayed onset of lethal outcomes. We found that loss of liver-resident macrophage, Kupffer cells, occurred prior to viral spread in hepatocytes and liver damage in these mice. Notably, mice lacking IFNAR1 in Kupffer cells, but not mice lacking IFNAR1 in hepatocytes, also lost Kupffer cell population and exhibited lethal liver damage, following HAZV and CCHFV infection. Our findings indicate that IFNAR1 signaling in mononuclear phagocytes, especially Kupffer cells, is essential for preventing viral spread and fatal liver damage and raise the possibility that inflammatory cytokines- and viral replication-mediated Kupffer cell loss synergistically drives both processes.
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.
antibodies
2026-09-26 | TRIM21 Neutralizes Hazara Virus Using a Dual Mechanism of Nucleoprotein Caging and Ubiquitination.
Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is a tick-borne bunyavirus with widespread and growing geographic distribution that causes severe hemorrhagic fever and death. Vaccine candidates targeting the viral nucleoprotein (NP) have shown efficacy in both mouse and non-human primate models but the mechanism of protection is unclear. Here we employ the closely related Hazara virus (HAZV) to investigate how the intracellular antibody receptor TRIM21 uses anti-NP antibodies to neutralize infection. We show that TRIM21 can detect incoming NP particles within hours of infection and that this results in a potent block to infection. Electroporated-antibody-dependent neutralization assay (EDNA) experiments reveal that TRIM21 inhibits viral transcription, protein expression and genome synthesis and reduces the production of infectious virions. Mutations and domain deletions within TRIM21 reveal that neutralization requires antibody-binding by the PRYSPRY domain but is only partially dependent on the E3 ubiquitin ligase RING domain. The data suggest a dual restriction mechanism in which NP cross-linking by TRIM21 physically interferes with NP function whilst parallel ubiquitination labels the protein for degradation. This dual mechanism is similar to that used by TRIM5 against retroviruses and suggests that antiviral TRIMs may utilize their capacity for self-assembly both for catalytic activation and viral caging.
2026-09-18 | Structural and mechanistic insights into protective non-neutralizing antibodies targeting Crimean-Congo hemorrhagic fever virus nucleocapsid protein.
Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is a tick-borne virus endemic to Africa, Asia, and expanding regions within Europe. With mortality rates approaching 40%, rising incidence, and no currently approved countermeasures, CCHFV is recognized as a priority public health threat. CCHFV nucleocapsid protein (NP) has long been a key target for diagnostics. Recently, NP-specific humoral responses have also been correlated with protection conferred by protective vaccines candidates. Additionally, the first non-neutralizing monoclonal antibody (mAb) 9D5 demonstrated protective efficacy against CCHFV challenge, underscoring NP as a viable antiviral target. Here, nine anti-NP mAb were utilized to identify four antigenic sites on NP as well as localize these sites to the head or stalk domains. These mAb also revealed variable levels of in vivo protection, independent from whether the epitope site is located in the head or stalk regions. Additionally, three X-ray crystallography structures were obtained that included CCHFV NP from strain Afg09-2990 in complex with the most potent mAb (9D5). This, along with additional structures of two unbound NPs, revealed structural elements critical for mAb-9D5 broad-spectrum protective characteristics. These findings provide a path towards the rapid identification of broadly protective anti-NP mAb countermeasures.
2026-09-14 | Non-neutralizing antibody responses control acute Crimean-Congo hemorrhagic fever virus infection in naïve mice.
Crimean-Congo hemorrhagic fever virus (CCHFV) is the cause of a sometimes-severe viral hemorrhagic fever, CCHF. Severe cases of CCHF often have little-to-no CCHFV-specific antibody responses prior to death. However, it is unclear if the failure to mount an antibody response is the cause of a poor outcome or a correlate of a failed host response. Here, we used a mouse-adapted strain of CCHFV (MA-CCHFV) to investigate the requirement of humoral immunity in control of acute CCHFV infection in immunocompetent mice. We found that mice infected with MA-CCHFV develop a rapid non-neutralizing antibody response, consistent with humans infected with CCHFV. Further, we found that the absence of humoral immunity in male but not female mice resulted in near-uniform mortality. Lastly, we determined that complement but not activating Fc-receptors nor the cytoplasmic Fc-receptor tripartite motif containing protein 21 contributed to antibody-mediated control of MA-CCHFV infection. Together, our findings identify rapid humoral immune responses as a critical component of the host response to acute CCHFV infection in naive hosts.IMPORTANCECrimean-Congo hemorrhagic fever virus (CCHFV) is the cause of a serious viral hemorrhagic fever in humans. Severe disease and poor outcomes are correlated with little-to-no CCHFV-specific antibody. However, it is unknown if the lack of CCHFV-specific antibody is a direct cause or merely a correlate of a poor outcome. Here, we investigated the contribution of humoral immunity in control of acute CCHFV infection in naive immunocompetent mice. We found that mice develop a rapid, non-neutralizing antibody response that is crucial for control of the acute infection. Further, we found that loss of complement but not activating Fc receptors or the cytoplasmic Fc receptor TRIM21 worsened disease. Together, our findings suggest that lack of CCHFV-specific antibody responses may directly contribute to poor outcomes in CCHFV-infected humans.
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.
small molecules
2026-09-30 | Meta-analysis of Maternal and Fetal Outcomes of Crimean-Congo Hemorrhagic Fever during Pregnancy.
Crimean-Congo hemorrhagic fever (CCHF) during pregnancy is associated with severe maternal and fetal complications, but evidence remains limited to heterogeneous case reports. We synthesized patient-level data from published and unpublished cases identified through systematic database searches and direct collaboration with centers in CCHF-endemic areas. We harmonized patient-level clinical, laboratory, obstetric, treatment, and outcome data for 55 pregnancies. The maternal mortality rate was 28.8% (15/52), and fetal loss occurred in 57.4% (31/54) of cases. Maternal mortality rates increased with advancing gestation, reaching 31.3% in the third trimester, but fetal loss was highest (85.7%) in the first trimester. Ribavirin treatment during the third trimester was associated with lower observed maternal mortality rates (odds ratio 0.33, 95% CI 0.13-0.84; p = 0.031). Our findings highlight gestational age-specific risks of CCHF and support the need for standardized management protocols and strengthened CCHF surveillance during pregnancy in endemic regions.
2026-09-27 | Discovery of potential RdRp catalytic domain inhibitors against Crimean-Congo hemorrhagic fever virus from Andrographis paniculata via LC-MS/MS profiling and computational approaches.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic zoonotic virus associated with significant mortality and currently lacks FDA-approved therapeutic options. Owing to its endemic nature and epidemic potential, it has been included in WHO priority pathogen list under its R&D Blueprint, highlighting the urgent need for development of novel antiviral agents. The present study explores antiviral potential of phytoconstituents from Andrographis paniculata targeting viral catalytic domain of RNA-dependent RNA polymerase (RdRp). Cold Ethanolic leaf extract was prepared using ultrasonic-assisted extraction and subjected to LC-MS/MS QQQ profiling, leading to identification of 44 phytochemicals, mostly andrographolide diterpenes lactones and flavonoids. Among these, 11 major compounds were selected based on abundance and spectral reliability for computational evaluation. Molecular docking revealed strong binding affinities of bisandrographolide (- 8.212 kcal/mol), andrographiside (- 7.659 kcal/mol), 3-O-β-D-glucopyranosyl-andrographolide (- 7.653 kcal/mol), andrographidin A (- 7.540 kcal/mol) and neoandrographolide (- 7.353 kcal/mol) towards the catalytic domain of RdRp which is comparable to standard Ribavirin (- 8.314 kcal/mol). MD simulations of 100 ns were performed which demonstrated stable Andrographis paniculata ligand-RdRp complexes through consistent RMSD, RMSF, radius of gyration, hydrogen bonding, minimum distance (~ 0.25-0.30 nm) and SASA profiles, except for neoandrographolide, showed comparatively lower conformational stability. In silico ADMET analysis indicated generally acceptable pharmacokinetic and safety profiles, although some compounds exhibited low GIT absorption. Collectively, results suggest that Andrographis paniculata phytoconstituents, particularly andrographolide diterpenes lactones possess promising inhibitory potential against catalytic domain of CCHFV RdRp and may serve as lead candidates for antiviral drug development. Further mechanistic studies are needed to elucidate exact mode of RdRp catalytic domain inhibition while in vitro and in vivo validation is crucial to confirm their therapeutic potential and translational relevance.
2026-09-04 | Cryo-EM structures of CCHFV polymerase reveal a stepwise initiation stabilization pathway and a dual-site inhibition mechanism.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a high-priority pathogen with high case-fatality rates, yet approved therapeutics remain unavailable. The CCHFV L segment encodes a ∼450-kDa RNA-dependent RNA polymerase (L protein) orchestrating viral replication, but its structural mechanisms remain elusive. Here, we present high-resolution cryo-EM structures of the CCHFV L protein in apo, 5' vRNA-bound, 5'/3' promoter-bound, and inhibitor-bound states. The catalytic core exhibits the canonical architecture of the Bunyavirales order, featuring conserved motifs and coordinated promoter recognition via a 5' vRNA "hook" and a secondary 3' vRNA-binding site. Using suramin as a probe, we identified a dual-site mechanism of polymerase inhibition. Suramin competitively occludes the 5' vRNA-binding pocket through electrostatic mimicry of the RNA backbone and concurrently traps a distal linker-fingers interface, restricting the conformational dynamics required for catalysis. Collectively, these findings provide structural insights into CCHFV polymerase regulation and inhibition.
2026-08-27 | RNA synthesis and substrate analogue inhibition in the CCHFV polymerase.
The about 4,000-residue L proteins from the Nairoviridae are the largest known viral polymerases, lacking global structural information and promising nucleotide analogue inhibitors. Here we report structures of full-length Nairoviridae Crimean-Congo haemorrhagic fever virus (CCHFV) L, including a 3.0 Å resolution polymerase elongation complex that elucidates mechanisms of both early and late elongation stages. Large additions and insertions are found in all three major functional regions that contain the endonuclease RNA-dependent RNA polymerase (RdRP) and cap-binding domain of CCHFV L, extending RNA-binding paths on both sides of the RdRP active site and creating interaction networks critical for viral replication, as suggested by CCHFV minigenome assay data. Nucleotide analogues with ribose-2' modifications identical to the hepatitis C drug sofosbuvir are found to specifically and efficiently inhibit CCHFV RdRP through an immediate chain termination mechanism. Using a sofosbuvir-hepatitis C virus RdRP system as the reference, the potency of these nucleotide analogues is further demonstrated in competition assays in the presence of corresponding nucleoside triphosphates.
2026-08-23 | Diagnosis, management, and prevention of Crimean-Congo haemorrhagic fever: a Delphi-based consensus study in Türkiye.
Crimean-Congo haemorrhagic fever (CCHF) is a widely distributed viral haemorrhagic fever with expanding geographic range. As new regions encounter the disease, clinicians must make high-stakes decisions despite limited standardised management frameworks. In this multicentre, modified Delphi study, infectious diseases specialists were recruited from 19 centres in Türkiye via an open call through the professional communication channels of the Turkish Society of Clinical Microbiology and Infectious Diseases (known as KLİMİK). Eligibility was determined based on self-reported clinical experience. Eligible participants reported managing more than ten patients with CCHF as primary physicians, with no additional demographic or professional exclusion criteria applied. The Delphi process included three sequential rounds of anonymous online surveys (between Sept 26 2025, and Jan 1, 2026) and an interim structured clarification meeting (Nov 28-29, 2025), to map areas of agreement and heterogeneity across diagnosis, monitoring, therapeutics, and exposure management. Statements were analysed using Likert-scale methodology. Responses were summarised using medians, interquartile ranges, and proportions of agreement. Consensus levels were defined a priori. Of 45 ID specialists invited to participate in Round 1, 35 completed the questionnaire and were included in the analysis (78% response rate). All 35 eligible participants were invited to Round 2, and 32 (91%) completed the questionnaire. All 32 participants completed Round 3, with no attrition between Rounds 2 and 3. All participants reported experience of managing more than ten patients with CCHF; ∼85% of participants reported managing at least 50 confirmed cases. In total, 146 candidate statements were evaluated, of which 72 achieved early consensus in Round 1. Following iterative refinement, 39 of 56 statements (69.6%) met predefined consensus criteria in the final round, including eight with very high agreement and 22 with high agreement. Strong convergence was observed for early molecular testing and risk-based hospitalisation, ribavirin initiation within 4 days of symptom onset in confirmed cases, risk-adapted transfusion strategies guided by bleeding severity, and post-exposure prophylaxis after high-risk occupational exposure. Persistent heterogeneity remained regarding ribavirin initiation beyond the early symptomatic window, immunomodulatory therapies, and transfusion de-escalation strategies in selected scenarios. These findings should not be interpreted as formal guidelines. By transparently quantifying expert agreement and non-consensus, this study synthesises specialist clinical experience from a high incidence country and delineates areas of convergence and ongoing uncertainty relevant to both endemic and newly affected regions. Prospective studies are needed to validate key therapeutic and management strategies identified in this work. None.
vaccines
2026-09-12 | Dual-antigen AdV5 vaccines against Crimean-Congo hemorrhagic fever virus induce superior humoral and Th1-biased cellular immunity.
Platforms based on adenoviral vectors have proven their efficiency in developing vaccines and therefore can be considered potential candidates for immunization strategies against CCHFV. In this study, four replication-deficient recombinant human adenovirus serotype 5 (AdV5) vectors were engineered to express CCHFV antigens: a dual-antigen NP-P2A-Gc construct and monocistronic constructs for nucleoprotein (NP), glycoprotein complex precursor (GPC), and mature glycoprotein (Gc). Following GMP-compatible production and purification, vaccine candidates were evaluated in BALB/c mice (n = 4 per group) for immunogenicity and in IFNAR-/- mice (n = 4 per group) for protective efficacy using antigenically homologous or heterologous prime-boost regimens. Animals received priming immunization on day 0 and booster on day 28 followed by lethal CCHFV challenge (1000 TCID50) on day 42. Immune responses were characterized via ELISA, virus neutralization tests, cytokine profiling, ELISpot, and flow cytometry. Post-challenge survival, viral loads in target organs, and safety profiles were assessed. All AdV5 constructs successfully expressed the target antigens and induced rapid seroconversion, with 75-100% of animals exhibiting antibody responses after priming with a single dose. The dual-antigen formulations elicited the strongest Th1-polarized responses particularly nucleoprotein + Gc combinations with interferon-γ production more than 30-fold above baseline and preferential expansion of CD4+ T helper cells (60-70% of CD3+ populations). Neutralizing antibody titers varied across groups (80-160 arbitrary units in high responders) but did not directly correlate with survival outcomes. After lethal challenge, multiple vaccine formulations achieved 100% survival throughout the 10-day observation period, while only control groups showed no protection. All vaccinated animals demonstrated significant viral load reduction of two to four logs in liver and spleen tissues, with some achieving complete clearance of the virus. Furthermore, no off-target vector dissemination was detected in examined tissues confirming safety profile of the constructs. Immunization with adenovirus serotype 5 (AdV5) vectors expressing CCHFV antigens elicited potent humoral and cellular immune responses, conferring 100% protection against lethal viral challenge across the majority of evaluated formulations. Sterilizing immunity was observed in some animals, along with evidence that protection operates through multiple immune mechanisms including both neutralizing and non-neutralizing antibody-mediated pathways. These results strongly support further clinical development of AdV5-based CCHFV vaccines, with multiple formulation strategies showing high efficacy and providing flexibility for clinical advancement. GMP-compatible production methods have been successfully implemented for these candidates, supporting their advancement toward non-human primate studies and Phase I clinical trials.
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.
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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.
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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 | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Ribavirin | small molecules | EMA | Pharmadev Healthcare Ltd |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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