Crimean-Congo Hemorrhagic Fever Virus (CCHFV)

Crimean-Congo haemorrhagic fever (CCHF) is a severe tick-borne illness caused by the CCHF virus (CCHFV). It is prevalent in Africa, the Middle East, Asia, and parts of Europe, with high fatality rates. The expanding range of the Hyalomma tick vector poses an increasing risk. While CCHFV infects various animal species, only humans experience severe illness, and subclinical infections may be more common than recognized. Currently, there are no licensed vaccines or specific antivirals available for CCHF treatment. Understanding the host and viral factors contributing to CCHFV pathogenesis remains limited.

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The Pathogen: CCHFV

CCHFV is a virus belonging to the Orthonairovirus genus in the Nairoviridae family. It was first identified in 1944 in Crimea and subsequently isolated in 1956 in Congo, leading to its current name. The virus has a spherical shape with a diameter of about 80-100 nm. The gene structure of CCHFV consists of three segments of single-stranded negative-sense RNA. Each segment encodes specific viral proteins essential for replication and assembly of the virus.

• Small (S) Segment
  The S segment is approximately 1.7 kilobases (kb) in length. It encodes the viral nucleoprotein (NP) in one reading frame and the small non-structural proteins (NSs) in an opposite-sense open reading frame.
• Medium (M) Segment
  The M segment is approximately 4.6 kb in length. It encodes the glycoprotein precursor (GPC), which is further processed into two envelope glycoproteins, GN and GC. These glycoproteins are responsible for viral attachment, entry into host cells, and immune evasion. Additionally, the M segment encodes various non-structural proteins involved in viral replication and pathogenesis.
• Large (L) Segment
  The L segment is the longest, approximately 12.2 kb in length. It encodes viral RNA-dependent RNA polymerase (RdRp) and an ovarian tumor-like protease (OTU) at the N terminus. RdRp is essential for viral RNA synthesis and replication. It plays a crucial role in transcribing viral RNA into messenger RNA (mRNA), which is then used for the production of viral proteins.

CCHFV strains are classified into seven genotypes (I to VII) based on the genetic sequence of the S segment. Genotype IV is further divided into subgenotypes IVf and IVg. The phylogeny of CCHFV varies among the three genome segments due to reassortment events between different genotypes.

Figure 1. Molecular biology of Crimean–Congo haemorrhagic fever virus.
(Source: Hawman, D. W. et al., 2023)

CCHF Treatments

Currently, therapeutic options for CCHFV are limited, and most efforts have centered around inhibiting viral replication or modulating the host's response to the infection.

• Antivirals
  Ribavirin is the only antiviral drug widely used clinically in patients with CCHF, but its effectiveness is controversial and may require early treatment. Favipiravir and its derivative (H44) have shown significant protective effects in animal models, even when treatment is initiated after infection. Other compounds, such as 2'-deoxy-2'-fluorocytidine, molnupiravir, TH3289, and a synthetic ubiquitin variant, have demonstrated antiviral activity against CCHFV in vitro. However, further validation in animal models and clinical trials is needed to determine their efficacy in treating CCHF in humans.
• Antibody-based therapies
  Limited evidence suggests that the administration of plasma or antibodies from CCHF survivors may benefit seriously ill patients. However, the scalability of convalescent plasma treatments is limited. Mouse and human monoclonal antibodies have shown efficacy in protecting lethally infected mice, but their effectiveness varies depending on the model and timing of administration. Some antibodies have demonstrated neutralizing activity, while others target non-neutralizing epitopes but still provide protection in animal models. Further studies are needed to define the therapeutic window and optimal use of neutralizing antibodies for CCHF treatment.
• Anti-inflammatory drugs
  Severe cases of CCHF are associated with an excessive inflammatory response and cytokine storms. Some attempts have been made to use anti-inflammatory drugs to suppress the hyperinflammatory response in CCHF patients. A study showed that high-dose methylprednisolone combined with ribavirin improved outcomes compared to ribavirin alone. Corticosteroids also appear beneficial in severely ill patients. Additionally, blocking TNF signaling in animal models has shown protective effects against CCHF. The availability of clinically approved TNF therapeutics and therapies targeting other host cytokines may warrant further evaluation for treating CCHF.

CCHFV-Related Antibodies

CCHFV-Related Antigens

CCHFV-Related ELISA Kits