Bovine Herpesvirus Type 4 (BoHV-4) Vector Delivering Nucleocapsid Protein of Crimean-Congo Hemorrhagic Fever Virus Induces Comparable Protective Immunity against Lethal Challenge in IFNα/β/γR-/- Mice Models

Viruses. 2019 Mar 9;11(3):237. doi: 10.3390/v11030237.


Crimean-Congo hemorrhagic fever virus (CCHFV) is the causative agent of a tick-borne infection with a significant mortality rate of up to 40% in endemic areas, with evidence of geographical expansion. Due to a lack of effective therapeutics and control measures, the development of a protective CCHFV vaccine remains a crucial public health task. This paper describes, for the first time, a Bovine herpesvirus type 4 (BoHV-4)-based viral vector (BoHV4-∆TK-CCHFV-N) and its immunogenicity in BALB/c and protection potential in IFNα/β/γR-/- mice models in comparison with two routinely used vaccine platforms, namely, Adenovirus type 5 and a DNA vector (pCDNA3.1 myc/His A), expressing the same antigen. All vaccine constructs successfully elicited significantly elevated cytokine levels and specific antibody responses in immunized BALB/c and IFNα/β/γR-/- mice. However, despite highly specific antibody responses in both animal models, the antibodies produced were unable to neutralize the virus in vitro. In the challenge experiment, only the BoHV4-∆TK-CCHFV-N and Ad5-N constructs produced 100% protection against lethal doses of the CCHFV Ank-2 strain in IFNα/β/γR-/- mice. The delivery platforms could not be compared due to similar protection rates in IFNα/β/γR-/- mice. However, during the challenge experiment in the T cell and passive antibody transfer assay, BoHV4-∆TK-CCHFV-N was dominant, with a protection rate of 75% compared to others. In conclusion, vector-based CCHFV N protein expression constitutes an effective approach for vaccine development and BoHV-4 emerged as a strong alternative to previously used viral vectors.

Keywords: Crimean-Congo hemorrhagic fever; IFNα/β/γR−/− mice; bovine herpesvirus type 4; lethal dose; nucleocapsid; passive antibody transfer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology
  • Cattle
  • Disease Models, Animal
  • Female
  • Genetic Vectors*
  • Hemorrhagic Fever Virus, Crimean-Congo / genetics
  • Hemorrhagic Fever Virus, Crimean-Congo / immunology*
  • Hemorrhagic Fever, Crimean / immunology
  • Hemorrhagic Fever, Crimean / prevention & control*
  • Herpesvirus 4, Bovine / genetics
  • Immunization, Passive*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Nucleocapsid Proteins / genetics
  • Nucleocapsid Proteins / immunology*
  • Receptors, Interferon / genetics*
  • Vaccination
  • Viral Vaccines / genetics
  • Viral Vaccines / immunology*


  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Nucleocapsid Proteins
  • Receptors, Interferon
  • Viral Vaccines