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

Abstract

Crimean-Congo hemorrhagic fever virus (CCHFV) is the causative agent of a tick-borne infection with significant mortality rate of up to 40% in the endemic areas, with evidence for geographical expansion. Lacking effective therapeutics and control measures, the development of protective CCHFV vaccine remains a crucial public health task. This manuscript describes, for the first time, a Bovine herpesvirus type 4 (BoHV-4) based viral vector (BoHV4-∆TK-CCHFV-N) and its immunogenicity and protection potential in BALB/c and IFNAR-/- mice models in comparison with Adenovirus type 5 (Ad5-N) and pCDNA3.1 myc/His A (pCD-N1), two widely used vaccine platforms. All constructs expressing viral nucleocapsid (N) protein successfully elicited cytokine and total/specific antibody responses in BALB/c mice. BoHV4-∆TK-CCHFV-N and Ad5-N constructs further produced 100% protection in IFNAR-/- mice during CCHFV Ank-2 strain lethal challenge. Despite elevated specific antibody responses in both animal models, the produced antibodies were unable to neutralize the virus in vitro. A comparison of delivery platforms was not possible, due to similar protection rates in IFNAR-/- mice. In conclusion, vector-based CCHFV N protein expression proved to constitute an effective approach for the vaccine development pipeline and BoHV-4 emerged as a strong alternative to previously-used virus vectors.

Advances and perspectives in the development of vaccines against highly pathogenic bunyaviruses

“…A human Ad serotype 5 (Ad5) expressing CCHFV NP was developed and found to stimulate NP-specific antibodies and elicit 78% protection after 2 doses ( Table 1 ) ( Zivcec et al., 2018 ). In contrast, Farzani et al ( Aligholipour Farzani et al., 2019b ). found that the Ad5-based vaccine expressing NP vaccine could induce strong T-cell and humoral responses with no nAbs detected, but 100% of mice were protected after a CCHFV challenge ( Table 1 ).…”

“…found that the Ad5-based vaccine expressing NP vaccine could induce strong T-cell and humoral responses with no nAbs detected, but 100% of mice were protected after a CCHFV challenge ( Table 1 ). After the comparison of above two Ad5-NP vaccines, it was suspected that the different development processes of the vaccines may have led to a difference in efficacy, because the Ad5-NP vaccine with 100% protection was generated by AdMax™HI-IQ Kit J, whereas the other study used Adeno-X Adenoviral System 3 ( Zivcec et al., 2018 ; Aligholipour Farzani et al., 2019b ). In any case, the feasibility of Ad-based vaccines against CCHFV need to be further explored.…”

“…The Bovine Herpesvirus Type 4 (BoHV-4) virus-based vector vaccine has been successfully explored for different pathogens, such as Ebola virus ( Rosamilia et al., 2016 ). Farzani et al ( Aligholipour Farzani et al., 2019b ). reported that BoHV4-ΔTK expressing CCHFV NP could provide complete protection against CCHFV in IFN α/β/γ R−/− mice, and in the T-cell and passive antibody transfer assay, both arms of the immune response were shown to be required for protection ( Dowall et al., 2016b ).…”

“…A study with pV-N13 vaccination expressing NP with pCD24 adjuvant showed that it could induce strong T-cell responses and protect 100% of IFNAR -/- mice from CCHFV infection, despite the lack of nAbs ( Table 1 ) ( Aligholipour Farzani et al., 2019c ). However, another study showed that an unadjuvanted pCD-N1 vaccine protected 75% of IFN α/β/γ-/- mice from challenge ( Table 1 ) ( Aligholipour Farzani et al., 2019b ), suggesting that adjuvants are needed for optimal protection with DNA-vectored vaccines. Garrison et al.…”