Nucleocapsid protein-based vaccine provides protection in mice against lethal Crimean-Congo hemorrhagic fever virus challenge

Zivcec, Marko; Safronetz, David; Scott, Dana; Robertson, Shelly J.; Feldmann, Heinz

doi:10.1371/journal.pntd.0006628

Cited by 65 publications

(74 citation statements)

References 39 publications

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“…In this study, we have evaluated an eukaryotic expression vector (pVAX-1) expressing antibodies have no in vitro neutralizing activity. These findings do not undermine N as a vaccine target as it has been previously documented in animal models that non-neutralizing antibodies could protect mice model from lethal challenges [3,6]. A similar phenomenon was also described in influenza vaccine studies with animals, where protective anti-influenza immunity is attained in the absence of measurable neutralizing antibodies [29].…”

Section: Discussionsupporting

confidence: 80%

“…The vectors [5][6][7]. It is also important to assess probable correlation between challenge protection and CD4 + and CD8 + responses [17].…”

Section: Discussionmentioning

confidence: 99%

“…Nucleocapsid protein (N) of CCHFV is the main Open Reading Frame (ORF) found in the S segment and involved in virus encapsidation. This protein is well-conserved among CCHFV strains and constitutes the immunodominant antigen with several T-cell epitopes and no known B cell targeting regions and is considered as a potential target in vaccine development for some Bunyaviruses such as Rift Valley virus [6]. The lack of B cell epitopes due to internal structure of this protein results in lower levels of neutralizing antibodies.…”

Section: Introductionmentioning

confidence: 99%

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Adjuvant Potential of CD24 on Immunogenicity and Lethal Challenge Protection of a DNA vector Expressing Nucleocapsid Protein of Crimean Congo Hemorrhagic Fever Virus

Farzani¹,

Hanifehnezhad²,

Földes³

et al. 2018

Preprint

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Crimean Congo hemorrhagic fever virus (CCHFV) is the causative agent of a globally-spread tick-borne zoonotic infection with an eminent risk of fatal human disease. Imminent public health threat posed by disseminated virus activity and lack of an approved therapeutic make CCHFV an urgent target for vaccine development. We described the construction of a DNA vector expressing nucleocapsid protein (N) of CCHFV (pV-N13) and investigated its potential to stimulate cytokine and total/specific antibody responses in BALB/c and challenge experiment in IFNAR-/- mice. Due to lack of sufficient antibody stimulation towards N protein, we have selected CD24 protein as a potential adjuvant which has proliferative effect on B and T cells. Overall, our N expressing construct when administered solely or in combination with pCD24 vector elicited significant cellular and humoral responses in BALB/c, despite variations in particular cytokines and total antibodies. However, the stimulated antibodies produced due to expression of N protein have shown no neutralizing ability in VNA. Furthermore, challenge experiments were revealed protection potential of N expressing construct in IFNAR -/- mice model. In conclusion, we have shown that CD24 has prominent effect as a genetic adjuvant when co-delivers with a synergic foreign gene expressing vector. Besides, targeting of S segment of CCHFV can be considered as a practical way in developing vaccine against this virus due to its ability to induce immune response which leads to protection in challenge assays in IFN-gamma defective mice models.

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Section: Discussionsupporting

confidence: 80%

“…The vectors [5][6][7]. It is also important to assess probable correlation between challenge protection and CD4 + and CD8 + responses [17].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Adjuvant Potential of CD24 on Immunogenicity and Lethal Challenge Protection of a DNA vector Expressing Nucleocapsid Protein of Crimean Congo Hemorrhagic Fever Virus

Farzani¹,

Hanifehnezhad²,

Földes³

et al. 2018

Preprint

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show abstract

“…Another vaccine candidate, an adenovirus‐based vaccine expressing the CCHF nucleoprotein, protected an immunocompromised mice model against CCHF virus challenge; thus, adenoviral vectors are thought to be suitable for CCHV vaccines (Zivcec et al . 2018). A draft CCHF research and development road‐map charted by the WHO (2018) prioritized the most suitable CCHF vaccine candidates to enter clinical trials by 2019.…”

Section: Crimean–congo Hemorrhagic Fever Virusmentioning

confidence: 99%

Tick‐borne viruses: Current trends in large‐scale viral surveillance

Park

Kim

et al. 2020

Entomological Research

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Ticks are ectoparasites that transmit pathogens, such as tick‐borne viruses, to their hosts. Tick‐borne viruses are diverse: they can be categorized into two orders, nine families, and at least 12 genera. Almost 25% of these viruses are infectious to humans and some are a serious threat to public health. The global rise in tick‐borne virus diseases has been linked to climate change which has reduced tick mortality in the winter and extended their active period. The spread of tick‐borne viral diseases to humans has received significant interest due to the increased threat to human life; epidemiological monitoring of tick‐borne viruses using molecular, immunological, and environmental methods is now a priority. Nevertheless, many tick‐borne diseases remain undiagnosed, which poses a challenge to public administration and health care officials. This review discusses three major tick‐borne RNA viruses that cause serious infection in humans: severe fever with thrombocytopenia syndrome (SFTS) virus, tick‐borne encephalitis (TBE), and Crimean–Congo hemorrhagic fever (CCHF) virus. Specifically, we discuss the epidemiological monitoring, vector control measures, molecular diagnostics, vaccines, and environmental determinants related to these viruses. Furthermore, we review the current surveillance of these tick‐borne viruses with a specific focus on diagnostic approaches that employ molecular interventions such as viral nucleic acid isolation, PCR‐based diagnostics, and high‐throughput sequencing technologies.

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“…Although the glycoproteins of CCHFV exhibit the greatest genetic diversity, we detected sustained CCHFV-specific T-cell responses against the more-conserved CCHFV nucleoprotein. Vaccine-induced responses solely against the nucleoprotein can be protective (24,25), and it is therefore likely that immune responses against the more-conserved CCHFV nucleoprotein could provide cross protection. Studies with monoclonal antibodies against the glycoproteins have shown that although there exist antigenic differences among diverse strains of CCHFV, there are neutralizing epitopes conserved among divergent strains (26,27).…”

Section: Figmentioning

confidence: 99%

Crimean-Congo Hemorrhagic Fever Mouse Model Recapitulating Human Convalescence

Hawman

Meade-White

Haddock

et al. 2019

J Virol

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Crimean-Congo hemorrhagic fever virus (CCHFV) is a cause of severe hemorrhagic fever. Its tick reservoir and vector are widely distributed throughout Africa, Southern and Eastern Europe, the Middle East, and Asia. Serological evidence suggests that CCHFV can productively infect a wide variety of species, but only humans develop severe, sometimes fatal disease. The role of the host adaptive immunity in control or contribution to the severe pathology seen in CCHF cases is largely unknown. Studies of adaptive immune responses to CCHFV have been limited due to lack of suitable small animal models. Wild-type mice are resistant to CCHFV infection, and type I interferon-deficient mice typically develop a rapid-onset fatal disease prior to development of adaptive immune responses. We report here a mouse model in which type I interferon-deficient mice infected with a clinical isolate of CCHFV develop a severe inflammatory disease but ultimately recover. Recovery was coincident with development of CCHFV-specific B- and T-cell responses that were sustained for weeks postinfection. We also found that recovery from a primary CCHFV infection could protect against disease following homologous or heterologous reinfection. Together this model enables study of multiple aspects of CCHFV pathogenesis, including convalescence, an important aspect of CCHF disease that existing mouse models have been unsuitable for studying. IMPORTANCE The role of antibody or virus-specific T-cell responses in control of acute Crimean-Congo hemorrhagic fever virus infection is largely unclear. This is a critical gap in our understanding of CCHF, and investigation of convalescence following severe acute CCHF has been limited by the lack of suitable small animal models. We report here a mouse model of CCHF in which infected mice develop severe disease but ultimately recover. Although mice developed an inflammatory immune response along with severe liver and spleen pathology, these mice also developed CCHFV-specific B- and T-cell responses and were protected from reinfection. This model provides a valuable tool to investigate how host immune responses control acute CCHFV infection and how these responses may contribute to the severe disease seen in CCHFV-infected humans in order to develop therapeutic interventions that promote protective immune responses.

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Nucleocapsid protein-based vaccine provides protection in mice against lethal Crimean-Congo hemorrhagic fever virus challenge

Cited by 65 publications

References 39 publications

Adjuvant Potential of CD24 on Immunogenicity and Lethal Challenge Protection of a DNA vector Expressing Nucleocapsid Protein of Crimean Congo Hemorrhagic Fever Virus

Adjuvant Potential of CD24 on Immunogenicity and Lethal Challenge Protection of a DNA vector Expressing Nucleocapsid Protein of Crimean Congo Hemorrhagic Fever Virus

Tick‐borne viruses: Current trends in large‐scale viral surveillance

Crimean-Congo Hemorrhagic Fever Mouse Model Recapitulating Human Convalescence

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