Crimean-Congo Hemorrhagic Fever Virus Subunit Vaccines Induce High Levels of Neutralizing Antibodies But No Protection in STAT1 Knockout Mice

Kortekaas, Jeroen; Vloet, Rianka P. M.; McAuley, Alexander J.; Shen, Xiaoli; Bosch, Berend Jan; Vries, Laura de; Moormann, R.J.M.; Bente, Dennis A.

doi:10.1089/vbz.2015.1855

Cited by 66 publications

(79 citation statements)

References 16 publications

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“…Correlates of protection against CCHF have been difficult to define due to the multiple vaccine and delivery platforms examined to date 16 . Several CCHFV experimental vaccines studies have identified cell-mediated and humoral involvement, with some instances of neutralizing antibody production 24,57 . In looking at what is known for human CCHF, survivors mount a humoral response whereas those who succumb, typically lack an IgG response 3 .…”

Section: Discussionmentioning

confidence: 99%

“…This study demonstrates that a rVSV expressing only the CCHFV-GP has the potential to serve as a replication competent vaccine platform against CCHF infections.Currently, there are several experimental vaccine candidates that have relied on the GPC as an antigenic component, which have been evaluated in immunocompromised signal transducer and activator of transcription 1 knock-out (STAT-1 −/− ), interferon α/β receptor knock-out (IFNAR), or interferon receptor antibody transiently suppressed (IS) mouse models for CCHFV, as they recapitulate clinical illness and are uniformly lethal models for CCHF [16][17][18][19][20] . Vaccine candidate approaches have focused on either DNA expression of CCHFV antigens in host tissues, replication deficient viral-like particles, inactivated whole virus preparations, subunit antigen preparations, or vectored vaccinia virus vaccines 16,[20][21][22][23][24][25] . Two of these preparations, a prime and boost strategy using modified recombinant Vaccinia virus (strain: Ankara) [MVA] encoding the GPC, and a prime, boost, and boost strategy with a DNA based vaccine encoding separate NP, G N , and G C antigens, have provided promising results with up to 100% protection in the IFNAR mouse model for CCHFV 23,25 .…”

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confidence: 99%

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Vesicular Stomatitis Virus-Based Vaccine Protects Mice against Crimean-Congo Hemorrhagic Fever

Rodriguez

Cross

Fenton

et al. 2019

Sci Rep

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Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne bunyavirus, can cause a life-threatening hemorrhagic syndrome in humans but not in its animal host. The virus is widely distributed throughout southeastern Europe, the Middle East, Africa, and Asia. Disease management has proven difficult and there are no broadly licensed vaccines or therapeutics. Recombinant vesicular stomatitis viruses (rVSV) expressing foreign glycoproteins (GP) have shown promise as experimental vaccines for several viral hemorrhagic fevers. Here, we developed and assessed a replication competent rVSV vector expressing the CCHFV glycoprotein precursor (GPC), which encodes CCHFV structural glycoproteins. This construct drives strong expression of CCHFV-GP, in vitro . Using these vectors, we vaccinated STAT-1 knock-out mice, an animal model for CCHFV. The vector was tolerated and 100% efficacious against challenge from a clinical strain of CCHFV. Anti-CCHFV-GP IgG and neutralizing antibody titers were observed in surviving animals. This study demonstrates that a rVSV expressing only the CCHFV-GP has the potential to serve as a replication competent vaccine platform against CCHF infections.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Vesicular Stomatitis Virus-Based Vaccine Protects Mice against Crimean-Congo Hemorrhagic Fever

Rodriguez

Cross

Fenton

et al. 2019

Sci Rep

Self Cite

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“…However, the Gc protein is considered more immunogenic (21). The majority of B-cell epitopes are in general directed to discontinuous epitopes that may be difficult to identify with short linear peptides (22).…”

Section: Discussionmentioning

confidence: 99%

Immunization with DNA Plasmids Coding for Crimean-Congo Hemorrhagic Fever Virus Capsid and Envelope Proteins and/or Virus-Like Particles Induces Protection and Survival in Challenged Mice

Hinkula

Devignot

Åkerström

et al. 2017

J Virol

106

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Crimean-Congo hemorrhagic fever virus (CCHFV) is a bunyavirus causing severe hemorrhagic fever disease in humans, with high mortality rates. The requirement of a high-containment laboratory and the lack of an animal model hampered the study of the immune response and protection of vaccine candidates. Using the recently developed interferon alpha receptor knockout (IFNAR−/−) mouse model, which replicates human disease, we investigated the immunogenicity and protection of two novel CCHFV vaccine candidates: a DNA vaccine encoding a ubiquitin-linked version of CCHFV Gc, Gn, and N and one using transcriptionally competent virus-like particles (tc-VLPs). In contrast to most studies that focus on neutralizing antibodies, we measured both humoral and cellular immune responses. We demonstrated a clear and 100% efficient preventive immunity against lethal CCHFV challenge with the DNA vaccine. Interestingly, there was no correlation with the neutralizing antibody titers alone, which were higher in the tc-VLP-vaccinated mice. However, the animals with a lower neutralizing titer, but a dominant cell-mediated Th1 response and a balanced Th2 response, resisted the CCHFV challenge. Moreover, we found that in challenged mice with a Th1 response (immunized by DNA/DNA and boosted by tc-VLPs), the immune response changed to Th2 at day 9 postchallenge. In addition, we were able to identify new linear B-cell epitope regions that are highly conserved between CCHFV strains. Altogether, our results suggest that a predominantly Th1-type immune response provides the most efficient protective immunity against CCHFV challenge. However, we cannot exclude the importance of the neutralizing antibodies as the surviving immunized mice exhibited substantial amounts of them.IMPORTANCE Crimean-Congo hemorrhagic fever virus (CCHFV) is responsible for hemorrhagic diseases in humans, with a high mortality rate. There is no FDA-approved vaccine, and there are still gaps in our knowledge of the immune responses to infection. The recently developed mouse models mimic human CCHF disease and are useful to study the immunogenicity and the protection by vaccine candidates. Our study shows that mice vaccinated with a specific DNA vaccine were fully protected. Importantly, we show that neutralizing antibodies are not sufficient for protection against CCHFV challenge but that an extra Th1-specific cellular response is required. Moreover, we describe the identification of five conserved B-cell epitopes, of which only one was previously known, that could be of great importance for the development of diagnostics tools and the improvement of vaccine candidates.

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“…Using purification tags, adjuvanted Gn or Gc ectodomains were shown to induce neutralising antibodies but they did not protect STAT-1 knockout mice [92] in a subsequent lethal virus challenge. While some insect cells retain similar patterns of glycosylation to mammalian cells, it is possible that the complicated glycosylation processes of CCHF GP may not have been fully supported in insect cells [118], and non-authentic GP may not have been able to induce protective responses.…”

Section: Vaccine Progressmentioning

confidence: 99%

“…Additionally, the use of convalescent plasma as a post-exposure prophylactic has not been particularly effective [63]. Recent vaccine studies have also indicated that the induction of neutralisation antibodies does not correspond to vaccine efficacy [91], [92]. Thus cell-mediated immunity looks likely to play a major role in developing effective protection against CCHFV.…”

Section: The Case and Need For Vaccinesmentioning

confidence: 99%

Development of vaccines against Crimean-Congo haemorrhagic fever virus

Dowall

Carroll

Hewson

2017

Vaccine

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Crimean-Congo haemorrhagic fever virus (CCHFV) is a deadly human pathogen of the utmost seriousness being highly lethal causing devastating disease symptoms that result in intense and prolonged suffering to those infected. During the past 40 years, this virus has repeatedly caused sporadic outbreaks responsible for relatively low numbers of human casualties, but with an alarming fatality rate of up to 80% in clinically infected patients. CCHFV is transmitted to humans by Hyalomma ticks and contact with the blood of viremic livestock, additionally cases of human-to-human transmission are not uncommon in nosocomial settings. The incidence of CCHF closely matches the geographical range of permissive ticks, which are widespread throughout Africa, Asia, the Middle East and Europe. As such, CCHFV is the most widespread tick-borne virus on earth. It is a concern that recent data shows the geographic distribution of Hyalomma ticks is expanding. Migratory birds are also disseminating Hyalomma ticks into more northerly parts of Europe thus potentially exposing naïve human populations to CCHFV. The virus has been imported into the UK on two occasions in the last five years with the first fatal case being confirmed in 2012. A licensed vaccine to CCHF is not available. In this review, we discuss the background and complications surrounding this limitation and examine the current status and recent advances in the development of vaccines against CCHFV.

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Crimean-Congo Hemorrhagic Fever Virus Subunit Vaccines Induce High Levels of Neutralizing Antibodies But No Protection in STAT1 Knockout Mice

Cited by 66 publications

References 16 publications

Vesicular Stomatitis Virus-Based Vaccine Protects Mice against Crimean-Congo Hemorrhagic Fever

Vesicular Stomatitis Virus-Based Vaccine Protects Mice against Crimean-Congo Hemorrhagic Fever

Immunization with DNA Plasmids Coding for Crimean-Congo Hemorrhagic Fever Virus Capsid and Envelope Proteins and/or Virus-Like Particles Induces Protection and Survival in Challenged Mice

Development of vaccines against Crimean-Congo haemorrhagic fever virus

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