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The Bluetongue Disabled Infectious Single Animal (DISA) Vaccine Platform Based on Deletion NS3/NS3a Protein Is Safe and Protective in Cattle and Enables DIVA.

ABSTRACT: The bluetongue virus (BTV) is transmitted by Culicoides biting midges and causes bluetongue (BT), an OIE-notifiable disease of ruminants. At least 29 BTV serotypes are described as determined by the outer shell proteins VP2 and VP5. Vaccination is the most effective control measure. Inactivated and live-attenuated vaccines (LAVs) are currently available. These vaccines have their specific pros and cons, and both are not DIVA vaccines. The BT Disabled Infectious Single Animal (DISA) vaccine platform is based on LAV without nonessential NS3/NS3a expression and is applicable for many serotypes by the exchange of outer shell proteins. The DISA vaccine is effective and completely safe. Further, transmission of the DISA vaccine by midges is blocked (DISA principle). Finally, the DISA vaccine enables DIVA because of a lack of antibodies against the immunogenic NS3/NS3a protein (DIVA principle). The deletion of 72 amino acids (72aa) in NS3/NS3a is sufficient to block virus propagation in midges. Here, we show that a prototype DISA vaccine based on LAV with the 72aa deletion enables DIVA, is completely safe and induces a long-lasting serotype-specific protection in cattle. In conclusion, the in-frame deletion of 72-aa codons in the BT DISA/DIVA vaccine platform is sufficient to fulfil all the criteria for modern veterinary vaccines.

SUBMITTER: van Rijn PA

PROVIDER: S-EPMC8151055 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:UnlabelledAfrican horse sickness virus (AHSV) is a virus species in the genus Orbivirus of the family Reoviridae. There are nine serotypes of AHSV showing different levels of cross neutralization. AHSV is transmitted by species of Culicoides biting midges and causes African horse sickness (AHS) in equids, with a mortality rate of up to 95% in naive horses. AHS has become a serious threat for countries outside Africa, since endemic Culicoides species in moderate climates appear to be competent vectors for the related bluetongue virus (BTV). To control AHS, live-attenuated vaccines (LAVs) are used in Africa. We used reverse genetics to generate "synthetic" reassortants of AHSV for all nine serotypes by exchange of genome segment 2 (Seg-2). This segment encodes VP2, which is the serotype-determining protein and the dominant target for neutralizing antibodies. Single Seg-2 AHSV reassortants showed similar cytopathogenic effects in mammalian cells but displayed different growth kinetics. Reverse genetics for AHSV was also used to study Seg-10 expressing NS3/NS3a proteins. We demonstrated that NS3/NS3a proteins are not essential for AHSV replication in vitro. NS3/NS3a of AHSV is, however, involved in the cytopathogenic effect in mammalian cells and is very important for virus release from cultured insect cells in particular. Similar to the concept of the bluetongue disabled infectious single animal (BT DISA) vaccine platform, an AHS DISA vaccine platform lacking NS3/NS3a expression was developed. Using exchange of genome segment 2 encoding VP2 protein (Seg-2[VP2]), we will be able to develop AHS DISA vaccine candidates for all current AHSV serotypes.ImportanceAfrican horse sickness virus is transmitted by species of Culicoides biting midges and causes African horse sickness in equids, with a mortality rate of up to 95% in naive horses. African horse sickness has become a serious threat for countries outside Africa, since endemic Culicoides species in moderate climates are supposed to be competent vectors. By using reverse genetics, viruses of all nine serotypes were constructed by the exchange of Seg-2 expressing the serotype-determining VP2 protein. Furthermore, we demonstrated that the nonstructural protein NS3/NS3a is not essential for virus replication in vitro. However, the potential spread of the virus by biting midges is supposed to be blocked, since the in vitro release of the virus was strongly reduced due to this deletion. VP2 exchange and NS3/NS3a deletion in African horse sickness virus were combined in the concept of a disabled infectious single animal vaccine for all nine serotypes.

Project description:The performance of different bluetongue control measures related to both vaccination and protection from bluetongue virus (BTV) vectors was assessed. By means of a mathematical model, it was concluded that when vaccination is applied on 95% of animals even for 3 years, bluetongue cannot be eradicated and is able to re-emerge. Only after 5 years of vaccination, the infection may be close to the eradication levels. In the absence of vaccination, the disease can persist for several years, reaching an endemic condition with low level of prevalence of infection. Among the mechanisms for bluetongue persistence, the persistence in the wildlife, the transplacental transmission in the host, the duration of viraemia and the possible vertical transmission in vectors were assessed. The criteria of the current surveillance scheme in place in the EU for demonstration of the virus absence need revision, because it was highlighted that under the current surveillance policy bluetongue circulation might occur undetected. For the safe movement of animals, newborn ruminants from vaccinated mothers with neutralising antibodies can be considered protected against infection, although a protective titre threshold cannot be identified. The presence of colostral antibodies interferes with the vaccine immunisation in the newborn for more than 3 months after birth, whereas the minimum time after vaccination of animal to be considered immune can be up to 48 days. The knowledge about vectors ecology, mechanisms of over-wintering and criteria for the seasonally vector-free period was updated. Some Culicoides species are active throughout the year and an absolute vector-free period may not exist at least in some areas in Europe. To date, there is no evidence that the use of insecticides and repellents reduce the transmission of BTV in the field, although this may reduce host/vector contact. By only using pour-on insecticides, protection of animals is lower than the one provided by vector-proof establishments.

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The Bluetongue Disabled Infectious Single Animal (DISA) Vaccine Platform Based on Deletion NS3/NS3a Protein Is Safe and Protective in Cattle and Enables DIVA.

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