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Recombinant viruses: a solution to vectorise antigens and stimulate the immune system

For many years now, researchers in immunology have been focusing on recombinant viruses for the development of vaccine platforms. Recent evolutions in biotechnology have enabled the targeting of genetic modifications in the genome of these micro-organisms. It is now possible to inactivate genes linked to replication to produce safe viral particles that are unable to grow in animal cells, and to insert into the modified genome a gene of interest that encodes for a specific pathogen-related antigen. This antigen may originate from a virus, a bacterium or a parasite. The use of a single viral antigenic protein can prevent any risks of recombination and reactivation of the pathogenic virus.

A fish virus as a vaccine platform

A research team in the Molecular Virology and Immunology Unit (VIM) has used a fish virus, the viral haemorrhagic septicaemia virus (VSHV) to develop a new vaccine platform for mammals. This virus from the Novirhabdovirus family (a rhabdovirus with an envelope from the Rhabdoviridae family), is well known to INRA research scientists who have studied it because of the considerable damage it can cause in fish farms. During their studies on VSHV, the scientists noted it displayed several interesting characteristics. Firstly, it is unusual in being unable to grow at temperatures higher than 20°C – thus in all homeothermic mammals -, and secondly its genome can accommodate additional genetic information of a relatively large size (up to 6 kb). Furthermore, the researchers have developed genomic engineering tools that are specific to manipulating the genome of RNA viruses (reverse genetics).

A target: West Nile Virus

West Nile Virus (WNV) can cause fatal encephalitis in humans and horses. Transmitted by blood-sucking insects such as mosquitoes, this virus is found in birds, which are its natural reservoir. The disease is notably present in North America and Europe. Equine vaccines are available on the European market, but they contain whole, inactivated virus, and require a lengthy process to achieve inactivation and then its validation.
The researchers used protein E from WNV as an antigen. This glycoprotein, which is the main component of the viral membrane, is the most immunogenic in WNV, and notably in its domain III (DIII). Several recombinant rVHSV viral constructs have been engineered, using either whole protein E or fragments of this protein, and notably DIII.
During a challenge assay in mice, the best protective results were obtained using the rVHSV virus carrying DIII flanked by the signal peptide (SP) and transmembrane sequence (TM) of the native G protein of VHSV. This fusion of antigens with sequences derived from a membrane protein enables satisfactory exposure of these antigens at the viral surface. They are then easily accessible to cells from the immune system, which is appropriately stimulated by the rVHSV, causing an adaptive response by the immune system and the production of immunoglobulins.

The scientists are now working to improve this protection by developing rVHSV carrying multimerised DIII (repetition of the DIII sequence) associated with the SP and TM sequences and combined with new vaccine adjuvants developed by the company Abivax, which is co-funding this research in the context of an exclusive option. In parallel, new applications using this rVHSV platform and targeting other major pathogenic agents, or the development of new therapeutic approaches in oncology, are currently under study.

This work was carried out in the context of Angella Nzonza's thesis project, and has been the subject of a patent application.