Studies towards the development of an FIV DIVA vaccine

Harris, Matthew (2018) Studies towards the development of an FIV DIVA vaccine. PhD thesis, University of Glasgow.

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Abstract

The introduction of Fel-O-Vax FIV in 2002 was the first commercially available lentiviral vaccine. Consisting of whole inactivated virus (WIV) and inactivated infected cells, vaccination lead to the production of a strong humoral and T-cell immune response. As FIV is a lentivirus, the viral genome must be integrated into the host genome and therefore leads to lifelong infection. For this reason, the detection of FIV specific antibodies has been used as a proxy for FIV infection and led to the development of several commercially available serology diagnosis kits. As vaccination leads to the development of FIV antibodies it is not possible to differentiate infected from vaccinated animals (DIVA) using conventional serology diagnosis assays. Several attempts have been made to DIVA FIV vaccinated cats, however no test can differentiate FIV vaccinated from infected animals and FIV uninfected and unvaccinated animals.

The data presented in this thesis demonstrates that it is possible to DIVA cats when vaccinated with a mutated chimeric virus representative of isolates circulating in the field. The identification and characterisation of a novel envelope glycoprotein, isolated from a client owned cat with broad neutralising antibodies to FIV, a unique potential N-linked glycosylation mutation at the apex of variable loop 2 revealed a neutralisation sensitive epitope. By swapping the env gene of a molecular clone of FIV-Glasgow8 with that of the novel field isolate, it was hypothesised that vaccinated with the chimaeric virus (FIV ΔV2) could elicit a broadly neutralising antibody response capable of protection against low does challenge with virulent UK primary isolate, FIV-Glasgow8. Additionally, by mutating the principal immunodominant (PID) of the transmembrane region of FIV ΔV2 from that of FIV to lion lentivirus subtype-E (LLV-E), it was proposed that the humoral immune response towards the wildtype sequence would be abolished, and recognise only LLV-E PID when plasma/sera were screened for reactivity to either PID sequence in a peptide ELISA format.
The pathogenesis of FIV ΔV2 revealed the rapid production of homologous neutralising antibodies that corresponded with a marked reduction in the proviral load. Although no heterologous neutralising antibodies were detected, it was thought that If the PID of the FIV ΔV2 virus were mutated to that of LLV-E (DIVA virus) and used as a whole inactivated virus candidate vaccine in a prime boost regime, cats may elicit both homologous and heterologous neutralising antibodies whilst at the same time demonstrate sufficient reactivities to the two different PID sequences that it would be possible to DIVA cats solely by conventional serology techniques.

The DIVA virus did not afford protection against low dose challenge with FIV-Glasgow8 and appeared to enhance infection as all vaccinates became infected before controls. Additionally, no homologous or heterologous neutralising were produced, although the antibody response towards the PID sequences differed substantially so that DIVA could be performed on cats by conventional serology. Such was the utility of the PID peptide ELISA it was possible to differentiate infected from vaccinate cats and unvaccinated from uninfected cats, an observation that has never previously been reported.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: feline immunodeficiency virus, DIVA, FIV, vaccine, diagnostic.
Subjects: Q Science > QR Microbiology > QR180 Immunology
Q Science > QR Microbiology > QR355 Virology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Centre for Virus Research
Funder's Name: Biotechnology and Biological Sciences Research Council (BBSRC)
Supervisor's Name: Hosie, Professor Margaret and Willett, Professor Brian
Date of Award: 2018
Depositing User: Mr Matthew Harris
Unique ID: glathesis:2018-8863
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 26 Apr 2018 13:26
Last Modified: 26 Apr 2018 13:37
URI: http://theses.gla.ac.uk/id/eprint/8863

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