Jabbar, Tamara Kusay Akram; (2012) Next generation vaccine for bluetongue virus serotype-8 and the neutralizing immune response in a mouse model. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The recent emergence of BT in Europe and the spread of BTV-8 further north in the region than ever before, has emphasised the importance of vaccination against this economically important pathogen. The chemically inactivated and live attenuated BTV vaccines that are currently available do provide significant levels of protection (Savini et al., 2007). However, there are safety concerns over both vaccines, and it has not been possible to 'distinguish infected from vaccinated animals' (DIVA assays), making surveillance more difficult. A new generation of BTV vaccines is therefore required for use as part of appropriate surveillance and control strategies. 'Next generation' BTV-8 subunit-vaccine-candidates were prepared as: individual bacterial-expressed viral-proteins; 'DNA vaccines' composed of plasmid DNA carrying BTV genes; and recombinant Modified Vaccinia Ankara (rMVA) also carrying BTV genes. These systems were used to explore the potential of BTV VP2-fragment-1, -2 and -3, VP2-complete, VPS and VP7 as subunit vaccines. Different vaccination strategies were evaluated in IFNAR-/- mice: by vaccination with bacterial expressed proteins (fragmented VP2+ VP5 + VP7; or complete VP2+ VP5 + VP7) combined with Montanide, in a prime-boost regime administered at a three week interval. A second vaccination strategy was based on (in situ) expression of viral proteins, by priming with plasmid DNA containing cDNA copies of BTV VP2, VPS and/or VP7 capsid-genes, followed by vaccination with recombinant Modified Vaccinia Ankara (rMVA) expressing the same proteins, at a three week interval. An alternative prime-boost regime was also used, vaccinating (prime and boost) with rMVA (expressing these proteins) on both occasions. The unvaccinated-control mice, as well as those vaccinated with VP7 (alone) or with (fragmented VP2+ VPS + VP7) were not protected against a subsequent challenge with a lethal dose (10pfu) of BTV-8. However, S0% of mice vaccinated with complete VP2+ VPS + VP7 were protected. All of the mice vaccinated with DNA-rMVA or rMVA-rMVA expressing VP2; or VP2, VPS and VP7, were protected, with VP2-alone generating the highest level of protection. Further work will be needed to test different combinations of these BTV-subunit vaccine candidates, to validate their use and efficacy in ruminants (the natural hosts for BTV infection), and further investigate their potential for protection against heterologous serotypes.

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