Martin, Stuart (2010) The potential of a novel Adenovirus vector for vaccination. PhD thesis, University of Warwick.

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Abstract

Adenoviruses (Ads) have many attractive characteristics for use as agents of genebased
vaccines and therapies. The most frequently used Ad vectors in preclinical
research are based on Ad5. However, in the clinical setting Ad5 vectors have severe
limitations. About 90% of the population have neutralising antibodies against Ad5
and infection requires expression of the viral receptor CAR, which is not present on
important cell types. Previous data from this laboratory suggested that the species D
adenovirus, Ad19a, may overcome some of these limitations. Most relevant for
vaccination is its high efficiency of infection of human dendritic cells (DCs), the
most important antigen presenting cells. This highly effective DC targeting was
retained in Ad19aGFP vectors. To investigate the potential of Ad19a vectors for
vaccination further, two transgenes, the nucleocapsid gene from pneumovirus of
mice (PVM-N), and a HIV polyprotein cassette (HIVA), were inserted into
replication-deficient Ad5 and Ad19a vectors using recombineering. rAd19aPVM and
rAd19aHIVA expressed a significantly higher amount of transgene compared with
their Ad5 homologues. Encouraging results were obtained when the ability of
rAd5PVM and rAd19aPVM to protect mice from lethal PVM challenge was
examined using various prime/boost vaccinations. A dose of 106 pfu of rAd19aPVM,
but not rAd5PVM, provided protection. rAd5PVM did, however, protect mice at the
same dose when combined with rAd19aPVM in a heterologous prime boost
schedule. Vaccination-induced IgG responses to PVM-N did not correlate with
protection, implicating cell-mediated immune responses in protection. Utilising
rAd19aGFP, evidence is also provided that Ad19a may use CD46 and to some extent
CAR as a receptor on CHO cells, expanding our knowledge of the basic biology of
this virus.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QR Microbiology > QR355 Virology
Library of Congress Subject Headings (LCSH):	Adenoviruses, Vaccination -- Methodology, Genetic vectors
Official Date:	October 2010
Dates:	Date Event October 2010 Submitted
Institution:	University of Warwick
Theses Department:	Department of Biological Sciences
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Burgert, Hans-Gerhard
Extent:	xviii, 305 leaves : ill., charts
Language:	eng

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