Characterisation of kunjin replicon vaccines

Ms Paweena Rattanasena (2008). Characterisation of kunjin replicon vaccines PhD Thesis, School of Population Health, The University of Queensland.

       
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Author Ms Paweena Rattanasena
Thesis Title Characterisation of kunjin replicon vaccines
School, Centre or Institute School of Population Health
Institution The University of Queensland
Publication date 2008-09
Thesis type PhD Thesis
Supervisor Associate Professor Andreas Suhrbier
Associate Professor Alex Khromykh
Total pages 287
Total colour pages 20
Total black and white pages 267
Subjects 320000 Medical and Health Sciences
Formatted abstract One of the recent focuses on vaccine development has been the use of viral vectors for
induction of CD8+ T cell responses. Self-amplifying, RNA-based replicons derived from the
flavivirus Kunjin (KUN) have been described as highly effective vectors for induction of CD8+ T
cell responses. This thesis aims to characterise several features of KUN replicon vectors that are
important for induction of CD8+ T cell responses and for future development of KUN repliconbased
vaccines.
An effective vaccine for human immunodeficiency virus (HIV) is urgently needed, and a
number of studies are currently using simian immunodeficiency virus (SIV) as a model for HIV.
SIV vaccines need to be evaluated in murine models prior to use in monkey trials. This thesis
describes the testing of four different KUN replicon virus-like particle (VLP) vaccines encoding
SIV Gag. Evaluation of these KUN VLP vaccines in mice illustrated that different constructs can
behave very differently in induction of effector memory and central memory T cell responses and
mediation of protection against challenge. This study also illustrated that certain constructs suffer
from deletions of the heterologous gene insert, which may occur during KUN VLP manufacture
(Chapter 2). A vaccine encoding Gag-pol performed optimally in these studies and was selected for
using in a monkey trial.
The efficacy of several viral vectors has been shown to be impaired by anti-vector
responses. KUN VLP immunisation induced both anti-KUN vector antibody and CD8+ T cell
responses in mice. Increase of anti-KUN neutralising antibodies significantly correlated with the
number of immunisations, but did not correlate with the immunisation dose, vaccine construct,
purity of KUN VLPs, replication of KUN RNA, or period after immunisation. Both anti-KUN
neutralising antibody and CD8+ T cell responses were capable of inhibiting immunogen-specific
CD8+ T cell induction by a KUN VLP vaccine. In addition, inflammatory responses induced by
Toll-like receptor agonists were found to inhibit KUN VLP vaccine efficacy. These data thus
showed that the KUN VLP system, like other viral vectors, can suffer from potential problems
associated with anti-vector responses (Chapter 3).
Heterologous prime-boost vaccination strategies have been used for effective induction of
CD8+ T cell responses in a number of vaccine studies and are currently being evaluated in several
clinical trials. In mice, KUN VLPs as a priming modality significantly outperformed DNA as a
priming modality for effector, effector memory and central memory CD8+ T cell responses, when
recombinant vaccinia (rVV) was used as a boosting modality. DNA priming did not improve the
induction of central memory CD8+ T cell responses when KUN VLPs were used for boosting.When combined with rVV, KUN VLPs were highly effective both as a priming modality and as a
boosting modality. These results illustrated that KUN VLPs can perform effectively in
heterologous prime-boost vaccination settings (Chapter 4).
Infection of DCs is believed to be one of the important characteristics of viral vectors as
these viral vectors are likely to deliver vaccine antigens into DCs’cytosol and ultimately lead to
effective priming of CD8+ T cells. This thesis shows that KUN VLPs could infect and express
heterologous genes in human monocyte-derived conventional DCs in vitro. However, KUN VLPinfected
DCs did not undergo maturation, even in the presence of maturation cytokines. Bystander
uninfected DCs in the same culture as KUN VLP-infected DCs also did not become mature, nor
could they be induced to mature by maturation cytokines. As the maturation of DCs is essential for
induction of CD8+ T cell responses, KUN VLP-infected DCs may transfer antigens to lymph noderesident
DCs that become mature and then present antigens to CD8+ T cells (Chapter 5).
These insights into the KUN replicon system may help in the future development and
utilisation of KUN replicon vaccines, which have shown considerable promise in murine systems.
Additional Notes Pages should be printed in colour: 28, 43, 51, 52, 71, 73, 75, 111, 113, 117, 181, 183, 185, 189, 191, 195, 197, 199, 201, and 217.

 
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Created: Wed, 03 Dec 2008, 23:06:33 EST by Ms Paweena Rattanasena on behalf of Library - Information Access Service