Biology Reference
In-Depth Information
least as immunogenic as conventional replicating Vaccinia virus [10]-[13] and
has the advantage of a considerably improved safety profile [14].
Attention has focussed on MVA not only as a possible 'next generation' small-
pox vaccine [15]-[17], but also as a recombinant vaccine vector, with particular
value in combination with other vectors (e.g. DNA, adenovirus, or an avian pox-
virus) as a component of heterologous prime-boost regimens designed to elicit
high frequencies of antigen-specific T cells [18]. This approach is undergoing
development and clinical trial for diseases such as HIV-AIDS [19], [20], tuber-
culosis [21], [22] and malaria [23], [24], where protective T cell responses are
required for vaccine efficacy. In the case of liver-stage malaria vaccines, specific
cytotoxic T cell responses correlate with the limited levels of protection achieved
so far in humans [25], but current vectors and regimens are not immunogenic
enough to achieve significant efficacy in malarious regions [26]. There is there-
fore a need to identify recombinant vaccine vectors with greater immunogenicity,
either by using novel vectors (e.g. simian adenoviruses [27]) or by improving
existing platforms.
The routes available for attempts to improve MVA vector immunogenicity
can be crudely divided into addition or removal of genes. Co-expression of co-
stimulatory molecules, such as B7.1 [28] and 4-1BB ligand [29] and various cy-
tokines, including IL-12 [30], IL-15 [31] and GM-CSF [32] have been reported
to increase recombinant poxvirus vaccine immunogenicity. These interventions
can achieve a two- to four-fold increase in peak murine IFN-
γ
T cell responses.
The parallel strategy is to delete poxviral genes encoding immunomodulators that
attenuate adaptive immune responses, but are not required for growth in vitro.
During attenuation MVA lost many such factors, including soluble decoy recep-
tors for IFN-
γ
[33], TNF-
α
[34], IFN-
α
/
β
[35] and various chemokines [36]; an
inhibitor of IL-1
β
converting enzyme [37], the complement control protein [38]
and an intracellular inhibitor of Toll-like receptor (TLR) and IL-1 receptor (IL-
1R) signalling [39]. On the other hand, it retains genes encoding secreted inter-
leukin- [40]-[42] and chemokine- [36], [43] binding proteins; a dehydrogenase
involved in steroid synthesis [44], [45], a second inhibitor of TLR/IL-1 recep-
tor signalling [46], and other genes implicated in poxviral virulence [47]-[50].
Evidence that deletion of such genes provides a route for improvement of MVA
immunogenicity is provided by reports of augmented protective mouse CD8+ T
cell responses elicited by MVA lacking B15R, encoding an IL-1
β
binding protein
[51], and A41L, encoding a chemokine binding protein of unknown specificity
[43].
In addition to a priori candidates, there are at least 30 MVA genes whose
function remains unknown. Although many poxviral proteins retain sequence
homology and functional similarity with host proteins, it has recently been shown
Search WWH ::
Custom Search