In the development of new vaccines, we face several restrictions: it is no longer possible to introduce “live” vaccines such as oral polio vaccines or, most probably, killed vaccines due to regulatory concerns about these systems, with the risk of adverse events outweighing their perceived benefits. This is particularly evident in environments where the risk from disease is now low. Therefore, it is clear that in terms of safety profiles, sub-unit vaccines are the way forward. However, these vaccines themselves have a range of problems, including their low immunogenicity and their need for multiple dosing and booster injections. To address these problems, the group is looking at an array of nanoparticulate systems, including liposomes, ISCOMs, Pluscoms, and nanoparticles to deliver these sub-unit vaccines.
Liposomes, which are well reported for their efficacy as delivery
systems, offer a range of advantages as possible vaccine adjuvants,
including their strong biocompatibility profile and ability to
entrap a variety of proteins and peptides. However, these systems
are inherently non-immunogenic; therefore, for application as a
vaccine delivery system, they require further formulation. One
approach is to supplement the bilayer with mannosylated
phosphatidyl ethanolamine. This approach is based on the fact
that many pathogens express glycoproteins on their surface and
to facilitate their recognition and clearance macrophages and
dendritic cells carry cell-surface mannose receptors. To
investigate mannosylated liposomes, the group formulated three
liposomal systems (neutral, anionic, and mannosylated systems),
and their physico-chemical properties and immunological
activity were tested.
In terms of their physical attributes, the size of the liposomes
was shown to be influenced by the charge of the liposomal
bilayer, with mannosylated liposomes being smaller than their
anionic and neutral counterparts. Looking at how these
attributes influenced blood monocyte-derived dendritic cell
uptake, it was found that the presence of mannose on the surface
cell proliferation, and in a tumour challenge model, these
liposomes significantly enhanced the time mice remained
tumour free. The efficacy of these liposomes was further
enhanced by supplementing the bilayer with Quil A, a potent
adjuvant, derived from the bark of Quillaja saponaria, a South
American tree. The authors summarised that an effective subunit
delivery system required not only a particulate nature but
also a danger signal.
By varying the ratio of phospholipid, cholesterol, and Quil A in
aqueous dispersion, the authors formulated a range of
nanoparticle systems, including ring-like micelles (approximately
10 nm in diameter), helical micelles, lipidic particles, and, most
importantly, cage-like spherical particles, termed immunestimulating
complexes (ISCOMs), with characteristic soccer
ball-like morphology and a very narrow size distribution around
40 nm. As these systems are “open,” the antigen has to be
inserted into the colloidal structure, in contrast to liposomes
where the antigen can be encapsulated into the core of the
liposome. Whilst these systems are highly immunogenic, loading
of hydrophilic antigens is difficult, and the sub-unit antigen had
to be chemically modified, e.g., by adding a fatty acid or
phospholipid moiety, to achieve incorporation of the antigen in
the adjuvant-containing nanoparticle. The group has also
developed a cationic alternative to the anionic ISCOMs (termed
Pluscoms) by replacing cholesterol with the cationic cholesterol
derivative DC-cholesterol, thereby greatly enhancing uptake of
the mostly anionic sub-unit proteins through electrostatic
interactions.
