In a trial of a malaria vaccine using QS21, two of 89 individuals developed severe vaccine allergy, a high complication rate
for a prophylactic vaccine.78 Further issues of QS21 safety have also surfaced with deaths of human subjects in an Alzheimer's disease vaccine trial using
QS21, although the contribution of QS21 to these encephalitis deaths is not clear.79
Mechanism of action.
ISCOMs are immunostimulating complexes containing a saponin, a sterol, and, optionally, a phospholipid. The preferred saponins
are Quil A or QS21, the preferred sterol cholesterol, and the phospholipid is generally phosphatidylethanolamine. ISCOMs have
been shown to help generate protective immunity in a variety of experimental models, and generate CTL responses to such antigens
as HIV envelope glycoprotein and influenza hemagglutinin.80,81 The principal advantage of ISCOMs is to reduce the dose of the highly toxic QS21 adjuvant component (the saponin component
is bound to cholesterol and is less free to interact with cell membranes, thereby reducing QS21 hemolytic activity.)82,83 ISCOMs, being particles, are also more likely to be phagocytosed directly by macrophages. The adjuvant activity of ISCOMs
is related to their ability to induce cytokines, including IFN-g and IL-12,5,84 consistent with an ability to skew immune responses in a Th1 direction.
Limitations of ISCOMs.
ISCOMs have suffered from issues including cost, manufacturing difficulty, and stability, in addition to reactogenicity, toxicity,
and safety concerns.6,85 Side effects in a Phase 1 human cancer trial included flu-like symptoms, fever, and malaise.86 A major part of ISCOM reactogenicity and toxicity reflects the inclusion of Quil A or QS21 as an active ingredient. Hence
all safety concerns about QS21 apply to ISCOMs.
Mechanism of action.
Liposomes are synthetic phospholipid spheres consisting of lipid layers that can encapsulate antigens and act as both vaccine
delivery vehicle and adjuvant.87 The adjuvanticity of liposomes depends on the number of lipid layers,88 electric charge,89 composition,90 and method of preparation.90-92 Their use enhances both humoral and cell-mediated immunity to protein and polysaccharide antigens.89,91 Liposome-based vaccines based on virosomes are approved in Europe for hepatitis A and influenza.93 They have been shown to better induce CTL to influenza in elderly humans compared to unadjuvanted vaccine.94 INFLUSOME-VAC, which contains IL2-supplemented trivalent liposomal influenza vaccine, showed enhanced immunogenicity when
compared with standard split-virion vaccine in elderly and young subjects, but at the expense of an overwhelming (83%) incidence
of pain at the injection site.95 The mechanism of liposomes is fusion with the cell membranes of macrophages, enabling delivery of proteins into the cytoplasm
where they can enter the MHC class I pathway and activate CD8 CTLs.96,97 Liposomes can be made with various charge properties and cationic lipid vesicles comprising cationic cholesterol derivatives,
and optionally neutral phospholipids98 are able to bind antigen on the surface and thereby enhance antigen presentation. Modified proteo-liposomal structures termed
cochleates have also shown utility as systemic adjuvants.99
Limitations of liposomes
. Liposomes have suffered from manufacturing difficulties, stability, and high cost, which have limited their use. Furthermore,
they are more antigen vehicles than true adjuvants and hence require addition of immunostimulatory components such as MPL
for potent adjuvant action. Injection site pain can be a major limitation in some liposome vaccines.