Limitations of oil-in-water emulsions.
Use of oil-in-water emulsions has been limited by their reactogenicity and potential for adverse reactions. Various types
of emulsions have been used, with different natural oils, in order to try to find more stable, potent, less reactogenic formulations.38 However, they still suffer from excessive reactogenicity and toxicity which restricts their suitability for prophylactic
vaccines, particularly those intended for children.
Mechanism of action.
Originally, Syntex adjuvant (containing squalene oil, a non-ionic surfactant, poloxamer L121, and threonyl muramyl dipeptide)
was developed as a replacement for CFA.39 However, this adjuvant proved too toxic for human use40 and Chiron subsequently developed MF59 adjuvant as an alternative.41 MF59 is a submicron oil-in-water emulsion which contains 4–5% w/v squalene, 0.5% w/v Tween 80, 0.5% Span 85, and optionally,
varying amounts of muramyl tripeptide phosphatidyl-ethanolamine (MTP-PE), which activates non-TLR sensing receptors known
as NOD-LRRs (reviewed in Akira42 ). Because of excessive reactogenicity and/or toxicity, the current version of MF59 used in an adjuvanted influenza vaccine
(FLUAD) registered in Italy does not contain MTP but instead just squalene oil and surfactants.43,44 Published data suggests addition of MF59 only induces a modest (about 25%) increase in antibody levels in the elderly and
no difference in younger individuals when compared to unadjuvanted influenza vaccine.4,45 Furthermore, there was little evidence that MF59 is antigen-sparing for influenza vaccines, since the same antigen dose
is required for MF59 as for the unadjuvanted vaccine.4,45 MF59 has been shown to be superior to alum in inducing antibody responses to hepatitis B vaccine in baboons46 and humans.47
Limitations of MF59.
On the negative side, MF59, like all other oil-in-water adjuvants, is associated with major increases in injection site pain
and reactogenicity.4 Another concern with squalene oil is its ability to induce chronic inflammatory arthritis in susceptible animal models.48 Susceptibility to squalene arthritis is genetically determined, raising the risk that adjuvants based on squalene oil may
also induce or exacerbate inflammatory arthritis in genetically susceptible humans.48
Monophosphoryl Lipid A (MPL)
Mechanism of action.
Bacteria-derived immunostimulants constitute a major potential source of adjuvants. Lipopolysaccharide (LPS),49 containing the active Lipid A moiety, is very potent but too toxic for human use. MPL is a chemically detoxified derivative
of native Lipid A from Salmonella minnesota R595, which is used in complex adjuvant formulations with alum, QS21, liposomes, and emulsions, and is a component of GlaxoSmithKline's
proprietary AS02 and AS04 adjuvants.7,8,50
Like LPS, MPL interacts with TLR4 on macrophages, resulting in the release of proinflammatory cytokines including TNF, IL-2
and IFN-gamma, which promote the generation of Th1 responses.51,52 MPL has been extensively evaluated in human subjects for applications including vaccines for cancer and infectious disease
(genital herpes, HBV, malaria, and HPV), and allergies. Approved vaccines containing MPL include a melanoma vaccine approved
in Canada, a hepatitis B vaccine for hemodialysis patients approved in Europe, and an HPV vaccine approved in Australia.
Limitations of MPL.
Although MPL lacks some of the more extreme toxicities of LPS, it is nevertheless able to strongly activate via TLR-4, inducing
pro-inflammatory cytokines, and thereby significant reactogenicity. In terms of production, like any bacterially-derived material,
there are issues of consistency of preparation, formulation, and cost.