Squalene Emulsions for Parenteral Vaccine and Drug Delivery

Fox, Christopher B.

doi:10.3390/molecules14093286

Cited by 179 publications

(120 citation statements)

References 138 publications

(245 reference statements)

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“…Squalene has an excellent safety profi le (Christian , 1982 ;Fox , 2009 ). Injected squalene (21 mg) into over million cases (including infants) showed very low incidence rate of side effects (mostly pain at injection site) (Ketomaki et al , 2004 ).…”

Section: Safety Of Hypercholesterolemia Therapymentioning

confidence: 99%

Squalene monooxygenase – a target for hypercholesterolemic therapy

Belter¹,

Skupińska²,

Giel-Pietraszuk

et al. 2011

BCHM

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Squalene monooxygenase catalyzes the epoxidation of C-C double bond of squalene to yield 2,3-oxidosqualene, the key step of sterol biosynthesis pathways in eukaryotes. Sterols are essential compounds of these organisms and squalene epoxidation is an important regulatory point in their synthesis. Squalene monooxygenase downregulation in vertebrates and fungi decreases synthesis of cholesterol and ergosterol, respectively, which makes squalene monooxygenase a potent and attractive target of hypercholesterolemia and antifungal therapies. Currently some fungal squalene monooxygenase inhibitors (terbinafi ne, naftifi ne, butenafi ne) are in clinical use, whereas mammalian enzymes ' inhibitors are still under investigation. Research on new squalene monooxygenase inhibitors is important due to the prevalence of hypercholesterolemia and the lack of both suffi cient and safe remedies. In this paper we (i) review data on activity and the structure of squalene monooxygenase, (ii) present its inhibitors, (iii) compare current strategies of lowering cholesterol level in blood with some of the most promising strategies, (iv) underline advantages of squalene monooxygenase as a target for hypercholesterolemia therapy, and (v) discuss safety concerns about hypercholesterolemia therapy based on inhibition of cellular cholesterol biosynthesis and potential usage of squalene monooxygenase inhibitors in clinical practice. After many years of use of statins there is some clinical evidence for their adverse effects and only partial effectiveness. Currently they are drugs of choice but are used with many restrictions, especially in case of children, elderly patients and women of childbearing potential. Certainly, for the next few years, statins will continue to be a suitable tool for cost-effective cardiovascular prevention; however research on new hypolipidemic drugs is highly desirable. We suggest that squalene monooxygenase inhibitors could become the hypocholesterolemic agents of the future.

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Section: Safety Of Hypercholesterolemia Therapymentioning

confidence: 99%

Squalene monooxygenase – a target for hypercholesterolemic therapy

Belter¹,

Skupińska²,

Giel-Pietraszuk

et al. 2011

BCHM

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“…Various emulsifier compositions exist, with squalene being the preferred metabolizable oil for vaccine adjuvant applications (1)(2)(3). Commonly used emulsifiers include Pluronics®, Tweens®, Spans®, and phospholipids.…”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory and Physical Effects of Phospholipid Composition in Vaccine Adjuvant Emulsions

et al. 2012

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Abstract. Egg phosphatidylcholine is commonly used as an emulsifier in formulations administered parenterally. However, synthetic phosphatidylcholine (PC) emulsifiers are now widely available and may be desirable substitutes for egg-derived phospholipids due to stability, purity, and material source considerations.In earlier work, we demonstrated that a squalene-1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) emulsion provided equivalent physical stability compared to a squalene-egg PC emulsion. In the present manuscript, we evaluate the physical stability of vaccine adjuvant emulsions containing a range of other synthetic phosphatidylcholine emulsifiers. Besides the POPC emulsion, the 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) emulsion showed good particle size and visual stability compared to emulsions made with other synthetic phospholipids. Moreover, comparable immune responses were elicited by squalene emulsions employing various synthetic PC or egg PC emulsifiers in combination with an inactivated influenza vaccine or a recombinant malaria antigen, and these responses were generally enhanced compared to antigen without adjuvant. Therefore, we show that (1) some synthetic PCs (DMPC, POPC, and to a lesser extent 1,2-dioleoyl-sn-glycero-3-phosphocholine) are effective stabilizers of squalene emulsion over a range of storage temperatures while others are not (1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, and 1,2-dilauroyl-sn-glycero-3-phosphocholine) and (2) the immunogenicity of stable squalene emulsions is similar regardless of PC source.

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“…The most notable o/w emulsions are MF59 and AS03, which are produced by Novartis and GSK Biologicals, respectively. Both of these adjuvants contain squalene at ϳ2.5% (vol/vol) in the final vaccine formulation (13). However, until recently, only a few reports regarding the motivation for selecting this squalene concentration were published (9,21,25).…”

mentioning

confidence: 99%

Effects on Immunogenicity by Formulations of Emulsion-Based Adjuvants for Malaria Vaccines

Fox¹,

Baldwin²,

Vedvick³

et al. 2012

Clin. Vaccine Immunol.

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bNew malaria vaccines are urgently needed to improve vaccine protective efficacy. PfCelTOS is a recombinant malaria vaccine antigen that has shown protective efficacy in a small-animal challenge model when combined with a water-in-oil emulsion adjuvant (Montanide ISA 720). In this report, we show that PfCelTOS vaccines containing GLA-SE (a stable oil-in-water emulsion combined with a Toll-like receptor 4 [TLR4] agonist) elicit strong Th1-type immune responses in BALB/c mice. These responses include higher antigen-specific IgG2a antibody titers and more gamma interferon (IFN-␥) production than those seen with a PfCelTOS vaccine containing Montanide ISA 720. Furthermore, reducing the emulsion dose from 2% to 1% or 0.5% (vol/vol) squalene in GLA-SE did not compromise immunogenicity. Emulsion dose titration in the absence of formulated GLA caused some reduction in humoral and cellular immune responses compared to those with the 2% squalene emulsion dose. Oil-in-water (o/w) emulsions have been used safely and successfully as adjuvants in modern vaccines. The most notable o/w emulsions are MF59 and AS03, which are produced by Novartis and GSK Biologicals, respectively. Both of these adjuvants contain squalene at ϳ2.5% (vol/vol) in the final vaccine formulation (13). However, until recently, only a few reports regarding the motivation for selecting this squalene concentration were published (9,21,25). Moreover, a recent study showed that dilution of MF59 did not compromise the immune response in a pandemic influenza vaccine clinical trial (20). If adjuvant activity can be maintained with a reduction of the squalene dose, then the local reactogenicity of o/w emulsions can potentially be reduced. Furthermore, the vaccine cost could decrease while the available adjuvant supply would increase, thus making vaccine and adjuvant production in resource-poor countries more achievable.The recombinant malaria antigen PfCelTOS (Plasmodium falciparum cell traversal protein for ookinetes and sporozoites) combined with an emulsion adjuvant (Montanide ISA 720) protected 60% of mice in a heterologous challenge model (8). PfCelTOS inhibits sporozoite motility and hepatocyte infectivity and could be an important component of new malaria vaccines. Both cellular and humoral immune responses are important for protective efficacy directed against this antigen (7,8).In this work, we evaluated squalene-based stable emulsion (SE) adjuvant dose effects on humoral and cellular immune responses to PfCelTOS. Moreover, we investigated the effect of including a formulated synthetic Toll-like receptor 4 (TLR4) agonist, glucopyranosyl lipid adjuvant (GLA), in the vaccine formulation. We show that squalene concentrations of Ͻ2% (vol/vol) in GLA-SE may induce adjuvant responses equivalent to those seen with a 2% (vol/vol) squalene concentration. This finding has important implications for vaccine adjuvant production and dosing as well as for novel routes of administration (such as intradermal routes), which may be more sensitive to oil concentrations. Mo...

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Squalene Emulsions for Parenteral Vaccine and Drug Delivery

Cited by 179 publications

References 138 publications

Squalene monooxygenase – a target for hypercholesterolemic therapy

Squalene monooxygenase – a target for hypercholesterolemic therapy

Immunomodulatory and Physical Effects of Phospholipid Composition in Vaccine Adjuvant Emulsions

Effects on Immunogenicity by Formulations of Emulsion-Based Adjuvants for Malaria Vaccines

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