MF59 Emulsion Is an Effective Delivery System for a Synthetic TLR4 Agonist (E6020)

Baudner, Barbara C.; Ronconi, Vanessa; Casini, Daniele; Tortoli, Marco; Kazzaz, Jina; Singh, Manmohan; Hawkins, Lynn D.; Wack, Andreas; O’Hagan, Derek T.

doi:10.1007/s11095-009-9859-5

Cited by 80 publications

(55 citation statements)

References 60 publications

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“…The immunological data in the present work demonstrate that influenza and malaria vaccines adjuvanted with emulsions made with different natural or synthetic phosphatidylcholines elicit similar antibody responses. Moreover, the qualitative immunogenicity of the emulsions employed in this work are in line with literature reports; for instance, emulsions (without TLR agonists) appear to induce only modest increases in IgG2a responses compared to antigen alone (19). Subtle differences were evident between emulsions in experiments with the influenza vaccine, illustrating that the lipid emulsifiers may differ slightly in biological effects.…”

Section: Discussionsupporting

confidence: 88%

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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Section: Discussionsupporting

confidence: 88%

Immunomodulatory and Physical Effects of Phospholipid Composition in Vaccine Adjuvant Emulsions

et al. 2012

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“…These adjuvants stimulate local inflammatory responses at the injection site, which lead to leukocyte recruitment, antigen transport to draining lymph nodes, and APC activation (17). In preclinical models, adjuvants like MF59 appear to stimulate lymphocyte priming through a TLR-independent MyD88-dependent pathway (18) and subsequent Th2-mediated antibody responses (19), whereas the majority of helper CD4 T cells induced in people are biased to a Th0/Th1 phenotype (20,21). A separate strategy for inducing anti-viral Th1 responses involves activation of TLR4, which is unique among the TLR family in its ability to activate MyD88 and IFN production through the TRIF pathway (8).…”

Section: Discussionmentioning

confidence: 99%

Adjuvant solution for pandemic influenza vaccine production

Clegg

Roque

Hoeven

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Extensive preparation is underway to mitigate the next pandemic influenza outbreak. New vaccine technologies intended to supplant egg-based production methods are being developed, with recombinant hemagglutinin (rHA) as the most advanced program for preventing seasonal and avian H5N1 Influenza. Increased efforts are being focused on adjuvants that can broaden vaccine immunogenicity against emerging viruses and maximize vaccine supply on a worldwide scale. Here, we test protection against avian flu by using H5N1-derived rHA and GLA-SE, a two-part adjuvant system containing glucopyranosyl lipid adjuvant (GLA), a formulated synthetic Toll-like receptor 4 agonist, and a stable emulsion (SE) of oil in water, which is similar to the best-in-class adjuvants being developed for pandemic flu. Notably, a single submicrogram dose of rH5 adjuvanted with GLA-SE protects mice and ferrets against a high titer challenge with H5N1 virus. GLA-SE, relative to emulsion alone, accelerated induction of the primary immune response and broadened its durability against heterosubtypic H5N1 virus challenge. Mechanistically, GLA-SE augments protection via induction of a Th1-mediated antibody response. Innate signaling pathways that amplify priming of Th1 CD4 T cells will likely improve vaccine performance against future outbreaks of lethal pandemic flu.

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“…*, P Ͻ 0.05 versus CelTOS alone; §, P Ͻ 0.05 versus 2% SE. emulsion, including TLR4 and TLR9 ligands, which not only boost IFN-␥ levels but also actively suppress IL-5 (6,27). Besides dendritic cells, other cell types, such as macrophages, monocytes, granulocytes, and myocytes, are also activated by vaccine adjuvants such as MF59 and aluminum salts and may play significant roles in biological activity (24,28), although this remains to be explored further for GLA-containing adjuvants.…”

Section: Figmentioning

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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MF59 Emulsion Is an Effective Delivery System for a Synthetic TLR4 Agonist (E6020)

Abstract: Combining adjuvants like E6020 and MF59 allowed a finer tuning of the immune response towards a particular Th bias, thus have significant implications for the development of improved influenza vaccines.

Cited by 80 publications

References 60 publications

Immunomodulatory and Physical Effects of Phospholipid Composition in Vaccine Adjuvant Emulsions

Immunomodulatory and Physical Effects of Phospholipid Composition in Vaccine Adjuvant Emulsions

Adjuvant solution for pandemic influenza vaccine production

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

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