Enhancement of humoral immune responses against viral vaccines by a non-pyrogenic 6-O-acyl-muramyldipeptide and synthetic low toxicity analogues of lipid A

Tsujimoto, M; Kotani, Shozo; Okunaga, Takafumi; Kubo, Takao; Takada, Haruhiko; Kubo, Takasi; Shiba, Tetsuo; Kusumoto, Shoichi; Takahashi, Takashi; Goto, Yoji; Kinoshita, Fumio

doi:10.1016/0264-410x(89)90009-1

Cited by 21 publications

(7 citation statements)

References 31 publications

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“…Moreover, we did not see an additive effect of LA-15-PH-liposomes over that of gp195-liposomes. Our results for MPL in rabbits contrast with those described by Mashihi et al (20) and Tsujimoto et al (38), who showed that MPL or its derivatives enhanced antibody responses to influenza subunit vaccine and hepatitis B vaccine in mice over the levels obtained with alum or liposomes. Richards et al (27) studied the antibody responses to the recombinant CSP protein (R32tet32) of P. falciparum in rabbits and monkeys.…”

Section: Discussioncontrasting

confidence: 99%

“…However, protection was dependent on the administration of FCA as an adjuvant. Recently, two synthetic, low-toxicity derivatives of MDP and MPL, namely, B30-MDP (lipophilic MDP) and LA-15-PH (synthetic equivalent of MPL), respectively, were shown to induce potent antibody and cellmediated responses to a variety of antigens, including the influenza A split vaccine and the hepatitis B surface antigen (15,(37)(38)(39). The objective of the present study was to evaluate the ability of these two synthetic immunomodulators to potentiate the antibody response to gp195 in rabbits.…”

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confidence: 99%

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Synthetic low-toxicity muramyl dipeptide and monophosphoryl lipid A replace Freund complete adjuvant in inducing growth-inhibitory antibodies to the Plasmodium falciparum major merozoite surface protein, gp195

et al. 1991

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The Plasmodium falciparum major merozoite surface protein (gp195) is a protective antigen against lethal malaria. However, increasing evidence indicates that the efficacy of a malaria vaccine will require a strong adjuvant that is safe for human use. We compared the efficacies of two low-toxicity synthetic immunomodulators, B30-MDP (a lipophilic muramyl dipeptide derivative) and LA-15-PH (a synthetic equivalent of monophosphoryl lipid A), with that of Freund complete adjuvant (FCA) in eliciting an antibody response to gp195. Rabbits were imunized with native gp195 and B30-MDP, LA-15-PH, or the two in combination, with Uposomes as the vehicle. Aluminum hydroxide and FCA were used as reference adjuvants. Results showed that adjuvant formulations based on B30-MDP alone or in combination with LA-15-PH induced high antibody titers to gp195, as compared with FCA. LA-15-PH alone was less effective. Aluminum hydroxide induced significantly lower antibody titers. The functional activity of the rabbit anti-gp195 antibodies induced by different adjuvants was evaluated in an in vitro parasite growth inhibition assay previously shown to correlate with anti-gp195 immunity in the Aotus monkey model. AU rabbits immunized with B30-MDP-LA-15-PH and two of three rabbits immunized with B30-MDP alone produced sera that strongly inhibited parasite growth. The degree of growth inhibition was similar to that with FCA. The antibody titers of the rabbits receiving B30-MDP-LA-15-PH strongly correlated with the degree of in vitro growth inhibition. Our findings provided strong evidence that adjuvant formulations based on synthetic B30-MDP and LA-15-PH can replace FCA as adjuvants in stimulating protective inmunity specific for gp195.

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Section: Discussioncontrasting

confidence: 99%

mentioning

confidence: 99%

Synthetic low-toxicity muramyl dipeptide and monophosphoryl lipid A replace Freund complete adjuvant in inducing growth-inhibitory antibodies to the Plasmodium falciparum major merozoite surface protein, gp195

et al. 1991

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“…Adjuvant activity of peptidoglycan monomer has been documented in several studies but only one report concerns its activity in liposomal formulation (Tomašic and Hršak, 1982). More studies were published on the activity of structurally related muramyl peptides or adamantylpeptides encapsulated into liposomes (Brynestad et al, 1990;Turanek et al, 1994;Davis and Gregoriadis, 1989;Ullrich and Fidler, 1992;Tsujimoto et al, 1989;Gregoriadis and Panagiotidi, 1989;Bui et al, 1994;Allison and Byars, 1986;Iinuma et al, 1995). In most of these studies the adjuvant activity of liposomal formulations containing immunomodulators was confirmed (Brynestad et al, 1990;Turanek et al, 1994;Davis and Gregoriadis, 1989;Ullrich and Fidler, 1992;Tsujimoto et al, 1989;Gregoriadis and Panagiotidi, 1989;Bui et al, 1994).…”

Section: Discussionmentioning

confidence: 90%

Effect of Liposomal Formulations and Immunostimulating Peptidoglycan Monomer (PGM) on the Immune Reaction to Ovalbumin in Mice

Habjanec

Frkanec

Halassy

et al. 2006

Journal of Liposome Research

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The adjuvant activity of liposomes and immunostimulating peptidoglycan monomer (PGM) in different formulations has been studied in mice model using ovalbumin (OVA) as an antigen. PGM is a natural compound of bacterial origin with well-defined chemical structure: GlcNAc-MurNAc-L-Ala-D-isoGln-mesoDpm(epsilonNH2)-D-Ala-D-Ala. It is a non-toxic, non-pyrogenic, and water-soluble immunostimulator. The aim of this study was to investigate the influence of different liposomal formulations of OVA, with or without PGM, on the production of total IgG, as well as of IgG1 and IgG2a subclasses of OVA-specific antibodies (as indicators of Th2 and Th1 type of immune response, respectively). CBA mice were immunized s.c. with OVA mixed with liposomes, OVA with PGM mixed with liposomes, OVA encapsulated into liposomes and OVA with PGM encapsulated into liposomes. Control groups were OVA in saline, OVA with PGM in saline, and OVA in CFA/IFA adjuvant formulation. The entrapment efficacy of OVA was monitored by HPLC method. The adjuvant activity of the mixture of OVA and empty liposomes, the mixture of OVA, PGM, and liposomes and PGM encapsulated with OVA into liposomes on production of total anti-OVA IgG was demonstrated. The mixture of PGM and liposomes exhibited additive immunostimulating effect on the production of antigen-specific IgGs. The analysis of IgG subclasses revealed that encapsulation of OVA into liposomes favors the stimulation of IgG2a antibodies, indicating the switch toward the Th1 type of immune response. When encapsulated into liposomes or mixed with liposomes, PGM induced a switch from Th1 to Th2 type of immune response. It could be concluded that appropriate formulations of antigen, PGM, and liposomes differently affect the humoral immune response and direct the switch in the type of immune response (Th1/Th2).

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“…There are at least two reports describing the effective use of one of the most common nutritional supplementation emulsions, the soybean oil-based Intralipid®, as a vaccine formulation including antigen and additional immunostimulatory molecules (muramyl dipeptide or avridine) [34, 42]. Tsujimoto et al found that the soybean emulsion with an influenza vaccine elicited similar HAI titers to the control vaccine (in PBS); however, when an additional immunostimulant (muramyl dipeptide analogue) was present, the vaccine containing the emulsion appeared to elicit higher HAI titers than the vaccine containing immunostimulant without the soybean oil emulsion [42], although the physical interaction between the immunostimulant and the emulsion was not characterized. Similarly, our results described in the present work showed negligible adjuvant activity associated with the soybean, grapeseed, and sesame oil emulsions.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory and physical effects of oil composition in vaccine adjuvant emulsions

Fox

Baldwin

Duthie

et al. 2011

Vaccine

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Squalene-based oil-in-water emulsions have been used for years in some seasonal and pandemic influenza vaccines. However, concerns have been expressed regarding squalene source and potential biological activities. Little information is available regarding the immunomodulatory activity of squalene in comparison with other metabolizable oils in the context of oil-in-water emulsions formulated with vaccines. The present work describes the manufacture and physical characterization of emulsions composed of different classes of oils, including squalene, long chain triglycerides, a medium chain triglyceride, and a perfluorocarbon, all emulsified with egg phosphatidylcholine. Some differences were apparent among the non-squalene oils in terms of emulsion stability, including higher size polydispersity in the perfluorocarbon emulsion, more rapid visual instability at 60 °C for the long-chain triglyceride and perfluorocarbon emulsions, and an increased creaming rate in the medium-chain triglyceride emulsion at 60 °C as detected by laser scattering optical profiling. The biological activity of each of these emulsions was compared when formulated with either a recombinant malaria antigen or a split-virus inactivated influenza vaccine. Overall, vaccines containing the squalene emulsion elicited higher antibody titers and more abundant long-lived plasma cells than vaccines containing emulsions based on other oils. Since squalene-based emulsions show higher adjuvant potency compared to the other oils tested, non-squalene oils may be more suitable as carriers of amphiphilic or hydrophobic immunostimulatory molecules (such as TLR agonists) rather than as stand-alone adjuvants.

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Enhancement of humoral immune responses against viral vaccines by a non-pyrogenic 6-O-acyl-muramyldipeptide and synthetic low toxicity analogues of lipid A

Cited by 21 publications

References 31 publications

Synthetic low-toxicity muramyl dipeptide and monophosphoryl lipid A replace Freund complete adjuvant in inducing growth-inhibitory antibodies to the Plasmodium falciparum major merozoite surface protein, gp195

Synthetic low-toxicity muramyl dipeptide and monophosphoryl lipid A replace Freund complete adjuvant in inducing growth-inhibitory antibodies to the Plasmodium falciparum major merozoite surface protein, gp195

Effect of Liposomal Formulations and Immunostimulating Peptidoglycan Monomer (PGM) on the Immune Reaction to Ovalbumin in Mice

Immunomodulatory and physical effects of oil composition in vaccine adjuvant emulsions

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