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Jill Adler-Moore,
Meilen Munoz,
Hana Kim,
Juan Romero,
Terrence Tumpey,
Hui Zeng,
Chris Petro,
William Ernst,
Suzie Kosina,
Gretchen Jimenez,
Gary Fujii
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ABSTRACT: While the current influenza vaccine strategy is dependent on eliciting neutralizing antibodies to the hemagglutinin (H or HA) surface glycoprotein, antigenic drifts and occasional antigenic shifts necessitate constant surveillance and annual updates to the vaccine components. The ectodomain of the matrix 2 (M2e) channel protein has been proposed as a universal vaccine candidate, although it has not yet been shown to elicit neutralizing antibodies. Utilizing a liposome-based vaccine technology, an M2e vaccine (L-M2e-HD/MPL) was tested and shown to stimulate the production of anti-M2e antibodies which precipitated with whole virus and inhibited viral cell lysis by multiple type A strains of influenza virus using a novel in vitro assay. The anti-M2e antibodies also conferred complete protection following passive transfer from L-M2e-HD/MPL vaccinated mice to naïve mice challenged with H1N1 virus. Significantly higher levels of IL-4 compared to IFN-γ were secreted by the splenocytes of L-M2e-HD/MPL vaccinated mice incubated with M2e. In addition, depletion of CD4 cells or CD4 cells plus CD8 cells from L-M2e-HD/MPL vaccinated mice using monoclonal antibodies markedly decreased the level of protection of the vaccine when compared to just CD8 depletion of L-M2e-HD/MPL vaccinated mice. These results suggest that the protective immune response elicited by this vaccine is mediated primarily by a Th2 mechanism.
Vaccine 06/2011; 29(27):4460-8. · 3.77 Impact Factor
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ABSTRACT: The VesiVax system is based upon the concept that highly potent vaccines can be designed by engineering proteins that are capable of stably inserting themselves into liposomes. Such a nanoscale liposomal particle can then serve as an immunogen for vaccine development. The VesiVax vaccine technology platform is designed to make it relatively easy to engineer and produce new vaccines quickly. Vaccines based on the VesiVax system have been designed against the influenza virus and herpes simplex type 2 virus, the causative agents of the "flu" and genital herpes, respectively. Both vaccines have been tested in animal models and have demonstrated significant protective efficacy from challenge with lethal doses of virus. Assays of the immunological parameters suggest that both T and B cell responses can be elicited by VesiVax vaccines. The safety profile of the VesiVax vaccines is expected to be much better than that of vaccines prepared by conventional techniques. Taken together, the inherent flexibility of the VesiVax platform is expected to facilitate the rapid development of new vaccines which are effective at stimulating protective immune responses.
Frontiers in Bioscience 02/2008; 13:1968-80. · 3.52 Impact Factor
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Kasturi Mukhopadhyay,
William Whitmire,
Yan Q Xiong,
Jaime Molden,
Tiffanny Jones,
Andreas Peschel,
Petra Staubitz, Jill Adler-Moore,
Peter J McNamara,
Richard A Proctor,
Michael R Yeaman,
Arnold S Bayer
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ABSTRACT: Thrombin-induced platelet microbicidal proteins (e.g. tPMP-1) are small cationic peptides released from mammalian platelets. As the cytoplasmic membrane (CM) is a primary target of tPMPs, distinct CM characteristics are likely to affect the cells' susceptibility profiles. In Staphylococcus aureus, CM surface charge and hydrophobicity are principally determined by the content and distribution of its three major phospholipid (PL) constituents: negatively charged phosphatidylglycerol (PG) and cardiolipin (CL) and positively charged lysyl-PG (LPG). PL composition profiles, and inner vs outer CM leaflet PL distributions, were compared in an isogenic tPMP-susceptible (tPMP(S)) and -resistant (tPMP(R)) S. aureus strain pair (ISP479C vs ISP479R respectively). All PLs were asymmetrically distributed between the outer and inner CM leaflets in both strains. However, in ISP479R, the outer CM leaflet content of LPG was significantly increased vs ISP479C (27.3+/-11.0 % vs 18.6+/-7.0 % respectively; P=0.05). This observation correlated with reduced binding of the cationic proteins cytochrome c, poly-L-lysine, tPMP-1 and the tPMP-1-mimetic peptide, RP1, to tPMP-1(R) whole cells and to model liposomal CMs with LPG content and distribution similar to that of tPMP-1(R) strains. Collectively, selected CM parameters correlated with reduced staphylocidal capacities of tPMP-1 against certain S. aureus strains, including relative increases in outer CM leaflet positive charge and reduced surface binding of cationic molecules. These findings offer new insights into mechanisms of antimicrobial peptide susceptibility and resistance in S. aureus.
Microbiology 05/2007; 153(Pt 4):1187-97. · 3.06 Impact Factor
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ABSTRACT: Fusarium solani infections are notoriously difficult to treat. We compared the efficacy of polyenes and an echinocandin in treating murine fusariosis to identify the optimal therapeutic regimen.
Neutropenic mice infected intravenously with F. solani were treated with amphotericin B (AmB), liposomal AmB (LAmB), amphotericin B lipid complex (ABLC), caspofungin acetate or a combination of LAmB and caspofungin. Treatment was initiated prior to infection (prophylactic therapy), 24 h post-infection (delayed therapy) or 2 days before infection and continued for 1 day after (continuous therapy).
Prophylaxis only with LAmB significantly reduced brain or kidney fungal burden compared with placebo. No prophylactic treatment improved survival. LAmB levels in the kidneys were higher than ABLC or AmB levels, which were often undetectable. In the delayed therapy model, neither polyenes nor caspofungin improved survival. In the continuous therapy model, LAmB or LAmB plus caspofungin did not improve survival even though they did decrease fungal burden. In contrast, continuous caspofungin at 1 but not 5 mg/kg/day improved survival, but did not decrease fungal burden. Kidney inflammation and tissue necrosis were markedly decreased in mice treated with caspofungin compared with other treatments.
These studies demonstrate a dissociation between survival and tissue fungal burden during murine fusariosis. Although prophylactic LAmB may be useful at reducing tissue fungal burden, polyenes had limited survival benefit for active fusariosis. Caspofungin at 1 but not 5 mg/kg/day mediated surprising improvements in survival during active fusariosis, despite lack of reduction in fungal burden. Further studies are warranted.
Journal of Antimicrobial Chemotherapy 12/2006; 58(5):973-9. · 5.07 Impact Factor
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Caryn Bern, Jill Adler-Moore,
Juan Berenguer,
Marleen Boelaert,
Margriet den Boer,
Robert N Davidson,
Concepcion Figueras,
Luigi Gradoni,
Dimitris A Kafetzis,
Koert Ritmeijer,
Eric Rosenthal,
Catherine Royce,
Rosario Russo,
Shyam Sundar,
Jorge Alvar
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ABSTRACT: During the past decade, liposomal amphotericin B has been used with increasing frequency to treat visceral leishmaniasis (VL). The World Health Organization convened a workshop to review current knowledge and to develop guidelines for liposomal amphotericin B use for VL. In Europe, liposomal amphotericin B is widely used to treat VL. In Africa and Asia, the VL disease burden is high and drug access is poor; liposomal amphotericin B is available only through preferential pricing for nonprofit groups in East Africa. Clinical trials and experience demonstrate high efficacy and low toxicity for liposomal amphotericin B (total dose, 20 mg/kg) in immunocompetent patients with VL. Combination trials in areas with antileishmanial drug resistance, and treatment and secondary prophylaxis trials in VL-human immunodeficiency virus-coinfected patients, are important to safeguard the current armamentarium and to optimize regimens. The public health community should work to broaden access to preferential liposomal amphotericin B pricing by public sector VL treatment programs.
Clinical Infectious Diseases 11/2006; 43(7):917-24. · 9.15 Impact Factor
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ABSTRACT: Perturbation of the Staphylococcus aureus cytoplasmic membrane (CM) is felt to play a key role in the microbicidal mechanism of many antimicrobial peptides (APs). However, it is not established whether membrane permeabilization (MP) alone is sufficient to kill susceptible staphylococci or if the cell wall (CW) and/or intracellular targets contribute to AP-induced lethality. We hypothesized that the relationships between MP and killing may differ for distinct APs. In this study, we investigated the association between AP-induced MP and lethality in S. aureus whole cells versus CW-free protoplasts, and in comparison to the MP of liposomes modeled after whole CMs in terms of phospholipid composition, fluidity and charge. Four APs with different structure-activity relationships were examined: thrombin-induced platelet microbicidal protein 1 (tPMP-1), human neutrophil protein 1 (hNP-1), gramicidin D, and polymyxin B. MP was quantified fluorometrically by calcein release. All APs tested, except polymyxin B, caused concentration-dependent MP and killing of whole cells, but not of protoplasts. The reduced AP susceptibility of protoplasts was associated with increased cardiolipin and lysyl-phosphatidylglycerol content and reduced fluidity of their CMs. However, liposomal MP induced by tPMP-1, hNP-1, and gramicidin D paralleled that of whole cells. Collectively, these results indicate that (i) structurally distinct APs likely exert their staphylocidal effects by differing mechanisms, (ii) MP is not the sole event leading to AP-induced staphylocidal activity, (iii) a complex interrelationship exists between the CM and CW in AP-induced killing, and (iv) liposomes modeled upon whole cell or protoplast CMs can recapitulate the respective susceptibilities to killing by distinct APs.
Antimicrobial Agents and Chemotherapy 09/2005; 49(8):3114-21. · 4.84 Impact Factor
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ABSTRACT: Amphotericin B reformulated into the liposomal formulation known as AmBisome (amphotericin B, hydrogenated soy phosphatidylcholine, cholesterol and dimyristoyl phosphatidylglycerol) can be safely administered at dosages 15 times higher than the conventional drug with the same broad spectrum of activity. Increased doses demonstrate non-linear clearance with saturation of the reticuloendothelial system (RES) and redistribution of the drug into non-RES tissues. The efficacy of this liposomal amphotericin B formulation appears to be related both to improved tissue penetration in the lungs, brain, kidneys, liver and spleen along with sustained bioactivity of therapeutic drug levels in these target tissues.
Current opinion in investigational drugs (London, England: 2000) 03/2003; 4(2):179-85. · 3.31 Impact Factor
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ABSTRACT: Amphotericin B is the treatment of choice for life-threatening systemic fungal infections such as candidosis and aspergillosis. To improve this drug's efficacy and reduce its acute and chronic toxicities, several lipid formulations of the drug have been developed, including AmBisome, a liposomal formulation of amphotericin B. The liposome is composed of high transition temperature phospholipids and cholesterol, designed to incorporate amphotericin B securely into the liposomal bilayer. AmBisome can bind to fungal cell walls, where the liposome is disrupted. The amphotericin B, after being released from the liposomes, is thought to transfer through the cell wall and bind to ergosterol in the fungal cell membrane. This mechanism of action of AmBisome results in its potent in vitro fungicidal activity while the integrity of the liposome is maintained in the presence of mammalian cells, for which it has minimal toxicity. In animal models, AmBisome is effective in treating both intracellular (leishmaniasis and histoplasmosis) and extracellular (candidosis and aspergillosis) systemic infections. Because of its low toxicity at the organ level, intravenous AmBisome can be safely delivered at markedly high doses of amphotericin B (1-30 mg/kg) for the treatment of systemic fungal infections. AmBisome has a circulating half-life of 5-24 h in animals, and in animal models appears to localize at sites of infection in the brain (cryptococcosis, aspergillosis, coccidioidomycosis), lungs (blastomycosis, paracoccidioidomycosis, aspergillosis) and kidneys (candidosis), delivering amphotericin B that remains bioavailable in tissues for several weeks following treatment.
Journal of Antimicrobial Chemotherapy 03/2002; 49 Suppl 1:21-30. · 5.07 Impact Factor
