6 results on '"Lacy, Michael J."'
Search Results
2. Use of protective antigen of Bacillus anthracis as a model recombinant antigen to evaluate toll-like receptors 2, 3, 4, 7 and 9 agonists in mice using established functional antibody assays, antigen-specific antibody assays and cellular assays.
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Inglefield, Jon, Catania, Jason, Harris, Andrea, Hickey, Thomas, Ma, Zhidong, Minang, Jacob, Baranji, Katalin, Spangler, Tarl, Look, Jee, Ruiz, Christian, Lu, Hang, Alleva, David, Reece, Joshua J., and Lacy, Michael J.
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TOLL-like receptors , *BACILLUS anthracis , *IMMUNOGLOBULINS , *PEPTIDES , *ANTIBODY formation , *IMMUNOGLOBULIN G , *ANTIGENS - Abstract
• TLR agonists in mice predominantly are stimulatory regardless of formulation (Alhydrogel or squalene) • Functional (toxin-neutralizing) antigen-specific antibodies are a functional subset of IgG antigen-specific serum antibodies. • Ratios for antigen-specific IgG1:IgG2a redirection in mice were established using quantitative ELISA achieving 1:1 for profound redirection effect, 10:1 for partial redirection and 40:1 for an Alhydrogel vaccine with no redirection. • Overall, an accelerated immunization regimen (2 immunizations 7 days apart) had less negative effect upon vaccines that contained CPG 7909. Toll-like receptor (TLR) agonists can act as immune stimulants alone or as part of alum or oil formulations. Humoral and cellular immune responses were utilized to assess quantitative and qualitative immune response enhancement by TLR agonists using recombinant protective antigen (rPA) of B. anthracis as a model antigen. To rPA, combined with aluminum hydroxide (Alhydrogel; Al(OH)3) or squalene (AddaVax™), was added one of 7 TLR agonists: TLR2 agonist Pam3CysSK4 (PamS), TLR3 agonist double stranded polyinosinic:polycytidylic acid (PolyIC), TLR4 agonists Monophosphoryl lipid A (MPLA) or glucopyranosyl lipid A (GLA), TLR7-8 agonists 3M−052 or Resiquimod (Resiq), or TLR9 agonist CPG 7909 (CPG). CD-1 or BALB/c mice received two intraperitoneal or intramuscular immunizations 14 days apart, followed by serum or spleen sampling 14 days later. All TLR agonists except PamS induced high levels of B. anthracis lethal toxin-neutralizing antibodies and immunoglobulin G (IgG) anti-PA. Some responses were >100-fold higher than those without a TLR agonist, and IP delivery (0.5 mL) induced higher TLR-mediated antibody response increases compared to IM delivery (0.05 mL). TLR7-8 and TLR9 agonists induced profound shifts of IgG anti-PA response to IgG2a or IgG2b. Compared to the 14-day immunization schedule, use of a shortened immunization schedule of only 7 days between prime and boost found that TLR9 agonist CPG in a squalene formulation maintained higher interferon-γ-positive cells than TLR4 agonist GLA. Variability in antibody responses was lower in BALB/c mice than CD-1 mice but antibody responses were higher in CD-1 mice. Lower serum 50% effective concentration (EC50) values were found for rPA-agonist formulations and squalene formulations compared to Al(OH)3 formulations. Lower EC50 values also were associated with low frequency detection of linear peptide epitopes. In summary, TLR agonists elicited cellular immune responses and markedly boosted humoral responses. [ABSTRACT FROM AUTHOR]
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- 2022
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3. Correlation between anthrax lethal toxin neutralizing antibody levels and survival in guinea pigs and nonhuman primates vaccinated with the AV7909 anthrax vaccine candidate.
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Savransky, Vladimir, Shearer, Jeffry D., Gainey, Melicia R., Sanford, Daniel C., Sivko, Gloria S., Stark, Gregory V., Li, Na, Ionin, Boris, Lacy, Michael J., and Skiadopoulos, Mario H.
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ANTHRAX vaccines , *ANTHRAX toxin , *NEUTRALIZATION (Chemistry) , *ANTIBODY formation , *GUINEA pigs as laboratory animals - Abstract
The anthrax vaccine candidate AV7909 is being developed as a next generation vaccine for a post-exposure prophylaxis (PEP) indication against anthrax. AV7909 consists of the Anthrax Vaccine Adsorbed (AVA, BioThrax®) bulk drug substance adjuvanted with the immunostimulatory oligodeoxynucleotide (ODN) compound, CPG 7909. The addition of CPG 7909 to AVA enhances both the magnitude and the kinetics of antibody responses in animals and human subjects, making AV7909 a suitable next-generation vaccine for use in a PEP setting. The studies described here provide initial information on AV7909-induced toxin-neutralizing antibody (TNA) levels associated with the protection of animals from lethal Bacillus anthracis challenge. Guinea pigs or nonhuman primates (NHPs) were immunized on Days 0 and 28 with various dilutions of AV7909, AVA or a saline or Alhydrogel + CPG 7909 control. Animals were challenged via the inhalational route with a lethal dose of aerosolized B. anthracis (Ames strain) spores and observed for clinical signs of disease and mortality. The relationship between pre-challenge serum TNA levels and survival following challenge was determined in order to calculate a threshold TNA level associated with protection. Immunisation with AV7909 induced a rapid, highly protective TNA response in guinea pigs and NHPs. Surprisingly, the TNA threshold associated with a 70% probability of survival for AV7909 immunized animals was substantially lower than the threshold which has been established for the licensed AVA vaccine. The results of this study suggest that the TNA threshold of protection against anthrax could be modified by the addition of an immune stimulant such as CPG 7909 and that the TNA levels associated with protection may be vaccine-specific. [ABSTRACT FROM AUTHOR]
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- 2017
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4. Enhanced early innate and T cell-mediated responses in subjects immunized with Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909).
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Minang, Jacob T., Inglefield, Jon R., Harris, Andrea M., Lathey, Janet L., Alleva, David G., Sweeney, Diane L., Hopkins, Robert J., Lacy, Michael J., and Bernton, Edward W.
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T cells , *IMMUNE response , *IMMUNIZATION , *CLINICAL trials , *INTRAMUSCULAR injections , *C-reactive protein , *BIOMARKERS , *PHYSIOLOGY - Abstract
NuThrax™ (Anthrax Vaccine Adsorbed with CPG 7909 Adjuvant) (AV7909) is in development. Samples obtained in a phase Ib clinical trial were tested to confirm biomarkers of innate immunity and evaluate effects of CPG 7909 (PF-03512676) on adaptive immunity. Subjects received two intramuscular doses of commercial BioThrax ® (Anthrax Vaccine Adsorbed, AVA), or two intramuscular doses of one of four formulations of AV7909. IP-10, IL-6, and C-reactive protein (CRP) levels were elevated 24–48 h after administration of AV7909 formulations, returning to baseline by Day 7. AVA (no CPG 7909) resulted in elevated IL-6 and CRP, but not IP-10. Another marker of CpG, transiently decreased absolute lymphocyte counts (ALCs), correlated with transiently increased IP-10. Cellular recall responses to anthrax protective antigen (PA) or PA peptides were assessed by IFN-γ ELISpot assay performed on cryopreserved PBMCs obtained from subjects prior to immunization and 7 days following the second immunization (study day 21). One-half of subjects that received AV7909 with low-dose (0.25 mg/dose) CPG 7909 possessed positive Day 21 T cell responses to PA. In contrast, positive T cell responses occurred at an 11% average rate (1/9) for AVA-treated subjects. Differences in cellular responses due to dose level of CPG 7909 were not associated with differences in humoral anti-PA IgG responses, which were elevated for recipients of AV7909 compared to recipients of AVA. Serum markers at 24 or 48 h (i.e. % ALC decrease, or increase in IL-6, IP-10, or CRP) correlated with the humoral (antibody) responses 1 month later, but did not correlate with cellular ELISpot responses. In summary, biomarkers of early responses to CPG 7909 were confirmed, and adding a CpG adjuvant to a vaccine administered twice resulted in increased T cell effects relative to vaccine alone. Changes in early biomarkers correlated with subsequent adaptive humoral immunity but not cellular immunity. [ABSTRACT FROM AUTHOR]
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- 2014
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5. Taking toll: lipid A mimetics as adjuvants and immunomodulators
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Persing, David H., Coler, Rhea N., Lacy, Michael J., Johnson, David A., Baldridge, Jory R., Hershberg, Robert M., and Reed, Steven G.
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LIPIDS , *IMMUNE response , *VACCINES - Abstract
Vaccine adjuvants based on the structure of lipid A, such as monophosphoryl lipid A (MLA), have proven to be safe and effective in inducing immune responses to heterologous proteins in animal and human vaccines. Recent work on the development of a recombinant vaccine for leishmaniasis has demonstrated that a clinical grade MLA formulation – MPL® adjuvant – is essential in the development of a protective response. Preliminary evidence suggests that MLA and a chemically distinct family of lipid A mimetics – the aminoalkyl glucosaminide 4-phosphates – act on Toll-like receptor 4 (TLR4). As TLR4 agonists, they have potent immunomodulatory effects when used both as vaccine adjuvants and as stand-alone products. Novel approaches to vaccine development could benefit from taking full advantage of the effects of these compounds on innate and adaptive responses. [ABSTRACT FROM AUTHOR]
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- 2002
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6. Structure-Activity Relationship of Synthetic Toll-like Receptor 4 Agonists.
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Stöver, Axel G., Correia, Jean Da Silva, Evans, Jay T., Cluff, Christopher W., Elliott, Mark W., Jeffery, Eric W., Johnson, David A., Lacy, Michael J., Baldridge, Jory R., Probst, Peter, Ulevitch, Richard J., Persing, David H., and Hershberg, Robert M.
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LIPIDS , *POLYSACCHARIDES , *CELLS , *BIOCHEMISTRY , *BIOLOGY , *CHEMISTRY - Abstract
Important questions remain regarding the impact of variations in the structure of the lipid A portion of lipopolysaccharide on activation of cells via the Toll-like receptor 4 complex. We have studied a series of synthetic lipid A mimetic compounds known as aminoalkyl glucosaminide phosphates in which the length of the secondary acyl chain has been systematically varied. Using transcriptional profiling of human monocytes and responses of Toll-like receptor 4 complex cell transfectants, we demonstrate a clear dependence of length on secondary acyl chain on Toll-like receptor 4 activation. Compounds with secondary acyl chains less than eight carbons in length have dramatically reduced activity, and substitutions of the left-sided secondary acyl chain had the most important effect on the Toll-like receptor 4 agonist activity of these molecules. The structure-function relationships of these compounds assessed via the induction of chemokines and cytokines following in vivo administration closely mirrored those seen with cellbased studies. This novel set of synthetic lipid A mimetics will be useful for Toll-like receptor 4-based investigations and may have clinical utility as stand-alone immunomodulators. [ABSTRACT FROM AUTHOR]
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- 2004
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