Marked enhancement of the immune response to BioThrax® (Anthrax Vaccine Adsorbed) by the TLR9 agonist CPG 7909 in healthy volunteers

Rynkiewicz, Dianna L.; Rathkopf, Melinda M.; Sim, Iain S.; Waytes, A. Thomas; Hopkins, Robert J.; Giri, Lallan; DeMuria, Deborah; Ransom, Janet H.; Quinn, James A.; Nabors, Gary S.; Nielsen, Carl J.

doi:10.1016/j.vaccine.2011.05.047

Cited by 83 publications

(80 citation statements)

References 36 publications

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“…This unexpected finding led us to further investigate the potential impact of TLR9 activation on immune cells from HIV-infected individuals. However, the significant toxicity associated with treatment with such a CpG-ODN is a significant barrier to clinical development (10,12,13). The phosphorothioate backbone that prevents nuclease-mediated degradation of CpG-ODN molecules has off-target immunostimulatory effects, which may increase and/or worsen adverse events (14).…”

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confidence: 99%

A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4 ⁺ T Cells

Offersen

Nissen

Rasmussen

et al. 2016

J Virol

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Toll-like receptor (TLR) agonists are potent enhancers of innate antiviral immunity and may also reverse HIV-1 latency. Therefore, TLR agonists have a potential role in the context of a "shock-and-kill" approach to eradicate HIV-1. Our extensive preclinical evaluation suggests that a novel TLR9 agonist, MGN1703, may indeed perform both functions in an HIV-1 eradication trial. Over the past decade, the importance of NK cells in controlling human immunodeficiency virus type 1 (HIV-1) infection in vivo has become increasingly clearer (1-3). In response, novel approaches to induce NK cell-directed enhancement of immune function are being developed (4). One approach to improving NK cell function is via Toll-like receptor 9 (TLR9) activation.TLR9 ligands stimulate potent antiviral responses via an activation pathway initiated by the TLR9 recognition of nonmethylated cytosine-guanine dinucleotide (CG) motifs found in bacterial, viral, and mitochondrial DNAs (5). This pathway is initiated by pattern recognition in plasmacytoid dendritic cells (pDCs) and B cells, as these cells exhibit high levels of TLR9 expression. Following TLR9 engagement, type I interferon (primarily interferon alpha [IFN-␣]) is produced and secreted by pDCs. IFN-␣ activates NK cells as well as the promoters of interferon-stimulated genes (e.g., CXCL-10), resulting in a targeted antiviral inflammatory environment. T and NK cells within this local environment become further activated (e.g., upregulated CD69 surface expression on NK and T cells and altered expression of NK cell receptors) (6). The overall function of activated T and NK cells is to clear the pathogen that initiated the cascade in the TLR9-expressing cells.

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confidence: 99%

A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4 ⁺ T Cells

Offersen

Nissen

Rasmussen

et al. 2016

J Virol

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“…However, work from our group has previously shown that the toxin-neutralizing quality of PA antibodies from AVA recipients is highly variable (42). This has led to research seeking to develop more effective anthrax vaccines, including recombinant PA (43)(44)(45)(46), alternative adjuvants (47,48), and additional vaccine targets (49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Anthrax Vaccine Precipitated Induces Edema Toxin-Neutralizing, Edema Factor-Specific Antibodies in Human Recipients

Dumas

Gross

Larabee

et al. 2017

Clin Vaccine Immunol

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Edema toxin (ET), composed of edema factor (EF) and protective antigen (PA), is a virulence factor of Bacillus anthracis that alters host immune cell function and contributes to anthrax disease. Anthrax vaccine precipitated (AVP) contains low but detectable levels of EF and can elicit EF-specific antibodies in human recipients of AVP. Active and passive vaccination of mice with EF can contribute to protection from challenge with Bacillus anthracis spores or ET. This study compared humoral responses to ET in recipients of AVP (n ϭ 33) versus anthrax vaccine adsorbed (AVA; n ϭ 66), matched for number of vaccinations and time postvaccination, and further determined whether EF antibodies elicited by AVP contribute to ET neutralization. AVP induced higher incidence (77.8%) and titer (229.8 Ϯ 58.6) of EF antibodies than AVA (4.2% and 7.8 Ϯ 8.3, respectively), reflecting the reported low but detectable presence of EF in AVP. In contrast, PA IgG levels and ET neutralization measured using a luciferase-based cyclic AMP reporter assay were robust and did not differ between the two vaccine groups. Multiple regression analysis failed to detect an independent contribution of EF antibodies to ET neutralization in AVP recipients; however, EF antibodies purified from AVP sera neutralized ET. Serum samples from at least half of EF IgG-positive AVP recipients bound to nine decapeptides located in EF domains II and III. Although PA antibodies are primarily responsible for ET neutralization in recipients of AVP, increased amounts of an EF component should be investigated for the capacity to enhance next-generation, PA-based vaccines.

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“…The aim of the present work was to expand the mathematical modeling framework developed to incorporate the pharmacodynamic effects triggered by coadjuvants in immunotherapy, capturing the key biologic mechanisms implied in a simple but meaningful way. Moreover, we evaluated the translational impact of the semimechanistic PK/PD drug combination model by comparing model-based simulations with efficacy results derived from clinical trials extracted from literature (Höltl et al, 2005;Rynkiewicz et al, 2011;Walter et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Modeling Tumor Response after Combined Administration of Different Immune-Stimulatory Agents

Parra-Guillén

Berraondo

Ribba

et al. 2013

J Pharmacol Exp Ther

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The aims of this work were as follows: 1) to develop a semimechanistic pharmacodynamic model describing tumor shrinkage after administration of a previously developed antitumor vaccine (CyaA-E7) in combination with CpG (a TLR9 ligand) and/ or cyclophosphamide (CTX), and 2) to assess the translational capability of the model to describe tumor effects of different immune-based treatments. Population approach with NONMEM version 7.2 was used to analyze the previously published data. These data were generated by injecting 5 Â 10 5 tumor cells expressing human papillomavirus (HPV)-E7 proteins into C57BL/6 mice. Large and established tumors were treated with CpG and/or CTX administered alone or in combination with CyaA-E7. Applications of the model were assessed by comparing model-based simulations with preclinical and clinical outcomes obtained from literature. CpG effects were modeled: 1) as an amplification of the immune signal triggered by the vaccine and 2) by shortening the delayed response of the vaccine. CTX effects were included through a direct decrease of the tumor-induced inhibition of vaccine efficacy over time, along with a delayed induction of tumor cell death. A pharmacodynamic model, built based on plausible biologic mechanisms known for the coadjuvants, successfully characterized tumor response in all experimental scenarios. The model developed was satisfactory applied to reproduce clinical outcomes when CpG or CTX was used in combination with different vaccines. The results found after simulation exercise indicated that the contribution of the coadjuvants to the tumor response elicited by vaccines can be predicted for other immune-based treatments.

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Marked enhancement of the immune response to BioThrax® (Anthrax Vaccine Adsorbed) by the TLR9 agonist CPG 7909 in healthy volunteers

Cited by 83 publications

References 36 publications

A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4 ⁺ T Cells

A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4 ⁺ T Cells

Anthrax Vaccine Precipitated Induces Edema Toxin-Neutralizing, Edema Factor-Specific Antibodies in Human Recipients

Modeling Tumor Response after Combined Administration of Different Immune-Stimulatory Agents

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Marked enhancement of the immune response to BioThrax® (Anthrax Vaccine Adsorbed) by the TLR9 agonist CPG 7909 in healthy volunteers

Cited by 83 publications

References 36 publications

A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4 + T Cells

A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4 + T Cells

Anthrax Vaccine Precipitated Induces Edema Toxin-Neutralizing, Edema Factor-Specific Antibodies in Human Recipients

Modeling Tumor Response after Combined Administration of Different Immune-Stimulatory Agents

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Product

Resources

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A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4 ⁺ T Cells

A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4 ⁺ T Cells