A human immunodeficiency virus type 1 Env-granulocyte-macrophage colony-stimulating factor fusion protein enhances the cellular immune response to Env in a vaccinia virus-based vaccine.

Rodr√≠guez, D; Rodr√≠guez, J R; Llorente, Mercedes Guinea; V√°zquez, I; Lucas, Pilar; Esteban, Mariano; Mart√≠nez-A, C; Real, Gustavo del

doi:10.1099/0022-1317-80-1-217

Cited by 20 publications

(5 citation statements)

References 28 publications

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“…For instance, the immunogenicity of vectors such as MVA and NYVAC can be improved by removal of genes associated with immune evasion which counteract immune responses to the vaccine (Kibler et al, 2011; Gomez et al, 2012; Garcia-Arriaza et al, 2013). In other cases, addition of cytokine-encoding genes such as type 1 interferons, IL-12 or GM-CSF can enhance vaccine efficacy (Gherardi et al, 1999, 2000; Rodriguez et al, 1999; Ramshaw and Ramsay, 2000; Bayer et al, 2011). Furthermore, chemokines such as CCL3 which recruits professional APCs can be co-delivered with HIV antigens to enhance vaccine immunogenicity (Lietz et al, 2012).…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

The influence of delivery vectors on HIV vaccine efficacy

Ondondo

2014

Front. Microbiol.

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Development of an effective HIV/AIDS vaccine remains a big challenge, largely due to the enormous HIV diversity which propels immune escape. Thus novel vaccine strategies are targeting multiple variants of conserved antibody and T cell epitopic regions which would incur a huge fitness cost to the virus in the event of mutational escape. Besides immunogen design, the delivery modality is critical for vaccine potency and efficacy, and should be carefully selected in order to not only maximize transgene expression, but to also enhance the immuno-stimulatory potential to activate innate and adaptive immune systems. To date, five HIV vaccine candidates have been evaluated for efficacy and protection from acquisition was only achieved in a small proportion of vaccinees in the RV144 study which used a canarypox vector for delivery. Conversely, in the STEP study (HVTN 502) where human adenovirus serotype 5 (Ad5) was used, strong immune responses were induced but vaccination was more associated with increased risk of HIV acquisition than protection in vaccinees with pre-existing Ad5 immunity. The possibility that pre-existing immunity to a highly promising delivery vector may alter the natural course of HIV to increase acquisition risk is quite worrisome and a huge setback for HIV vaccine development. Thus, HIV vaccine development efforts are now geared toward delivery platforms which attain superior immunogenicity while concurrently limiting potential catastrophic effects likely to arise from pre-existing immunity or vector-related immuno-modulation. However, it still remains unclear whether it is poor immunogenicity of HIV antigens or substandard immunological potency of the safer delivery vectors that has limited the success of HIV vaccines. This article discusses some of the promising delivery vectors to be harnessed for improved HIV vaccine efficacy.

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Section: Perspectives and Conclusionmentioning

confidence: 99%

The influence of delivery vectors on HIV vaccine efficacy

Ondondo

2014

Front. Microbiol.

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“…Notably, none of the cytokine-NAg fusion proteins augmented EAE (Mannie and Abbott, 2007; Mannie et al, 2007, 2009b; Blanchfield and Mannie, 2010; Abbott et al, 2011). In studies by other groups, many of the same cytokine domains, particularly GM-CSF, were coupled to foreign proteins and were found to augment immunity to those foreign proteins (Wortham et al, 1998; Rodriguez et al, 1999; Tso et al, 2001; Wang et al, 2009; Zhai et al, 2009; van Montfort et al, 2011). At the outset of this project, the anticipation was that the cytokine domain would be more important than the antigenic domain for determining the balance of tolerance versus immunity.…”

Section: Attributes Of Nag-specific Cytokine-nag Vaccinesmentioning

confidence: 99%

Cytokine-Neuroantigen Fusion Proteins as a New Class of Tolerogenic, Therapeutic Vaccines for Treatment of Inflammatory Demyelinating Disease in Rodent Models of Multiple Sclerosis

et al. 2012

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Myelin-specific induction of tolerance represents a promising means to modify the course of autoimmune inflammatory demyelinating diseases such as multiple sclerosis (MS). Our laboratory has focused on a novel preclinical strategy for the induction of tolerance to the major encephalitogenic epitopes of myelin that cause experimental autoimmune encephalomyelitis (EAE) in rats and mice. This novel approach is based on the use of cytokine-NAg (neuroantigen) fusion proteins comprised of the native cytokine fused either with or without a linker to a NAg domain. Several single-chain cytokine-NAg fusion proteins were tested including GMCSF-NAg, IFNbeta-NAg, NAgIL16, and IL2-NAg. These cytokine-NAg vaccines were tolerogenic, therapeutic vaccines that had tolerogenic activity when given as pre-treatments before encephalitogenic immunization and also were effective as therapeutic interventions during the effector phase of EAE. The rank order of inhibitory activity was as follows: GMCSF-NAg, IFNbeta-NAg > NAgIL16 > IL2-NAg > MCSF-NAg, IL4-NAg, IL-13-NAg, IL1RA-NAg, and NAg. Several cytokine-NAg fusion proteins exhibited antigen-targeting activity. High affinity binding of the cytokine domain to specific cytokine receptors on particular subsets of APC resulted in the concentrated uptake of the NAg domain by those APC which in turn facilitated the enhanced processing and presentation of the NAg domain on cell surface MHC class II glycoproteins. For most cytokine-NAg vaccines, the covalent linkage of the cytokine domain and NAg domain was required for inhibition of EAE, thereby indicating that antigenic targeting of the NAg domain to APC was also required in vivo for tolerogenic activity. Overall, these studies introduced a new concept of cytokine-NAg fusion proteins as a means to induce tolerance and to inhibit the effector phase of autoimmune disease. The approach has broad application for suppressive vaccination as a therapy for autoimmune diseases such as MS.

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“…Thus, we postulate that foreign antigens presented by DCs to CD4 + T cells result in high-efficiency antigen recognition events that activate the CD40L/CD40 pathway to provide high levels of costimulation and pro-inflammatory cytokines that, in turn, drive Treg destabilization and robust induction of effector/memory Tcon responses. Consistent with this concept, vaccines comprised of GM-CSF and foreign viral or bacterial antigens have immunogenic pathogenspecific T cell activity [38][39][40].…”

Section: Gmcsf-mog Preferentially Expanded Tregs From a Memory T Cellmentioning

confidence: 85%

A GM-CSF-neuroantigen tolerogenic vaccine elicits inefficient antigen recognition events below the CD40L triggering threshold to expand CD4+ CD25+ FOXP3+ Tregs that inhibit experimental autoimmune encephalomyelitis (EAE)

Moorman

Bastian

DeOca

et al. 2020

J Neuroinflammation

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Background: Tolerogenic vaccines represent antigen-specific interventions designed to re-establish self-tolerance and thereby alleviate autoimmune diseases, which collectively comprise over 100 chronic inflammatory diseases afflicting more than 20 million Americans. Tolerogenic vaccines comprised of single-chain GM-CSF-neuroantigen (GMCSF-NAg) fusion proteins were shown in previous studies to prevent and reverse disease in multiple rodent models of experimental autoimmune encephalomyelitis (EAE) by a mechanism contingent upon the function of CD4 + CD25 + FOXP3 + regulatory T cells (Tregs). GMCSF-NAg vaccines inhibited EAE in both quiescent and inflammatory environments in association with low-efficiency T cell receptor (TCR) signaling events that elicited clonal expansion of immunosuppressive Tregs. Methods: This study focused on two vaccines, including GMCSF-MOG (myelin oligodendrocyte glycoprotein 35-55/MOG 35-55) and GMCSF-NFM (neurofilament medium peptide 13-37/NFM 13-37), that engaged the transgenic 2D2 TCR with either low or high efficiencies, respectively. 2D2 mice were crossed with FOXP3 IRES eGFP (FIG) mice to track Tregs and further crossed with Rag −/− mice to reduce pre-existing Treg populations.

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A human immunodeficiency virus type 1 Env-granulocyte-macrophage colony-stimulating factor fusion protein enhances the cellular immune response to Env in a vaccinia virus-based vaccine.

Abstract: Vaccinia virus (VV) infection induces protective T-and B-cell responses

Cited by 20 publications

References 28 publications

The influence of delivery vectors on HIV vaccine efficacy

The influence of delivery vectors on HIV vaccine efficacy

Cytokine-Neuroantigen Fusion Proteins as a New Class of Tolerogenic, Therapeutic Vaccines for Treatment of Inflammatory Demyelinating Disease in Rodent Models of Multiple Sclerosis

A GM-CSF-neuroantigen tolerogenic vaccine elicits inefficient antigen recognition events below the CD40L triggering threshold to expand CD4+ CD25+ FOXP3+ Tregs that inhibit experimental autoimmune encephalomyelitis (EAE)

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