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Co-Administration of Molecular Adjuvants Expressing NF-Kappa B Subunit p65/RelA or Type-1 Transactivator T-bet Enhance Antigen Specific DNA Vaccine-Induced Immunity.

Shedlock DJ, Tingey C, Mahadevan L, Hutnick N, Reuschel EL, Kudchodkar S, Flingai S, Yan J, Kim JJ, Ugen KE, Weiner DB, Muthumani K - Vaccines (Basel) (2014)

Bottom Line: Specifically the co-delivery of (a) RelA, a subunit of the NF-κB transcription complex or (b) T-bet, a Th1-specific T box transcription factor, along with a prototypical DNA vaccine expressing HIV-1 proteins was evaluated.As such, this study demonstrated that co-delivery of either adjuvant resulted in enhanced T and B cell responses, specifically characterized by increased T cell numbers, IFN-γ production, as well as enhanced antibody responses.This study demonstrates the use of cellular transcription factors as adjuvants for enhancing DNA vaccine-induced immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. shedlock@mail.med.upenn.edu.

ABSTRACT
DNA vaccine-induced immunity can be enhanced by the co-delivery of synthetic gene-encoding molecular adjuvants. Many of these adjuvants have included cytokines, chemokines or co-stimulatory molecules that have been demonstrated to enhance vaccine-induced immunity by increasing the magnitude or type of immune responses and/or protective efficacy. In this way, through the use of adjuvants, immune responses can be highly customizable and functionally tailored for optimal efficacy against pathogen specific (i.e., infectious agent) or non-pathogen (i.e., cancer) antigens. In the novel study presented here, we examined the use of cellular transcription factors as molecular adjuvants. Specifically the co-delivery of (a) RelA, a subunit of the NF-κB transcription complex or (b) T-bet, a Th1-specific T box transcription factor, along with a prototypical DNA vaccine expressing HIV-1 proteins was evaluated. As well, all of the vaccines and adjuvants were administered to mice using in vivo electroporation (EP), a technology demonstrated to dramatically increase plasmid DNA transfection and subsequent transgene expression with concomitant enhancement of vaccine induced immune responses. As such, this study demonstrated that co-delivery of either adjuvant resulted in enhanced T and B cell responses, specifically characterized by increased T cell numbers, IFN-γ production, as well as enhanced antibody responses. This study demonstrates the use of cellular transcription factors as adjuvants for enhancing DNA vaccine-induced immunity.

No MeSH data available.


Related in: MedlinePlus

Improved B cell responses with pEnv vaccination and co-administered transcriptional molecular adjuvant. B cell/antibody responses were assessed in the sera of vaccinated mice (n = 4/group) seven days following the third immunization with pEnv alone, pEnv in combination with either pRelA or pTbet, each of the molecular adjuvants alone, or with empty vector control plasmid (pVax1). Anti-Env p120 antibody-binding titers were determined by ELISA. Data are presented as the mean endpoint titers. Statistically significant values are indicated; ***p < 0.001 (comparison between pEnv alone and pEnv + pRelA or pEnv + pT-bet) and ****p < 0.0001 (comparison between pRelA alone and pEnv + pRelA or pT-bet alone and pEnv + pT-bet).
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vaccines-02-00196-f004: Improved B cell responses with pEnv vaccination and co-administered transcriptional molecular adjuvant. B cell/antibody responses were assessed in the sera of vaccinated mice (n = 4/group) seven days following the third immunization with pEnv alone, pEnv in combination with either pRelA or pTbet, each of the molecular adjuvants alone, or with empty vector control plasmid (pVax1). Anti-Env p120 antibody-binding titers were determined by ELISA. Data are presented as the mean endpoint titers. Statistically significant values are indicated; ***p < 0.001 (comparison between pEnv alone and pEnv + pRelA or pEnv + pT-bet) and ****p < 0.0001 (comparison between pRelA alone and pEnv + pRelA or pT-bet alone and pEnv + pT-bet).

Mentions: Based on the observed adjuvant mediated increase in T cell IFN-γ and proliferative responses, the effects of these molecular adjuvants on B-cell induction was evaluated. HIV-1 Env-specific IgG was measured in the sera of vaccinated animals seven days following the third vaccination. As indicated, mice received pEnv either with or without co-administered pRelA or pTbet, pRelA or pTbet alone, or a pVax1 control plasmid (Figure 4). Measurable IgG responses were induced by pEnv alone at dilutions ranging from 1:50 to 1:500, but were non longer measurable at a dilution of 1:1000. Importantly, these responses were augmented at all dilutions by the inclusion of the pRelA or pTbet adjuvant when compared to the pEnv group alone. Specifically, differences were observed at the 1:50 sera dilution, where administration of pRelA and pTbet significantly enhanced the induction of HIV-1 Env-specific IgG responses (p = 0.0388 and p = 0.0062, respectively). Enhanced IgG responses were specific for Env since minimal antibody responses were observed in the sera from mice that were administered the pRelA or pTbet adjuvant alone. These data suggest that both transcription factor adjuvants elicited an enhanced humoral immune response that was analogous and consistent with the elevated IFN-γ levels and T cell proliferative responses observed following vaccination with pRelA or pTbet.


Co-Administration of Molecular Adjuvants Expressing NF-Kappa B Subunit p65/RelA or Type-1 Transactivator T-bet Enhance Antigen Specific DNA Vaccine-Induced Immunity.

Shedlock DJ, Tingey C, Mahadevan L, Hutnick N, Reuschel EL, Kudchodkar S, Flingai S, Yan J, Kim JJ, Ugen KE, Weiner DB, Muthumani K - Vaccines (Basel) (2014)

Improved B cell responses with pEnv vaccination and co-administered transcriptional molecular adjuvant. B cell/antibody responses were assessed in the sera of vaccinated mice (n = 4/group) seven days following the third immunization with pEnv alone, pEnv in combination with either pRelA or pTbet, each of the molecular adjuvants alone, or with empty vector control plasmid (pVax1). Anti-Env p120 antibody-binding titers were determined by ELISA. Data are presented as the mean endpoint titers. Statistically significant values are indicated; ***p < 0.001 (comparison between pEnv alone and pEnv + pRelA or pEnv + pT-bet) and ****p < 0.0001 (comparison between pRelA alone and pEnv + pRelA or pT-bet alone and pEnv + pT-bet).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494262&req=5

vaccines-02-00196-f004: Improved B cell responses with pEnv vaccination and co-administered transcriptional molecular adjuvant. B cell/antibody responses were assessed in the sera of vaccinated mice (n = 4/group) seven days following the third immunization with pEnv alone, pEnv in combination with either pRelA or pTbet, each of the molecular adjuvants alone, or with empty vector control plasmid (pVax1). Anti-Env p120 antibody-binding titers were determined by ELISA. Data are presented as the mean endpoint titers. Statistically significant values are indicated; ***p < 0.001 (comparison between pEnv alone and pEnv + pRelA or pEnv + pT-bet) and ****p < 0.0001 (comparison between pRelA alone and pEnv + pRelA or pT-bet alone and pEnv + pT-bet).
Mentions: Based on the observed adjuvant mediated increase in T cell IFN-γ and proliferative responses, the effects of these molecular adjuvants on B-cell induction was evaluated. HIV-1 Env-specific IgG was measured in the sera of vaccinated animals seven days following the third vaccination. As indicated, mice received pEnv either with or without co-administered pRelA or pTbet, pRelA or pTbet alone, or a pVax1 control plasmid (Figure 4). Measurable IgG responses were induced by pEnv alone at dilutions ranging from 1:50 to 1:500, but were non longer measurable at a dilution of 1:1000. Importantly, these responses were augmented at all dilutions by the inclusion of the pRelA or pTbet adjuvant when compared to the pEnv group alone. Specifically, differences were observed at the 1:50 sera dilution, where administration of pRelA and pTbet significantly enhanced the induction of HIV-1 Env-specific IgG responses (p = 0.0388 and p = 0.0062, respectively). Enhanced IgG responses were specific for Env since minimal antibody responses were observed in the sera from mice that were administered the pRelA or pTbet adjuvant alone. These data suggest that both transcription factor adjuvants elicited an enhanced humoral immune response that was analogous and consistent with the elevated IFN-γ levels and T cell proliferative responses observed following vaccination with pRelA or pTbet.

Bottom Line: Specifically the co-delivery of (a) RelA, a subunit of the NF-κB transcription complex or (b) T-bet, a Th1-specific T box transcription factor, along with a prototypical DNA vaccine expressing HIV-1 proteins was evaluated.As such, this study demonstrated that co-delivery of either adjuvant resulted in enhanced T and B cell responses, specifically characterized by increased T cell numbers, IFN-γ production, as well as enhanced antibody responses.This study demonstrates the use of cellular transcription factors as adjuvants for enhancing DNA vaccine-induced immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. shedlock@mail.med.upenn.edu.

ABSTRACT
DNA vaccine-induced immunity can be enhanced by the co-delivery of synthetic gene-encoding molecular adjuvants. Many of these adjuvants have included cytokines, chemokines or co-stimulatory molecules that have been demonstrated to enhance vaccine-induced immunity by increasing the magnitude or type of immune responses and/or protective efficacy. In this way, through the use of adjuvants, immune responses can be highly customizable and functionally tailored for optimal efficacy against pathogen specific (i.e., infectious agent) or non-pathogen (i.e., cancer) antigens. In the novel study presented here, we examined the use of cellular transcription factors as molecular adjuvants. Specifically the co-delivery of (a) RelA, a subunit of the NF-κB transcription complex or (b) T-bet, a Th1-specific T box transcription factor, along with a prototypical DNA vaccine expressing HIV-1 proteins was evaluated. As well, all of the vaccines and adjuvants were administered to mice using in vivo electroporation (EP), a technology demonstrated to dramatically increase plasmid DNA transfection and subsequent transgene expression with concomitant enhancement of vaccine induced immune responses. As such, this study demonstrated that co-delivery of either adjuvant resulted in enhanced T and B cell responses, specifically characterized by increased T cell numbers, IFN-γ production, as well as enhanced antibody responses. This study demonstrates the use of cellular transcription factors as adjuvants for enhancing DNA vaccine-induced immunity.

No MeSH data available.


Related in: MedlinePlus