The Experts below are selected from a list of 7599 Experts worldwide ranked by ideXlab platform
Dan H Barouch - One of the best experts on this subject based on the ideXlab platform.
-
late endosomal trafficking of alternative serotype Adenovirus Vaccine vectors augments antiviral innate immunity
Journal of Virology, 2014Co-Authors: Jeffrey E Teigler, Dan H Barouch, Jonathan C KaganAbstract:ABSTRACT Adenovirus (Ad) Vaccine vectors have found widespread use as Vaccine platforms against multiple infections and cancers, and multiple serotypes have been shown to differ significantly in their biological properties and immune phenotypes. Our laboratory and others have previously described differential innate immune stimulation elicited by various Ad serotypes. Here, we show that Ad serotype 5 (Ad5) traffics rapidly to the nucleus following infection, whereas Ad35 and Ad26 accumulate in late endosomes 2 to 8 h postinfection. Innate immune cytokine elicitation by all Ad serotypes was abrogated by blockade of endosomal acidification, cathepsin B, and caspase 1, suggesting that virus interactions with acid-dependent sensors, such as Toll-like receptor- and cathepsin-dependent inflammasome activation in late endosomes, may trigger innate immunity. These data suggest a mechanism by which Ad vectors from various serotypes differentially trigger innate antiviral pathways via distinct intracellular trafficking to late endosomes. IMPORTANCE Adenoviruses (Ad) are widely used for vaccination and gene therapy applications. Importantly, Ad vectors have been shown to differ significantly in their innate immune profiles both in vivo and in vitro . The molecular mechanism that underlies these observed differences has important implications for the development of improved Vaccines. In this study, we propose a mechanism in which the degree of late endosomal trafficking of Ad vectors results in differential stimulation of late endosomal pattern recognition receptors.
-
aberrant differentiation and exhaustion of Adenovirus Vaccine elicited cd8 t cells primed in the absence of cd4 t cells vac3p 940
Journal of Immunology, 2014Co-Authors: Nicholas M Provine, Erica N Borducchi, Rafael A Larocca, Pablo Penalozamacmaster, William Haining, Dan H BarouchAbstract:Replication-incompetent recombinant Adenovirus (Ad) vectors have garnered considerable interest as candidate Vaccine platforms for an array of diseases. However, the efficacy of such Vaccines in settings of impaired CD4 T cell function remains poorly understood. We demonstrate that monoclonal antibody-mediated depletion of CD4 T cells prior to Ad immunization of C57BL/6 mice impaired expansion of responding CD8 T cells and led to aberrant differentiation and exhaustion. The absence of CD4 T cells resulted in a failure of antigen-specific CD8 T cells to differentiate into KLRG1hiCD127lo effector cells. This phenotypic defect corresponded to reduced ex vivo cytotoxicity and decreased expression of IFN-γ and TNF-α. Strikingly, CD8 T cells primed in the absence of CD4 T cells expressed elevated levels of the inhibitory molecules PD-1, LAG-3, and Tim-3. Consistent with this, these cells were identified as exhausted using gene expression profiling and gene set enrichment analysis. Blockade of PD-1 signaling by administration of anti-PDL-1 antibody at the time of immunization rescued expansion of antigen-specific CD8 T cells primed in the absence of CD4 T cells. This treatment also rescued differentiation into KLRG1hiCD127lo effector cells, and corrected defects in expression of IFN-γ and TNF-α. Collectively, these data suggest a novel mechanism of CD4 T cell help whereby CD4 T cells prevent the exhaustion of Vaccine-elicited CD8 T cells by modulating PD-1 signaling during priming.
-
alternative serotype Adenovirus Vaccine vectors elicit memory t cells with enhanced anamnestic capacity compared to ad5 vectors
Journal of Virology, 2013Co-Authors: Pablo Penalozamacmaster, Nathaniel L Simmons, Dan H Barouch, Erica N Borducchi, Nicholas M Provine, Anna Mcnally, Mark Justin IampietroAbstract:The failure of the Adenovirus serotype 5 (Ad5) vector-based human immunodeficiency virus type 1 (HIV-1) Vaccine in the STEP study has led to the development of Adenovirus vectors derived from alternative serotypes, such as Ad26, Ad35, and Ad48. We have recently demonstrated that Vaccines using alternative-serotype Ad vectors confer partial protection against stringent simian immunodeficiency virus (SIV) challenges in rhesus monkeys. However, phenotypic differences between the T cell responses elicited by Ad5 and those of alternative-serotype Ad vectors remain unexplored. Here, we report the magnitude, phenotype, functionality, and recall capacity of memory T cell responses elicited in mice by Ad5, Ad26, Ad35, and Ad48 vectors expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP). Our data demonstrate that memory T cells elicited by Ad5 vectors were high in magnitude but exhibited functional exhaustion and decreased anamnestic potential following secondary antigen challenge compared to Ad26, Ad35, and Ad48 vectors. These data suggest that vaccination with alternative-serotype Ad vectors offers substantial immunological advantages over Ad5 vectors, in addition to circumventing high baseline Ad5-specific neutralizing antibody titers.
-
vitamin a deficiency impairs Vaccine elicited gastrointestinal immunity
Journal of Immunology, 2011Co-Authors: David R Kaufman, Jaime De Calisto, Nathaniel L Simmons, Ashley N Cruz, Eduardo J Villablanca, Rodrigo J Mora, Dan H BarouchAbstract:Vitamin A deficiency is highly prevalent in much of the developing world, where vaccination programs are of paramount importance to public health. However, the impact of vitamin A deficiency on the immunogenicity and protective efficacy of Vaccines has not been defined previously. In this article, we show that the vitamin A metabolite retinoic acid is critical for trafficking of Vaccine-elicited T lymphocytes to the gastrointestinal mucosa and for Vaccine protective efficacy in mice. Moderate vitamin A deficiency abrogated Ag-specific T lymphocyte trafficking to the gastrointestinal tract, gastrointestinal cellular immune responses, and protection against a mucosal challenge following immunization with a recombinant Adenovirus Vaccine vector. Oral vitamin A supplementation as well as retinoic acid administration fully restored the mucosal immune responses and Vaccine protective efficacy. These data suggest that oral vitamin A supplementation may be important for optimizing the success of Vaccines against HIV-1 and other mucosal pathogens in the developing world, highlighting a critical relationship between host nutritional status and Vaccine efficacy.
Anne C. Moore - One of the best experts on this subject based on the ideXlab platform.
-
low Adenovirus Vaccine doses administered to skin using microneedle patches induce better functional antibody immunogenicity as compared to systemic injection
Vaccine, 2021Co-Authors: Olivia Flynn, Simon J. Draper, Kate Dillane, Juliane Sousa Lanza, Jennifer M Marshall, Jing Jin, Sarah E Silk, Anne C. MooreAbstract:Adenovirus-based Vaccines are demonstrating promising clinical potential for multiple infectious diseases, including COVID-19. However, the immunogenicity of the vector itself decreases its effectiveness as a boosting Vaccine due to the induction of strong anti-vector neutralizing immunity. Here we determined how dissolvable microneedle patches (DMN) for skin immunization can overcome this issue, using a clinically-relevant Adenovirus-based Plasmodium falciparum malaria Vaccine, AdHu5-PfRH5, in mice. Incorporation of Vaccine into patches significantly enhanced its thermostability compared to the liquid form. Conventional high dose repeated immunization by the intramuscular (IM) route induced low antigen-specific IgG titres and high anti-vector immunity. A low priming dose of Vaccine, by the IM route, but more so using DMN patches, induced the most efficacious immune responses, assessed by parasite growth inhibitory activity (GIA) assays. Administration of low dose AdHu5-PfRH5 using patches to the skin, boosted by high dose IM, induced the highest antigen-specific serum IgG response after boosting, the greatest skewing of the antibody response towards the antigen and away from the vector, and the highest efficacy. This study therefore demonstrates that repeated use of the same Adenovirus Vaccine can be highly immunogenic towards the transgene if a low dose is used to prime the response. It also provides a method of stabilizing Adenovirus Vaccine, in easy-to-administer dissolvable microneedle patches, permitting storage and distribution out of cold chain.
-
Microneedle-mediated immunization of an Adenovirus-based malaria Vaccine enhances antigen-specific antibody immunity and reduces anti-vector responses compared to the intradermal route
Scientific Reports, 2014Co-Authors: John B. Carey, Anto Vrdoljak, Conor O'mahony, Adrian V. S. Hill, Simon J. Draper, Anne C. MooreAbstract:Substantial effort has been placed in developing efficacious recombinant attenuated Adenovirus-based Vaccines. However induction of immunity to the vector is a significant obstacle to its repeated use. Here we demonstrate that skin-based delivery of an Adenovirus-based malaria Vaccine, HAdV5-PyMSP1_42, to mice using silicon microneedles induces equivalent or enhanced antibody responses to the encoded antigen, however it results in decreased anti-vector responses, compared to intradermal delivery. Microneedle-mediated Vaccine priming and resultant induction of low anti-vector antibody titres permitted repeated use of the same Adenovirus Vaccine vector. This resulted in significantly increased antigen-specific antibody responses in these mice compared to ID-treated mice. Boosting with a heterologous Vaccine; MVA-PyMSP1_42 also resulted in significantly greater antibody responses in mice primed with HAdV5-PyMSP1_42 using MN compared to the ID route. The highest protection against blood-stage malaria challenge was observed when a heterologous route of immunization (MN/ID) was used. Therefore, microneedle-mediated immunization has potential to both overcome some of the logistic obstacles surrounding needle-and-syringe-based immunization as well as to facilitate the repeated use of the same Adenovirus Vaccine thereby potentially reducing manufacturing costs of multiple Vaccines. This could have important benefits in the clinical ease of use of Adenovirus-based immunization strategies.
Stephen C De Rosa - One of the best experts on this subject based on the ideXlab platform.
-
hiv dna priming alters t cell responses to hiv Adenovirus Vaccine even when responses to dna are undetectable
Journal of Immunology, 2011Co-Authors: Stephen C De Rosa, Evan P Thomas, John Bui, Yunda Huang, Allan C Decamp, Cecilia MorganAbstract:Many candidate HIV Vaccines are designed to primarily elicit T cell responses. Although repeated immunization with the same Vaccine boosts Ab responses, the benefit for T cell responses is ill defined. We compared two immunization regimens that include the same recombinant adenoviral serotype 5 (rAd5) boost. Repeated homologous rAd5 immunization fails to increase T cell responses, but increases gp140 Ab responses 10-fold. DNA prime, as compared with rAd5 prime, directs long-term memory CD8+ T cells toward a terminally differentiated effector memory phenotype with cytotoxic potential. Based on the kinetics of activated cells measured directly ex vivo, the DNA vaccination primes for both CD4+ and CD8+ T cells, despite the lack of detection of the latter until after the boost. These results suggest that heterologous prime-boost combinations have distinct immunological advantages over homologous prime-boosts and suggest that the effect of DNA on subsequent boosting may not be easily detectable directly after the DNA vaccination.
Jan Pravsgaard Christensen - One of the best experts on this subject based on the ideXlab platform.
-
mhc class ii associated invariant chain linkage of antigen dramatically improves cell mediated immunity induced by Adenovirus Vaccines
Journal of Immunology, 2008Co-Authors: Peter Johannes Holst, Maria Rathmann Sorensen, Camilla Maria Mandrup Jensen, Cathrine Orskov, Allan Randrup Thomsen, Jan Pravsgaard ChristensenAbstract:The ideal Vaccine induces a potent protective immune response, which should be rapidly induced, long-standing, and of broad specificity. Recombinant adenoviral vectors induce potent Ab and CD8 + T cell responses against transgenic Ags within weeks of administration, and they are among the most potent and versatile Ag delivery vehicles available. However, the impact of chronic infections like HIV and hepatitis C virus underscore the need for further improvements. In this study, we show that the protective immune response to an Adenovirus-encoded Vaccine Ag can be accelerated, enhanced, broadened, and prolonged by tethering of the rAg to the MHC class II-associated invariant chain (Ii). Thus, Adenovirus-vectored Vaccines expressing lymphocytic choriomeningitis virus (LCMV)-derived glycoprotein linked to Ii increased the CD4 + and CD8 + T cell stimulatory capacity in vitro and in vivo. Furthermore, mice vaccinated with a single dose of Adenovirus-expressing LCMV-derived glycoprotein linked to Ii were protected against lethal virus-induced choriomeningitis, lethal challenge with strains mutated in immunodominant T cell epitopes, and systemic infection with a highly invasive strain. In therapeutic tumor vaccination, the Vaccine was as efficient as live LCMV. In comparison, animals vaccinated with a conventional Adenovirus Vaccine expressing unmodified glycoprotein were protected against systemic infection, but only temporarily against lethal choriomeningitis, and this Vaccine was less efficient in tumor therapy.
Pablo Penalozamacmaster - One of the best experts on this subject based on the ideXlab platform.
-
Adenovirus vector vaccination impacts nk cell rheostat function following lymphocytic choriomeningitis virus infection
Journal of Virology, 2018Co-Authors: Alexander Badamchizadeh, Eryn Blass, Malika Aid, Rafael A Larocca, Amanda J Martinot, Zi Han Kang, Pablo Penalozamacmaster, Keith R ReevesAbstract:Natural killer (NK) cells respond rapidly as a first line of defense against infectious pathogens. In addition, NK cells may provide a "rheostat" function and have been shown to reduce the magnitude of antigen-specific T cell responses following infection to avoid immunopathology. However, it remains unknown whether NK cells similarly modulate Vaccine-elicited T cell responses following virus challenge. We used the lymphocytic choriomeningitis virus (LCMV) clone 13 infection model to address whether NK cells regulate T cell responses in Adenovirus vector-vaccinated mice following challenge. As expected, NK cell depletion in unvaccinated mice resulted in increased virus-specific CD4+ and CD8+ T cell responses and immunopathology following LCMV challenge. In contrast, NK cell depletion had minimal to no impact on antigen-specific T cell responses in mice that were vaccinated with an Adenovirus serotype 5 (Ad5)-GP vector prior to LCMV challenge. Moreover, NK cell depletion in vaccinated mice prior to challenge did not result in immunopathology and did not compromise protective efficacy. These data suggest that Adenovirus Vaccine-elicited T cells may be less sensitive to NK cell rheostat regulation than T cells primed by LCMV infection.IMPORTANCE Recent data have shown that NK cell depletion leads to enhanced virus-elicited T cell responses that can result in severe immunopathology following LCMV infection in mice. In this study, we observed that NK cells exerted minimal to no impact on Vaccine-elicited T cells following LCMV challenge, suggesting that Adenovirus Vaccine-elicited T cells may be less subject to NK cell regulation. These data contribute to our understanding of NK cell regulatory functions and T cell-based Vaccines.
-
aberrant differentiation and exhaustion of Adenovirus Vaccine elicited cd8 t cells primed in the absence of cd4 t cells vac3p 940
Journal of Immunology, 2014Co-Authors: Nicholas M Provine, Erica N Borducchi, Rafael A Larocca, Pablo Penalozamacmaster, William Haining, Dan H BarouchAbstract:Replication-incompetent recombinant Adenovirus (Ad) vectors have garnered considerable interest as candidate Vaccine platforms for an array of diseases. However, the efficacy of such Vaccines in settings of impaired CD4 T cell function remains poorly understood. We demonstrate that monoclonal antibody-mediated depletion of CD4 T cells prior to Ad immunization of C57BL/6 mice impaired expansion of responding CD8 T cells and led to aberrant differentiation and exhaustion. The absence of CD4 T cells resulted in a failure of antigen-specific CD8 T cells to differentiate into KLRG1hiCD127lo effector cells. This phenotypic defect corresponded to reduced ex vivo cytotoxicity and decreased expression of IFN-γ and TNF-α. Strikingly, CD8 T cells primed in the absence of CD4 T cells expressed elevated levels of the inhibitory molecules PD-1, LAG-3, and Tim-3. Consistent with this, these cells were identified as exhausted using gene expression profiling and gene set enrichment analysis. Blockade of PD-1 signaling by administration of anti-PDL-1 antibody at the time of immunization rescued expansion of antigen-specific CD8 T cells primed in the absence of CD4 T cells. This treatment also rescued differentiation into KLRG1hiCD127lo effector cells, and corrected defects in expression of IFN-γ and TNF-α. Collectively, these data suggest a novel mechanism of CD4 T cell help whereby CD4 T cells prevent the exhaustion of Vaccine-elicited CD8 T cells by modulating PD-1 signaling during priming.
-
alternative serotype Adenovirus Vaccine vectors elicit memory t cells with enhanced anamnestic capacity compared to ad5 vectors
Journal of Virology, 2013Co-Authors: Pablo Penalozamacmaster, Nathaniel L Simmons, Dan H Barouch, Erica N Borducchi, Nicholas M Provine, Anna Mcnally, Mark Justin IampietroAbstract:The failure of the Adenovirus serotype 5 (Ad5) vector-based human immunodeficiency virus type 1 (HIV-1) Vaccine in the STEP study has led to the development of Adenovirus vectors derived from alternative serotypes, such as Ad26, Ad35, and Ad48. We have recently demonstrated that Vaccines using alternative-serotype Ad vectors confer partial protection against stringent simian immunodeficiency virus (SIV) challenges in rhesus monkeys. However, phenotypic differences between the T cell responses elicited by Ad5 and those of alternative-serotype Ad vectors remain unexplored. Here, we report the magnitude, phenotype, functionality, and recall capacity of memory T cell responses elicited in mice by Ad5, Ad26, Ad35, and Ad48 vectors expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP). Our data demonstrate that memory T cells elicited by Ad5 vectors were high in magnitude but exhibited functional exhaustion and decreased anamnestic potential following secondary antigen challenge compared to Ad26, Ad35, and Ad48 vectors. These data suggest that vaccination with alternative-serotype Ad vectors offers substantial immunological advantages over Ad5 vectors, in addition to circumventing high baseline Ad5-specific neutralizing antibody titers.