Immunogenicity without Efficacy of an Adenoviral Tuberculosis Vaccine in a Stringent Mouse Model for Immunotherapy during Treatment

Alyahya, S. Anisah; Nolan, Scott T.; Smith, Cara M. R.; Bishai, William R.; Sadoff, Jerald C.; Lamichhane, Gyanu

doi:10.1371/journal.pone.0127907

Cited by 7 publications

(4 citation statements)

References 42 publications

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“…1,2 They trigger a potent inflammatory response, 3,4 which initiates adaptive immune responses to the transgene product and the antigens of the Ad vector. 5 This has led to the development of different Ad serotypes as vaccine carriers for a plethora of antigens derived from viruses, 6-10 bacteria, 11,12 parasites, 13,14 or tumor cells, [15][16][17] which have consistently induced potent and sustained B and T cell responses to the transgene products.…”

Section: Introductionmentioning

confidence: 99%

A PartialE3Deletion in Replication-Defective Adenoviral Vectors Allows for Stable Expression of Potentially Toxic Transgene Products

Haut

Gill

Kurupati

et al. 2016

Human Gene Therapy Methods

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Adenovirus (Ad) is used extensively for construction of viral vectors, most commonly with deletion in its E1 and/or E3 genomic regions. Previously, our attempts to insert envelope proteins (Env) of HIV-1 into such vectors based on chimpanzee-derived Ad (AdC) viruses were thwarted. Here, we describe that genetic instability of an E1-and E3-deleted AdC vector of serotype C6 expressing Env of HIV-1 can be overcome by reinsertion of E3 sequences with anti-apoptotic activities. This partial E3 deletion presumably delays premature death of HEK-293 packaging cell lines due to Env-induced cell apoptosis. The same partial E3 deletion also allows for the generation of stable glycoprotein 140 (gp140)-and gp160-expressing Ad vectors based on AdC7, a distinct AdC serotype. Env-expressing AdC vectors containing the partial E3 deletion are genetically stable upon serial cell culture passaging, produce yields comparable to those of other AdC vectors, and induce transgene product-specific antibody responses in mice. A partial E3 deletion thereby allows expansion of the repertoire of transgenes that can be expressed by Ad vectors.Keywords: HIV-1, vaccine, genetic stability, immune responses INTRODUCTION REPLICATION-DEFECTIVE ADENOVIRUS (Ad) vectors efficiently deliver transgenes to multiple cell types. 1,2 They trigger a potent inflammatory response, 3,4 which initiates adaptive immune responses to the transgene product and the antigens of the Ad vector. 5 This has led to the development of different Ad serotypes as vaccine carriers for a plethora of antigens derived from viruses, 6-10 bacteria, 11,12 parasites, 13,14 or tumor cells, [15][16][17] which have consistently induced potent and sustained B and T cell responses to the transgene products.In most Ad vaccine vectors, the E1 and E3 domains are deleted from the genome. The E1 deletion renders Ad vectors replication defective and reduces synthesis of other Ad antigens. E3 encodes a number of polypeptides that have anti-apoptotic activity or allow the virus to escape immune surveillance. 18,19 The E3 domain, a region that is nonessential for viral replication, is generally deleted to allow for the insertion of lengthy transgene expression cassettes without exceeding the genome size of wild-type virus, as this could potentially result in genetic instability of Ad vectors. 20 Ad vectors have been explored extensively as vaccine carriers for antigens of human immunodeficiency virus (HIV)-1, 21-25 the causative agent of the acquired immunodeficiency syndrome (AIDS). While initial efforts focused on expression of internal antigens for the induction of CD8 + T cell responses against HIV-1, efforts have since shifted toward expression of the envelope protein (Env). The heavily glycosylated and highly variable Env of HIV-1 forms trimers composed of glycoprotein (gp) 120 and gp41 on the surface of the virion. These complexes allow HIV-1 to attach to its receptors and coreceptors and are thereby essential for CD4 + cell infection by HIV-1. Env is not only the sole target of HIV-1-specif...

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Section: Introductionmentioning

confidence: 99%

A PartialE3Deletion in Replication-Defective Adenoviral Vectors Allows for Stable Expression of Potentially Toxic Transgene Products

Haut

Gill

Kurupati

et al. 2016

Human Gene Therapy Methods

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show abstract

“…One area of interest in the TB vaccine field is whether the mucosal delivery of vaccines to lungs that have existing mycobacterial immunity can increase populations of potentially protective T cell subsets systemically, and, importantly, locally. Several studies in mice have explored the use of post-exposure vaccines either as a stand-alone intervention (24) or as an adjunct to antibiotic therapy (25)(26)(27)(28)(29)(30). Of these, one that tested mucosal vaccine delivery of an adenovirus vectored vaccine resulted in significantly increased antigen-specific lung CD8 T cells and markedly reduced bacterial burden after withdrawal of antibiotic therapy (30).…”

Section: Discussionmentioning

confidence: 99%

Mucosal and systemic immune responses after a single intranasal dose of nanoparticle and spore-based subunit vaccines in mice with pre-existing lung mycobacterial immunity

Vergara,

Tran,

Kim

et al. 2023

Front. Immunol.

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Tuberculosis (TB) is a major global health threat that claims more than one million lives annually. With a quarter of the global population harbouring latent TB, post-exposure vaccination aimed at high-risk populations that could develop active TB disease would be of great public health benefit. Mucosal vaccination is an attractive approach for a predominantly lung disease like TB because it elicits both local and systemic immunity. However, the immunological consequence of mucosal immunisation in the presence of existing lung immunity remains largely unexplored. Using a mycobacterial pre-exposure mouse model, we assessed whether pre-existing mucosal and systemic immune responses can be boosted and/or qualitatively altered by intranasal administration of spore- and nanoparticle-based subunit vaccines. Analysis of lung T cell responses revealed an increasing trend in the frequency of important CD4 and CD8 T cell subsets, and T effector memory cells with a Th1 cytokine (IFNγ and TNFα) signature among immunised mice. Additionally, significantly greater antigen specific Th1, Th17 and IL-10 responses, and antigen-induced T cell proliferation were seen from the spleens of immunised mice. Measurement of antigen-specific IgG and IgA from blood and bronchoalveolar lavage fluid also revealed enhanced systemic and local humoral immune responses among immunised animals. Lastly, peripheral blood mononuclear cells (PBMCs) obtained from the TB-endemic country of Mozambique show that individuals with LTBI showed significantly greater CD4 T cell reactivity to the vaccine candidate as compared to healthy controls. These results support further testing of Spore-FP1 and Nano-FP1 as post-exposure TB vaccines.

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“…At present, there are limited reports evaluating the immunogenicity and immune efficacy of vaccines in infected animals. Alyahya et al [ 39 ] reported that the cellular immune response and bacterial loads in tissues were decreased in mice following antibiotic treatment. In conclusion, the vaccine group showed similar changes in cellular immunology and organ bacterial loads to the antibiotic treatment group in the study by Alyahya and colleagues, suggesting that the AEC/BC02 vaccine provided effective anti-TB immune protection against latent Mtb infection in mice.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Effect of Subunit Vaccine AEC/BC02 on Mycobacterium tuberculosis Post-Chemotherapy Relapse Using a Latent Infection Murine Model

Guo

Wang

et al. 2022

Vaccines

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Tuberculosis (TB), caused by the human pathogen Mycobacterium tuberculosis (Mtb), is an infectious disease that presents a major threat to human health. Bacillus Calmette-Guérin (BCG), the only licensed TB vaccine, is ineffective against latent TB infection, necessitating the development of further TB drugs or therapeutic vaccines. Herein, we evaluated the therapeutic effect of a novel subunit vaccine AEC/BC02 after chemotherapy in a spontaneous Mtb relapse model. Immunotherapy followed 4 weeks of treatment with isoniazid and rifapentine, and bacterial loads in organs, pathological changes, and adaptive immune characteristics were investigated. The results showed slowly increased bacterial loads in the spleen and lungs of mice inoculated with AEC/BC02 with significantly lower loads than those of the control groups. Pathological scores for the liver, spleen, and lungs decreased accordingly. Moreover, AEC/BC02 induced antigen-specific IFN-γ-secreting or IL-2-secreting cellular immune responses, which decreased with the number of immunizations and times. Obvious Ag85b- and EC-specific IgG were observed in mice following the treatment with AEC/BC02, indicating a significant Th1-biased response. Taken together, these data suggest that AEC/BC02 immunotherapy post-chemotherapy may shorten future TB treatment.

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Immunogenicity without Efficacy of an Adenoviral Tuberculosis Vaccine in a Stringent Mouse Model for Immunotherapy during Treatment

Cited by 7 publications

References 42 publications

A PartialE3Deletion in Replication-Defective Adenoviral Vectors Allows for Stable Expression of Potentially Toxic Transgene Products

A PartialE3Deletion in Replication-Defective Adenoviral Vectors Allows for Stable Expression of Potentially Toxic Transgene Products

Mucosal and systemic immune responses after a single intranasal dose of nanoparticle and spore-based subunit vaccines in mice with pre-existing lung mycobacterial immunity

Therapeutic Effect of Subunit Vaccine AEC/BC02 on Mycobacterium tuberculosis Post-Chemotherapy Relapse Using a Latent Infection Murine Model

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