Adenoviral vectors persist in vivo and maintain activated CD8+ T cells: Implications for their use as vaccines

Wistar Institute, Philadelphia, PA 19104, USA.
Blood (Impact Factor: 10.43). 10/2007; 110(6):1916-23. DOI: 10.1182/blood-2007-02-062117
Source: PubMed

ABSTRACT CD8(+) T cell-numbers rapidly expand and then contract after exposure to their cognate antigen. Here we show that the sustained frequencies of transgene product-specific CD8(+) T cells elicited by replication-defective adenovirus vectors are linked to persistence of low levels of transcriptionally active adenovirus vector genomes at the site of inoculation, in liver, and lymphatic tissues. Continuously produced small amounts of antigen maintain fully active effector CD8(+) T cells, while also allowing for their differentiation into central memory cells. The long-term persistence of adenoviral vectors may be highly advantageous for their use as vaccines against pathogens for which T-cell-mediated protection requires both fully activated T cells for immediate control of virus-infected cells and central memory CD8(+) T cells that, because of their higher proliferative capacity, may be suited best to eliminate cells infected by pathogens that escaped the initial wave of effector T cells.

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Available from: Amaya I Wolf, Mar 12, 2014
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    • "Antibody titers continued to increase at least six weeks after immunization of both vectors. The continued elevation could suggest that expression of the transgene product is persistent, as in mice [41], although studies in cattle with different antigens have observed antibody titers reaching a plateau after just two weeks [24] and a marked reduction in transgene expression at the injection site after 24 h [23]. The kinetics of CD8 + T cell, CD4 + T cell, and antibody responses were similar after HAdV- 5 and ChAdOx1 vaccination, perhaps a function of the equivalence in magnitude of these responses in cattle. "
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    ABSTRACT: Adenovirus vaccine vectors generated from new viral serotypes are routinely screened in pre-clinical laboratory animal models to identify the most immunogenic and efficacious candidates for further evaluation in clinical human and veterinary settings. Here, we show that studies in a laboratory species do not necessarily predict the hierarchy of vector performance in other mammals. In mice, after intramuscular immunization, HAdV-5 (Human adenovirus C) based vectors elicited cellular and humoral adaptive responses of higher magnitudes compared to the chimpanzee adenovirus vectors ChAdOx1 and AdC68 from species Human adenovirus E. After HAdV-5 vaccination, transgene specific IFN-γ(+) CD8(+) T cell responses reached peak magnitude later than after ChAdOx1 and AdC68 vaccination, and exhibited a slower contraction to a memory phenotype. In cattle, cellular and humoral immune responses were at least equivalent, if not higher, in magnitude after ChAdOx1 vaccination compared to HAdV-5. Though we have not tested protective efficacy in a disease model, these findings have important implications for the selection of candidate vectors for further evaluation. We propose that vaccines based on ChAdOx1 or other Human adenovirus E serotypes could be at least as immunogenic as current licensed bovine vaccines based on HAdV-5. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 01/2015; 2(9). DOI:10.1016/j.vaccine.2015.01.042 · 3.49 Impact Factor
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    • "These studies have unequivocally shown that adenoviral vectors induce superior frequencies of CD8+ T cells and, importantly, induce better T cell mediated protection against simian human immunodeficiency virus challenge (SHIV) in NHP's. However, other general findings include a low proliferative potential of induced T cells, effector memory rather than central memory phenotype of the induced T cells and a low frequency of IL-2 producing T cells (Tatsis et al., 2007a; Yang et al., 2006; Yang et al., 2007). Although several studies have addressed potency and immunogenicity of antigen presentation from various vectors, few direct comparisons exists between adenoviral vectors and other popular virus vectored vaccine candidates, most notably MVA and fowlpox vectors. "
    Viral Gene Therapy, 07/2011; , ISBN: 978-953-307-539-6
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    • "Our results demonstrated that Ad5 but not MVA persist in vivo. These results are consistent with a recent report demonstrating the persistence of Ad5 vector and the expression of recombinant protein by the persisting vector both in mice and rhesus macaques [39]. MVA does not persist in vaccinated SCID mice and rhesus macaques [40]. "
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    ABSTRACT: The magnitude and functional quality of antiviral CD8 T cell responses are critical for the efficacy of T cell based vaccines. Here, we investigate the influence of two popular viral vectors, adenovirus type 5 (Ad5) and modified vaccinia Ankara (MVA), on expansion, contraction and memory differentiation of HIV-1 Gag insert-specific CD8 T cell responses following immunization and show different patterns for the two recombinant viral vectors. The Ad5 vector primed 6-fold higher levels of insert-specific CD8 effector T cells than the MVA vector. The Ad5-primed effector cells also underwent less contraction (<2-fold) than the MVA-primed cells (>5-fold). The Ad5-primed memory cells were predominantly CD62L negative (effector memory) whereas the MVA-primed memory cells were predominantly CD62L positive (central memory). Consistent with their memory phenotype, MVA-primed CD8 T cells underwent higher fold expansion than Ad5-primed CD8 T cells following a homologous or heterologous boost. Impressively, the Ad5 boost changed the quality of MVA-primed memory response such that they undergo less contraction with effector memory phenotype. However, the MVA boost did not influence the contraction and memory phenotype of Ad5-primed response. In conclusion, our results demonstrate that vaccine vector strongly influences the expansion, contraction and the functional quality of insert-specific CD8 T cell responses and have implications for vaccine development against infectious diseases.
    Vaccine 06/2011; 29(33):5399-406. DOI:10.1016/j.vaccine.2011.05.083 · 3.49 Impact Factor
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