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: 10.45). 10/2007; 110(6):1916-23. DOI: 10.1182/blood-2007-02-062117
Source: PubMed


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.

Download full-text


Available from: Amaya I Wolf, Mar 12, 2014
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 3.62 Impact Factor
  • Source
    • "The CD8+ T-cell response elicited by Ad5 is predominantly an effector memory phenotype [9]. Ad5 induces a CD8+ T-cell response with a protracted contraction phase and sustained memory population [10-12]. Ad-based vaccines have shown promise as a single dose vaccine in mice against respiratory syncytial virus [13], Mycobacterium tuberculosis[14] and measles virus [15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Peste des petits ruminants virus (PPRV) is a morbillivirus that can cause severe disease in sheep and goats, characterised by pyrexia, pneumo-enteritis, and gastritis. The socio-economic burden of the disease is increasing in underdeveloped countries, with poor livestock keepers being affected the most. Current vaccines consist of cell-culture attenuated strains of PPRV, which induce a similar antibody profile to that induced by natural infection. Generation of a vaccine that enables differentiation of infected from vaccinated animals (DIVA) would benefit PPR control and eradication programmes, particularly in the later stages of an eradication campaign and for countries where the disease is not endemic. In order to create a vaccine that would enable infected animals to be distinguished from vaccinated ones (DIVA vaccine), we have evaluated the immunogenicity of recombinant fowlpox (FP) and replication-defective recombinant human adenovirus 5 (Ad), expressing PPRV F and H proteins, in goats. The Ad constructs induced higher levels of virus-specific and neutralising antibodies, and primed greater numbers of CD8+ T cells than the FP-vectored vaccines. Importantly, a single dose of Ad-H, with or without the addition of Ad expressing ovine granulocyte macrophage colony-stimulating factor and/or ovine interleukin-2, not only induced strong antibody and cell-mediated immunity but also completely protected goats against challenge with virulent PPRV, 4 months after vaccination. Replication-defective Ad-H therefore offers the possibility of an effective DIVA vaccine.
    Veterinary Research 02/2014; 45(1):24. DOI:10.1186/1297-9716-45-24 · 2.82 Impact Factor
  • Source
    • "In addition to poxvirus vectors, adenoviral-vectored vaccines have been found to be potent vectors for inducing and boosting T-cell responses to recombinant transgene products.13,14,15 However, the widespread seroprevalence of antibodies to common human adenovirus serotype-5 (AdHu5)16 limits the utility of these viruses as vaccine vectors in humans and was implicated in the failure of an human immunodeficiency virus vaccine to demonstrate efficacy.17 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adenoviruses are potent vectors for inducing and boosting cellular immunity to encoded recombinant antigens. However, the widespread seroprevalence of neutralizing antibodies to common human adenovirus serotypes limits their use. Simian adenoviruses do not suffer from the same drawbacks. We have constructed a replication-deficient chimpanzee adenovirus-vectored vaccine expressing the conserved influenza antigens, nucleoprotein and matrix protein 1. Here we report safety and T-cell immunogenicity following vaccination with this novel recombinant simian adenovirus, ChAdOx1 NP+M1, in a first in human dose escalation study using a 3+3 study design, followed by boosting with MVA expressing the same antigens in some volunteers. We demonstrate ChAdOx1 NP+M1 to be safe and immunogenic. ChAdOx1 is a promising vaccine vector that could be used to deliver vaccine antigens where strong cellular immune responses are required for protection.Molecular Therapy (2013); doi:10.1038/mt.2013.284.
    Molecular Therapy 12/2013; 22(3). DOI:10.1038/mt.2013.284 · 6.23 Impact Factor
Show more