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      Pre-existing immunity against vaccine vectors – friend or foe?


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          Over the last century, the successful attenuation of multiple bacterial and viral pathogens has led to an effective, robust and safe form of vaccination. Recently, these vaccines have been evaluated as delivery vectors for heterologous antigens, as a means of simultaneous vaccination against two pathogens. The general consensus from published studies is that these vaccine vectors have the potential to be both safe and efficacious. However, some of the commonly employed vectors, for example Salmonella and adenovirus, often have pre-existing immune responses in the host and this has the potential to modify the subsequent immune response to a vectored antigen. This review examines the literature on this topic, and concludes that for bacterial vectors there can in fact, in some cases, be an enhancement in immunogenicity, typically humoral, while for viral vectors pre-existing immunity is a hindrance for subsequent induction of cell-mediated responses.

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          HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis.

          In the Step Study, the MRKAd5 HIV-1 gag/pol/nef vaccine did not reduce plasma viraemia after infection, and HIV-1 incidence was higher in vaccine-treated than in placebo-treated men with pre-existing adenovirus serotype 5 (Ad5) immunity. We assessed vaccine-induced immunity and its potential contributions to infection risk. To assess immunogenicity, we characterised HIV-specific T cells ex vivo with validated interferon-gamma ELISPOT and intracellular cytokine staining assays, using a case-cohort design. To establish effects of vaccine and pre-existing Ad5 immunity on infection risk, we undertook flow cytometric studies to measure Ad5-specific T cells and circulating activated (Ki-67+/BcL-2(lo)) CD4+ T cells expressing CCR5. We detected interferon-gamma-secreting HIV-specific T cells (range 163/10(6) to 686/10(6) peripheral blood mononuclear cells) ex vivo by ELISPOT in 77% (258/354) of people receiving vaccine; 218 of 354 (62%) recognised two to three HIV proteins. We identified HIV-specific CD4+ T cells by intracellular cytokine staining in 58 of 142 (41%) people. In those with reactive CD4+ T cells, the median percentage of CD4+ T cells expressing interleukin 2 was 88%, and the median co-expression of interferon gamma or tumor necrosis factor alpha (TNFalpha), or both, was 72%. We noted HIV-specific CD8+ T cells (range 0.4-1.0%) in 117 of 160 (73%) participants, expressing predominantly either interferon gamma alone or with TNFalpha. Vaccine-induced HIV-specific immunity, including response rate, magnitude, and cytokine profile, did not differ between vaccinated male cases (before infection) and non-cases. Ad5-specific T cells were lower in cases than in non-cases in several subgroup analyses. The percentage of circulating Ki-67+BcL-2(lo)/CCR5+CD4+ T cells did not differ between cases and non-cases. Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T cells. Our findings suggest that future candidate vaccines have to elicit responses that either exceed in magnitude or differ in breadth or function from those recorded in this trial.
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            Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity.

            Recent studies of human immunodeficiency virus type 1 (HIV-1) infection in humans and of simian immunodeficiency virus (SIV) in rhesus monkeys have shown that resolution of the acute viral infection and control of the subsequent persistent infection are mediated by the antiviral cellular immune response. We comparatively assessed several vaccine vector delivery systems-three formulations of a plasmid DNA vector, the modified vaccinia Ankara (MVA) virus, and a replication incompetent adenovirus type 5 (Ad5) vector-expressing the SIV gag protein for their ability to elicit such immune responses in monkeys. The vaccines were tested either as a single modality or in combined modality regimens. Here we show that the most effective responses were elicited by a replication-incompetent Ad5 vector, used either alone or as a booster inoculation after priming with a DNA vector. After challenge with a pathogenic HIV-SIV hybrid virus (SHIV), the animals immunized with Ad5 vector exhibited the most pronounced attenuation of the virus infection. The replication-defective adenovirus is a promising vaccine vector for development of an HIV-1 vaccine.
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              Immunity to intracellular bacteria.

               S Kaufmann (1992)
              Intracellular bacteria are endowed with the capacity to survive and replicate inside mononuclear phagocytes (MP) and, sometimes, within certain other host cells. MP are potent effectors cells that are able to engulf and kill many bacterial invaders. Therefore, intracellular bacteria had to exploit potent evasion mechanisms that allow their survival in this hostile environment. At the early phase, natural killer cells activate antibacterial defense mechanisms. During intracellular persistence, microbial proteins are processed and presented, thus initiating T cell activation. By secreting interleukins, CD4 alpha/beta TH1 cells activate MP, converting them from a habitat to a potent effector cell; TH2-dependent activities seem to be of minor importance. Cytolytic CD8 T cells represent a further element of protection. In the case of Listeria monocytogenes, the gene products responsible for virulence and for the introduction of antigens into the MHC class I pathway are being characterized. Increasing evidence points to a role of gamma/delta T lymphocytes in antibacterial immunity, although their precise function remains to be elucidated. Protection in the host is a local event focussed on granulomatous lesions. MP accumulate at the site of microbial growth and become activated through the CD4 T cell-interleukin-MP axis. Lysis of incapacitated MP and other host cells by CD8 T cells allows release and subsequent uptake by more efficient phagocytes, thus contributing to host protection. At the same time, lysis of host cells promotes microbial dissemination and causes tissue injury, which represent pathogenic aspects of the same mechanism. Research on the immune response against intracellular bacteria not only helps us to better understand how the immune system deals with "viable antigens" in constant trans-mutation, it also forms the basis for the rational design of control measures for major health problems.

                Author and article information

                Microbiology (Reading, Engl.)
                Society for General Microbiology
                January 2013
                January 2013
                : 159
                : Pt 1
                : 1-11
                [1 ]Ludwig Institute for Cancer Research, Heidelberg, Victoria, Australia
                [2 ]School of Applied Sciences, RMIT University, Bundoora, Victoria, Australia
                [3 ]Comparative Genomics Centre, School of Pharmacy and Molecular Sciences, James Cook University, Townsville, Queensland, Australia
                Author notes
                Correspondence Peter M. Smooker peter.smooker@ 123456rmit.edu.au

                These authors contributed equally to this work.

                © 2013 SGM

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                Stefan Sidorowicz
                Kendra Waite

                Microbiology & Virology


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