A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans

Mwau, Matilu; Cebere, Inese; Sutton, John; Chikoti, Priscilla; Winstone, Nicola; Wee, Edmund G.; Beattie, Tara; Chen, Yun‐Hsiang; Dorrell, Lucy; McShane, Helen; Schmidt, Claudia; Brooks, Mary; Patel, Sandip Pravin; Roberts, J. Timmons; Conlon, Christopher P.; Rowland‐Jones, Sarah; Bwayo, Job J.; McMichael, Andrew J.; Hanke, Tomáš

doi:10.1099/vir.0.19701-0

Cited by 201 publications

(144 citation statements)

References 32 publications

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“…The MVA.HIVA and pTHr.HIVA vaccines, which express the HIVA immunogen, have been described [48]. Eight subjects were vaccinated with Good Manufacturing Practice (GMP) lots of pTHr.HIVA (500 lg DNA in 1 mL normal saline twice over 3 wk), followed 2 years later with MVA.HIVA vaccines (5 Â 10 7 PFU in 0.1 mL normal saline twice over 4 wk), and eight subjects received MVA.HIVA vaccinations only [23].…”

Section: Vaccines and Vaccination Schedulesmentioning

confidence: 99%

“…The IFN-c ELISPOT assay was performed as described [23,48]. Briefly, freshly isolated PBMC (1 Â 10 5 /well) depleted of CD8 + cells by magnetic bead separation according to the manufacturer's instructions (Miltenyi Biotec, UK) were incubated in duplicate with (i) overlapping gag peptide matrix pools, (ii) medium alone (in quadruplicate), and (iii) PHA, 5 lg/mL (Murex, UK).…”

Section: Ifn-c Elispot Assaymentioning

confidence: 99%

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Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4⁺ T cell responses

et al. 2006

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Virus-specific CD4 + T cells with IL-2-secreting and/or proliferative capacity are detected readily in HIV-1-infected long-term nonprogressors and rarely in persons with untreated progressive infection. The contribution of these cells to viraemia control is uncertain, but this question might be addressed in clinical therapeutic vaccination studies. However, the quality of T helper responses induced by currently available HIV-1 vaccine candidates has not been explored in depth. We determined the effect of vaccination with modified vaccinia virus Ankara (MVA) expressing HIV-1 gag p24/p17 (MVA.HIVA) on HIV-1-specific CD4 + T cell responses in 16 chronically infected, highly active antiretroviral therapy (HAART)-treated subjects using CD8-depleted IFN-c ELISPOT assays, intracellular cytokine staining assays for IL-2 and IFN-c, and a CFSEbased proliferation assay. Gag-specific CD4 + T cell responses were significantly increased in magnitude and breadth after vaccination and targeted both known and new epitopes, several of which were also recognised by healthy HIV-uninfected volunteers immunised with the same vaccines. The frequencies of CD4 + T cells expressing IL-2 or IFN-c, alone or simultaneously, were also augmented. These findings indicate that functional virus-specific T helper cells can be boosted by vaccination in chronic HIV-1 infection. Further evaluation of their role in viraemia control is warranted. IntroductionThe rate of progression of HIV-1 infection to AIDS may be determined by the capacity for immunological recovery after early and extensive depletion of mucosal CD4 + T cells [1]. Highly active antiretroviral therapy (HAART) can restore CD4 + T cell-mediated responses to opportunistic pathogens, but maintenance of adequate CD4 + T cell counts requires lifelong antiretroviral therapy, which is associated with potentially serious adverse effects and is too costly for the majority of infected persons worldwide [2]. Furthermore, the capacity of HIV-1-specific CD4 + T cells to proliferate and secrete IL-2, characteristics which are typically preserved only in long-term nonprogressors, are not always restored after initiation of therapy, particularly when this is delayed beyond acute infection [3][4][5][6]. Loss of function may result from preferential infection of virus-specific cells by 7,8]. Enhancement of HIV-1-specific cellular responses by therapeutic vaccination in combination with fully suppressive antiretroviral therapy might be used to maintain HIV-1 control without continuous drug treatment [9]. While a critical role for virus-specific CD4 + T cells in the induction and maintenance of effective immunity against HIV-1 is inferred from animal models and other human virus infections such as hepatitis C, direct evidence for this is lacking [10][11][12][13][14]. In healthy macaques, CD4 + T cell proliferation and TNF-a secretion were induced by DNA-prime/poxvirus-boost vaccinations, and were inversely correlated with control of SIV replication following a pathogenic challenge [15]. In humans, cross-...

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Section: Vaccines and Vaccination Schedulesmentioning

confidence: 99%

Section: Ifn-c Elispot Assaymentioning

confidence: 99%

Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4⁺ T cell responses

et al. 2006

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“…Nevertheless, since the significance of the CTL responses as a correlate of protection is not entirely clear, a large Phase III trial is underway to measure the efficacy of a canarypox vector as part of an HIV vaccine regimen. While awaiting the canarypox Phase III results, modified Vaccinia Ankara (MVA) [62][63][64] and adenovirus vaccine vectors [24,65] are being evaluated in both preclinical and Phase I and II patient trials. Both vectors stimulate potent CMI responses in primates and a majority of human subjects.…”

Section: Discussionmentioning

confidence: 99%

HIV-189.6 Gag expressed from a replication competent HSV-1 vector elicits persistent cellular immune responses in mice

Parker

Rottinghaus

Zajac

et al. 2007

Vaccine

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We have constructed a replication competent, γ 1 34.5-deleted Herpes Simplex Virus type 1 (HSV-1) vector (J200) that expresses the gag gene from Human Immunodeficiency Virus type-1, primary isolate 89.6 (HIV-1 89.6 ), as a candidate vaccine for HIV-1. J200 replicates in vitro, resulting in abundant Gag protein production and accumulation in the extracellular media. Immunization of Balb/ c mice with a single intraperitoneal injection of J200 elicited strong Gag-specific CD8 responses, as measured by intracellular IFN-γ staining and flow cytometry analysis. Responses were highest between 6 weeks and 4 months, but persisted at 9 months post-immunization, the last time-point evaluated. These data highlight the potential utility of neuroattenuated, replication-competent HSV-1 vectors for delivery of HIV-1 immunogens.

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“…Here, in the F5 transfer model, almost complete depletion of CD4 + T cells affected the primary response to a rMVA vaccine and subsequent levels elicited CD8 + T cell memory. The parental MVA.HIVA vaccine from which MVA.HIVA-NP had been derived was immunogenic in trials in both healthy [26] and clinically stable HIV-1-infected individuals on the highly active antiretroviral therapy. Particularly in the later trial, MVA.HIVA stimulated HIV-1-specific T cells in all vaccinees, although we could not say with certainty whether or not any of these responses had been primed de novo (L. Dorrell, T. Hanke and A. J. McMichael, unpublished).…”

Section: Discussionmentioning

confidence: 99%

“…Modified virus Ankara (MVA) is a disabled poxvirus identified as a promising vaccine vector due to its safety and immunogenicity [23][24][25][26]. MVA infects a variety of cell types including DC, but exhibits little or no replication in most tested mammalian cells [27,28].…”

Section: Introductionmentioning

confidence: 99%

Altered primary CD8⁺ T cell response to a modified virus Ankara(MVA)‐vectored vaccine in the absence of CD4⁺ T cell help

Estcourt¹,

McMichael²,

Hanke³

2005

Eur J Immunol

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T cell receptor-transgenic F5 mice were used to assess primary CD8 + T cell responses to a modified virus Ankara (MVA)-vectored vaccine in the absence of CD4 + T cell help. Naive, CD8-enriched, CFSE-labelled F5 cells were transferred into normal or CD4 + celldepleted mice and the mice were vaccinated with MVA.HIVA-NP. At different time points during the primary response, F5 cells were re-isolated and analysed on divisional basis for a number of parameters. We demonstrated that the primary CD8 + T cell response in the absence of CD4 + T cell help differed from that in normal CD4 + cellundepleted mice. While in the absence of CD4 + T cell help, the initial migratory progress from the local response to a systemic one was not grossly affected, the proportion of dying F5 cells during the expansion phase was markedly increased and resulted in an overall smaller expansion and significantly decreased frequency of CD8 + T cell memory after contraction. T cells primed without help displayed accelerated proliferation and activation, while expression of interferon-c remained similar. These phenomena were observed in the lymph nodes draining the MVA.HIVA-NP immunization site and were similar, but delayed by 2-3 days in spleen and non-draining lymph nodes. IntroductionCD8 + T cells form an important part of the immune defence against many intracellular pathogens including viruses. Historically, CD8 + T cell responses against viral infections were considered to be independent from 'help' provided by CD4 + T cells. This was explained by direct activation of antigen-presenting DC by viruses, which provided ligands for Toll-like receptors and proinflammatory signals [1][2][3]. Recently, this view was revised by studies of non-inflammatory antigens which suggested that while primary CD8 + T cell response was CD4 + T cell-independent, secondary CD8 + T cell response, i.e. development of functional memory, was dependent on CD4 + T cell help during priming. These data led to the formulation of a programming model [4][5][6]. In contrast, another set of recent studies pointed towards an environmental model and proposed that CD4 + T cells were required to enhance survival of fully functional memory CD8 + T cells rather than imparting essential programming during the primary response [7,8]. The differences in these conclusions may be explained by the use of different antigens and immunization protocols, which might lead to differential activation of DC. Collectively, these and other experiments [9][10][11][12][13] not required for triggering the CD8 + T cell program of multiple cell divisions, effector function maturation and cell number contraction, but was needed for differentiation into functional CD8 + T cell memory and/or its maintenance.To date, most studies investigated secondary responses to make conclusions about the dependence of the CD8 + T cell responses on CD4 help. This is partially because induction of a good memory is the ultimate aim of a successful vaccination, but also because primary CD8 + T cell responses to non-inf...

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A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans

Cited by 201 publications

References 32 publications

Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4⁺ T cell responses

Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4⁺ T cell responses

HIV-189.6 Gag expressed from a replication competent HSV-1 vector elicits persistent cellular immune responses in mice

Altered primary CD8⁺ T cell response to a modified virus Ankara(MVA)‐vectored vaccine in the absence of CD4⁺ T cell help

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A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans

Cited by 201 publications

References 32 publications

Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4+ T cell responses

Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4+ T cell responses

HIV-189.6 Gag expressed from a replication competent HSV-1 vector elicits persistent cellular immune responses in mice

Altered primary CD8+ T cell response to a modified virus Ankara(MVA)‐vectored vaccine in the absence of CD4+ T cell help

Contact Info

Product

Resources

About

Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4⁺ T cell responses

Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4⁺ T cell responses

Altered primary CD8⁺ T cell response to a modified virus Ankara(MVA)‐vectored vaccine in the absence of CD4⁺ T cell help