Biomedical subjects

Tomas Hanke

Publications and source records attributed to Tomas Hanke.

7 recordsLinked to original sources

PubMed2006

Induction of multifunctional human immunodeficiency virus type 1 (HIV-1)-specific T cells capable of proliferation in healthy subjects by using a prime-boost regimen of DNA- and modified vaccinia virus Ankara-vectored vaccines expressing HIV-1 Gag coupled to CD8+ T-cell epitopes.

A double-blind randomized phase I trial was conducted in human immunodeficiency virus type 1 (HIV-1)-negative subjects receiving vaccines vectored by plasmid DNA and modified vaccinia virus Ankara (MVA) expressing HIV-1 p24/p17 gag linked to a string of CD8(+) T-cell epitopes. The trial had two groups. One group received either two doses of MVA.HIVA (2x MVA.HIVA) (n=8) or two doses of placebo (2x placebo) (n=4). The second group received 2x pTHr.HIVA followed by one dose of MVA.HIVA (n=8) or 3x placebo (n=4). In the pTHr.HIVA-MVA.HIVA group, HIV-1-specific T-cell responses peaked 1 week after MVA.HIVA vaccination in both ex vivo gamma interferon (IFN-gamma) ELISPOT (group mean, 210 spot-forming cells/10(6) cells) and proliferation (group mean stimulation index, 37), with assays detecting positive responses in four out of eight and five out of eight subjects, respectively. No HIV-1-specific T-cell responses were detected in either assay in the 2x MVA.HIVA group or subjects receiving placebo. Using a highly sensitive and reproducible cultured IFN-gamma ELISPOT assay, positive responses mainly mediated by CD4(+) T cells were detected in eight out of eight vaccinees in the pTHr.HIVA-MVA.HIVA group and four out of eight vaccinees in the 2x MVA.HIVA group. Importantly, no false-positive responses were detected in the eight subjects receiving placebo. Of the 12 responders, 11 developed responses to previously identified immunodominant CD4(+) T-cell epitopes, with 6 volunteers having responses to more than one epitope. Five out of 12 responders also developed CD8(+) T-cell responses to the epitope string. Induced T cells produced a variety of anti-viral cytokines, including tumor necrosis factor alpha and macrophage inflammatory protein 1 beta. These data demonstrate that prime-boost vaccination with recombinant DNA and MVA vectors can induce multifunctional HIV-1-specific T cells in the majority of vaccinees.

AIDS Vaccines↗

PubMed2005

Modified vaccinia Ankara expressing HIVA antigen stimulates HIV-1-specific CD8 T cells in ELISpot assays of HIV-1 exposed infants.

Recombinant modified vaccinia virus Ankara expressing HIV-1 antigens (MVA.HIVA) was used in ELISpot assays to monitor HIV-1-specific T cell responses in infants. Responses to MVA.HIVA and HIV-1 peptides were examined in 13 infected and 81 exposed uninfected infants in Nairobi, Kenya. Responses to MVA.HIVA (38%) and peptide stimulation (38%) were similar in frequency (p=1.0) and magnitude (mean 176 versus 385 HIVSFU/10(6), p=0.96) in HIV-1 infected infants. In exposed uninfected infants, MVA.HIVA detected more positive responses and higher magnitude responses as compared to peptide. MVA.HIVA ELISpot is a sensitive method for quantification of HIV-1-specific CD8+ T cell responses in HIV-1 exposed infants. These results demonstrate the relevance of HIV-1 clade A consensus-derived immunogen HIVA for the viruses currently circulating in Nairobi.

CD8-Positive T-Lymphocytes↗

PubMed2005

Enhanced immunogenicity using an alphavirus replicon DNA vaccine against human immunodeficiency virus type 1.

With the human immunodeficiency virus type 1 (HIV-1) epidemic expanding at increasing speed, development of a safe and effective vaccine remains a high priority. One of the most central vaccine platforms considered is plasmid DNA. However, high doses of DNA and several immunizations are typically needed to achieve detectable T-cell responses. In this study, a Semliki Forest virus replicon DNA vaccine designed for human clinical trials, DREP.HIVA, encoding an antigen that is currently being used in human trials in the context of a conventional DNA plasmid, pTHr.HIVA, was generated. It was shown that a single immunization of DREP.HIVA stimulated HIV-1-specific T-cell responses in mice, suggesting that the poor immunogenicity of conventional DNA vaccines may be enhanced by using viral replicon-based plasmid systems. The results presented here support the evaluation of Semliki Forest virus replicon DNA vaccines in non-human primates and in clinical studies.

Animals↗

PubMed2003

HIV vaccines 1983-2003.

Twenty years after the discovery of HIV, there is still no vaccine. This year, an envelope vaccine aimed at stimulating neutralizing antibodies was unable to protect against infection in phase 3 trials. But more than 20 HIV vaccines designed to stimulate T-cell responses are being developed. Will any of them work?

AIDS Vaccines↗

PubMed2002

Design and tests of an HIV vaccine.

It is likely that a successful vaccine against HIV will need to stimulate the innate immune system, generate high levels of neutralising antibody, strong cellular immune responses, and mucosal immunity. Early efforts to develop HIV vaccines attempted to use the virus glycoprotein, gp120, to induce neutralising antibody, but did not take into account the trimeric structure of the native glycoprotein or the complex nature of the CD4 and chemokine receptor binding sites. Recently, attention has been focused on cellular immune responses, particularly T-cell cytotoxicity, based on evidence from the SIV model and from exposed and uninfected humans. Recent experiments in macaques and man suggest that a prime boost regimen using DNA and recombinant pox virus is highly effective at stimulating cellular immunity. However, in addition to the problems of generating neutralising antibodies and mucosal immunity, the difficulty of inducing broad cellular responses able to protect against all clades of HIV, remains an important issue.

AIDS Vaccines↗

PubMed2002

Expression of human immunodeficiency virus type 1 gp120 from herpes simplex virus type 1-derived amplicons results in potent, specific, and durable cellular and humoral immune responses.

Herpes simplex virus type 1 (HSV-1) infects a wide range of cells, including dendritic cells. Consequently, HSV-1 vectors may be capable of eliciting strong immune responses to vectored antigens. To test this hypothesis, an HSV-1 amplicon plasmid encoding human immunodeficiency virus type 1 gp120 was constructed, and murine immune responses to helper virus-free amplicon preparations derived from this construct were evaluated. Initial studies revealed that a single intramuscular (i.m.) injection of 10(6) infectious units (i.u.) of HSV:gp120 amplicon particles (HSV:gp120) elicited Env-specific cellular and humoral immune responses. A potent, CD8(+)-T-cell-mediated response to an H-2D(d)-restricted peptide from gp120 (RGPGRAFVTI) was measured by a gamma interferon ELISPOT and was confirmed by standard cytotoxic-T-lymphocyte assays. Immunoglobulin G enzyme-linked immunosorbent assay analysis showed the induction of a strong, Env-specific antibody response. An i.m. or an intradermal administration of HSV:gp120 at the tail base elicited a more potent cellular immune response than did an intraperitoneal (i.p.) inoculation, although an i.p. introduction generated a stronger humoral response. The immune response to HSV:gp120 was durable, with robust cellular and humoral responses persisting at 171 days after a single 10(6)-i.u. inoculation. The immune response to HSV:gp120 was also found to be dose dependent: as few as 10(4) i.u. elicited a strong T-cell response. Finally, HSV:gp120 elicited significant Env-specific cellular immune responses even in animals that had been previously infected with wild-type HSV-1. Taken together, these data strongly support the use of helper-free HSV-1 amplicon particles as vaccine delivery vectors.

Animals↗

PubMed2002

Effects of cytotoxic T lymphocytes (CTL) directed against a single simian immunodeficiency virus (SIV) Gag CTL epitope on the course of SIVmac239 infection.

Vaccine-induced cytotoxic T lymphocytes (CTL) have been implicated in the control of virus replication in simian immunodeficiency virus (SIV)-challenged and simian-human immunodeficiency virus-challenged macaques. Therefore, we wanted to test the impact that vaccine-induced CTL responses against an immunodominant Gag epitope might have in the absence of other immune responses. By themselves, these strong CTL responses failed to control SIVmac239 replication.

Animals↗