LIVIVO - Search results -

Search results

Result 1 - 10 of total 11

Search options

Article ; Online: Drug discovery in Africa tackles zoonotic and related infections.

Hikaambo, Christabel N / Shakela, Natalia / Woodland, John G / Wicht, Kathryn J / Chibale, Kelly

2023 Volume 15, Issue 718, Page(s) eadj0035

Abstract: Zoonotic and related infections pose an enormous health threat to the world's second-most populous continent. Despite the challenges faced by drug discovery scientists in Africa, recent progress toward identifying potential medicines across diverse ... ...

Abstract	Zoonotic and related infections pose an enormous health threat to the world's second-most populous continent. Despite the challenges faced by drug discovery scientists in Africa, recent progress toward identifying potential medicines across diverse disease areas is a cause for optimism and an indicator of progress in African-led scientific initiatives.
MeSH term(s)	Humans ; Africa/epidemiology ; Physicians
Language	English
Publishing date	2023-10-18
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.adj0035
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 6941: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
ab Jg. 2022: Lesesaal (EG)

Order via subito

This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Screening and risk reducing surgery for endometrial or ovarian cancers in Lynch syndrome: a systematic review.

Lim, Natalie / Hickey, Martha / Young, Graeme P / Macrae, Finlay A / Kelly, Christabel

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society

2022 Volume 32, Issue 5, Page(s) 646–655

Abstract: Objective: Lynch syndrome is a hereditary cancer syndrome caused by mismatch repair gene mutations, and female carriers are at an increased risk of endometrial and ovarian cancer. The best approach to screening is not yet clear and practice varies ... ...

Abstract	Objective: Lynch syndrome is a hereditary cancer syndrome caused by mismatch repair gene mutations, and female carriers are at an increased risk of endometrial and ovarian cancer. The best approach to screening is not yet clear and practice varies across countries and centers. We aimed to provide evidence to inform the best approach to screening and risk reduction. Methods: A systematic search of the literature was conducted (Medline, Embase, PubMed). Studies evaluating the following were included: women with Lynch syndrome (by mismatch repair mutation or Amsterdam II criteria), screening methods for endometrial and/or ovarian cancer, intervention included endometrial biopsy, transvaginal ultrasound, or serum cancer antigen 125 (CA-125), outcomes evaluated were number of cancers and/or endometrial hyperplasia. Results: A total of 18 studies of Lynch syndrome carriers which screened for endometrial cancer using transvaginal ultrasound and/or hysteroscopy/endometrial biopsy revealed an incidence of 3.9% at the time of screening. Most (64.1%) endometrial cancers detected were from screening, with the balance detected in symptomatic women at the first screening visits, regular review, or between screening intervals. In mismatch repair carriers, the overall sensitivity of endometrial screening was 66.7%, and the number needed to screen ranged between 4 and 38 (median 7). The sensitivity of endometrial biopsy was 57.1% and the number needed to screen was 23-380 (median 78). The sensitivity of transvaginal ultrasound was 34.4% and the number needed to screen was 35-973 (median 170). Fourteen studies which screened for ovarian cancer using transvaginal ultrasound and/or CA-125 revealed an incidence of 1.3% at the time of screening and 42.9% of ovarian cancers were detected at asymptomatic screening. The sensitivity of ovarian screening was 54.6%, and the number needed to screen was 9-191 (median 23) in mismatch repair carriers. Thirteen studies reported 5.8% incident endometrial cancers and 0.5% ovarian cancers at time of risk reducing surgery. Conclusions: There is limited evidence to support screening for endometrial and ovarian cancer in Lynch syndrome and data on mortality reduction are not available. Further prospective, randomized trials comparing targeted screening methods are needed. Risk reducing surgery remains the most reliable way to reduce endometrial and ovarian cancer risk in Lynch syndrome.
MeSH term(s)	Carcinoma, Ovarian Epithelial ; Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/surgery ; DNA Mismatch Repair ; Early Detection of Cancer/methods ; Endometrial Neoplasms/diagnosis ; Endometrial Neoplasms/genetics ; Endometrial Neoplasms/surgery ; Female ; Humans ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/surgery
Language	English
Publishing date	2022-05-03
Publishing country	England
Document type	Journal Article ; Systematic Review
ZDB-ID	1070385-8
ISSN	1525-1438 ; 1048-891X
ISSN (online)	1525-1438
ISSN	1048-891X
DOI	10.1136/ijgc-2021-003132
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 3198: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Effectiveness of cascade testing strategies in relatives for familial hypercholesterolemia: A systematic review and meta-analysis.

Leonardi-Bee, Jo / Boateng, Christabel / Faria, Rita / Eliman, Kelly / Young, Ben / Qureshi, Nadeem

Atherosclerosis

2021 Volume 338, Page(s) 7–14

Abstract: Background and aims: Cascade testing in relatives of index cases is the most cost-effective approach to identifying people with familial hypercholesterolemia (FH); however, it is currently unclear which strategy to contact relatives would be the most ... ...

Abstract	Background and aims: Cascade testing in relatives of index cases is the most cost-effective approach to identifying people with familial hypercholesterolemia (FH); however, it is currently unclear which strategy to contact relatives would be the most effective. A systematic review was performed to quantify the effectiveness of different strategies in cascade testing of FH. Methods: Comprehensive searches of three electronic databases and grey literature sources were done (from inception to May 2020). Screening, data extraction and assessments of methodological quality were made independently by two reviewers. Meta-analyses of proportions were performed using random effects models. Effect measures are reported as percentages with 95% confidence intervals. Results: 24 non-comparative studies were included, of which 11 used a direct, 8 used an indirect, and 5 used a combination of both direct and indirect cascade strategies. The median number of new relatives with FH per known index case was approximately 1. The combination strategy resulted in the largest yields of relatives tested for FH out of those contacted (40%, 95% CI 37%-42%, 1 study) and relatives responding to testing out of those contacted (54%, 1 study); however, the direct strategy had the largest yield of index cases participating in cascade testing out of those with FH confirmed (94%, 8 studies) compared to other strategies (p ≤ 0.01 for all comparisons). Conclusions: Evidence is limited; however, a combination strategy, which allows the index case to decide on method of contacting relatives, appears to lead to better yields compared to using the direct or indirect strategy.
MeSH term(s)	Cost-Benefit Analysis ; Genetic Testing ; Humans ; Hyperlipoproteinemia Type II/diagnosis ; Hyperlipoproteinemia Type II/genetics ; Mass Screening
Language	English
Publishing date	2021-10-02
Publishing country	Ireland
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't ; Systematic Review
ZDB-ID	80061-2
ISSN	1879-1484 ; 0021-9150
ISSN (online)	1879-1484
ISSN	0021-9150
DOI	10.1016/j.atherosclerosis.2021.09.014
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 226: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Age-Related Alterations in Macrophage Distribution and Function Are Associated With Delayed Cutaneous Wound Healing.

Dube, Christabel Thembela / Ong, Yasmin Hui Binn / Wemyss, Kelly / Krishnan, Siddharth / Tan, Tiak Ju / Janela, Baptiste / Grainger, John R / Ronshaugen, Matthew / Mace, Kimberly A / Lim, Chin Yan

Frontiers in immunology

2022 Volume 13, Page(s) 943159

Abstract: Ageing-related delays and dysregulated inflammation in wound healing are well-documented in both human and animal models. However, cellular and molecular changes underlying this impairment in healing progression are not fully understood. In this study, ... ...

Abstract	Ageing-related delays and dysregulated inflammation in wound healing are well-documented in both human and animal models. However, cellular and molecular changes underlying this impairment in healing progression are not fully understood. In this study, we characterised ageing-associated changes to macrophages in wounds of young and aged mice and investigated transcriptomic differences that may impact the progression of wound healing. Full-thickness wounds created on the dorsum of C57BL/6J young and aged mice were excised on Days 3 and 7 post-wounding for analysis by immunohistochemistry, flow cytometry, and RNA sequencing. Our data revealed that macrophages were significantly reduced in aged wounds in comparison to young. Functional transcriptomic analyses showed that macrophages from aged wounds exhibited significantly reduced expression of cell cycle, DNA replication, and repair pathway genes. Furthermore, we uncovered an elevated pro-inflammatory gene expression program in the aged macrophages correlated with poor inflammation resolution and excessive tissue damage observed in aged wounds. Altogether, our work provides insights into how poorly healing aged wounds are phenotypically defined by the presence of macrophages with reduced proliferative capacity and an exacerbated inflammatory response, both of which are pathways that can be targeted to improve healing in the elderly.
MeSH term(s)	Aged ; Animals ; Humans ; Inflammation/metabolism ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Skin/metabolism ; Wound Healing/genetics
Language	English
Publishing date	2022-07-08
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.943159
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: How people come to recognise a problem and seek medical help for a person showing early signs of dementia: A systematic review and meta-ethnography.

Perry-Young, Lucy / Owen, Gareth / Kelly, Susan / Owens, Christabel

Dementia (London, England)

2016 Volume 17, Issue 1, Page(s) 34–60

Abstract: Evidence suggests that there is usually a long delay between noticing first signs of dementia and seeking medical help. We conducted a systematic review of what people experience and how they make decisions during this time, and used a meta-ethnographic ... ...

Abstract	Evidence suggests that there is usually a long delay between noticing first signs of dementia and seeking medical help. We conducted a systematic review of what people experience and how they make decisions during this time, and used a meta-ethnographic approach to synthesise the findings. Screening and quality assessment resulted in nine studies eligible for inclusion. People with dementia mainly report experiencing memory lapses, while carers focus on more subtle changes in personality. People respond to these changes in one of three ways: 1) they discount them as normal; 2) they reserve judgement as to their cause and significance, or 3) they misattribute them. Pivotal events can finally trigger help seeking. Active reflection and seeking of further evidence may lead to earlier recognition of the possibility of dementia and the need to seek help; it also reduces the risk of a pivotal event. Public education should aim to improve recognition of more subtle signs and to encourage repeated evaluation and reflection.
MeSH term(s)	Anthropology, Cultural ; Caregivers/psychology ; Dementia/diagnosis ; Help-Seeking Behavior ; Humans ; Memory Disorders ; Patient Acceptance of Health Care
Language	English
Publishing date	2016-01-12
Publishing country	England
Document type	Journal Article ; Review ; Systematic Review
ZDB-ID	2084045-7
ISSN	1741-2684 ; 1471-3012
ISSN (online)	1741-2684
ISSN	1471-3012
DOI	10.1177/1471301215626889
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Interferon lambdas: the next cytokine storm.

Kelly, Christabel / Klenerman, Paul / Barnes, Eleanor

Gut

2011 Volume 60, Issue 9, Page(s) 1284–1293

Abstract: For two decades the scientific community has sought to understand why some people clear hepatitis C virus (HCV) and others do not. Recently, several large genome-wide association studies have identified single nucleotide polymorphisms (SNPs) linked to ... ...

Abstract	For two decades the scientific community has sought to understand why some people clear hepatitis C virus (HCV) and others do not. Recently, several large genome-wide association studies have identified single nucleotide polymorphisms (SNPs) linked to interferon lambda 3 (IFNλ3) that are associated with the spontaneous resolution and successful treatment of HCV infection. These observations are generating intense research activity; the hope is that IFNλ3 genetic variants may serve as important predictive biomarkers of treatment outcome and offer new insights into the biological pathways involved in viral control. A pharmacogenomic treatment approach for HCV can now be envisaged, with the incorporation of host genetic variants into a predictive treatment algorithm with other factors. The SNPs associated with the clinical outcome of HCV infection are located some distance from the IFNλ3 gene itself, and causal genetic variants have yet to be clearly defined. Locating these causal variants, mapping in detail the IFNλ3 signalling pathways and determining the downstream genetic signature so induced will clarify the role of IFNλ3 in the pathogenesis of HCV. Clinical studies assessing safety and efficacy in the treatment of HCV with exogenous IFNλ3 are currently underway. Early results suggest that IFNλ3 treatment inhibits HCV replication and is associated with a limited side effect profile. However, hepatotoxicity in both healthy volunteers and HCV-infected patients has been described. This review discusses the genetic studies that link IFNλ3 to both the spontaneous resolution and treatment-induced clearance of HCV and the potential impact of this in clinical practice, the biology of IFNλ3 as currently understood and how this may impact on HCV infection, and describes the early studies that assess the role of this cytokine in the treatment of patients with HCV.
MeSH term(s)	Antiviral Agents/therapeutic use ; Genome-Wide Association Study ; Hepacivirus/genetics ; Hepatitis C, Chronic/drug therapy ; Hepatitis C, Chronic/virology ; Humans ; Interferons ; Interleukins/genetics ; Interleukins/physiology ; Interleukins/therapeutic use ; Polymorphism, Single Nucleotide
Chemical Substances	Antiviral Agents ; interferon-lambda, human ; Interleukins ; Interferons (9008-11-1)
Language	English
Publishing date	2011-02-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80128-8
ISSN	1468-3288 ; 0017-5749
ISSN (online)	1468-3288
ISSN	0017-5749
DOI	10.1136/gut.2010.222976
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 160: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Cross-reactivity of hepatitis C virus specific vaccine-induced T cells at immunodominant epitopes.

Kelly, Christabel / Swadling, Leo / Brown, Anthony / Capone, Stefania / Folgori, Antonella / Salio, Mariolina / Klenerman, Paul / Barnes, Eleanor

European journal of immunology

2014 Volume 45, Issue 1, Page(s) 309–316

Abstract: Viral diversity is a challenge to the development of a hepatitis C virus (HCV) vaccine. Following vaccination of humans with adenoviral vectors, we determined the capacity of T cells to target common viral variants at immundominant epitopes ex vivo. We ... ...

Abstract	Viral diversity is a challenge to the development of a hepatitis C virus (HCV) vaccine. Following vaccination of humans with adenoviral vectors, we determined the capacity of T cells to target common viral variants at immundominant epitopes ex vivo. We identified two major variants for epitopes NS3(1073) and NS3(1446), and multiple variants for epitope NS3(1406) that occurred in >5% of genotype 1 and 3 sequences at a population level. Cross-reactivity of vaccine-induced T cells was determined using variant peptides in IFN-γ ELISPOT assays. Vaccine-induced T cells targeted approximately 90% of NS3(1073) genotype 1 sequences and 50% of NS3(1446) genotype 1 and 3 sequences. For NS3(1406), 62% of subtype-1b sequences were targeted. Next, we assessed whether an in vitro priming system, using dendritic cells and T cells from healthy donors, could identify a variant of NS3(1406) that was maximally cross-reactive. In vitro priming assays showed that of those tested the NS3(1406) vaccine variant was the most immunogenic. T cells primed with genotype 1 variants from subtype 1a or 1b were broadly cross-reactive with other variants from the same subtype. We conclude that immunization with candidate HCV adenoviral vaccines generates cross-reactive T cells at immunodominant epitopes. The degree of cross-reactivity varies between epitopes and may be HCV-subtype specific.
MeSH term(s)	Amino Acid Sequence ; Antigens, Viral/genetics ; Antigens, Viral/immunology ; Cell Line ; Cross Reactions ; Dendritic Cells/cytology ; Dendritic Cells/immunology ; Enzyme-Linked Immunospot Assay ; Epitopes, T-Lymphocyte/genetics ; Epitopes, T-Lymphocyte/immunology ; Genotype ; Hepacivirus/genetics ; Hepacivirus/immunology ; Hepatitis C/immunology ; Hepatitis C/prevention & control ; Hepatitis C/virology ; Humans ; Interferon-gamma/genetics ; Interferon-gamma/immunology ; Interferon-gamma/metabolism ; Molecular Sequence Data ; Primary Cell Culture ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; Vaccination ; Viral Hepatitis Vaccines/administration & dosage ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/immunology
Chemical Substances	Antigens, Viral ; Epitopes, T-Lymphocyte ; NS3 protein, hepatitis C virus ; Viral Hepatitis Vaccines ; Viral Nonstructural Proteins ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2014-10-30
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201444686
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 85: Show issues

Order via subito

Details ▾

Article ; Online: Highly-Immunogenic Virally-Vectored T-cell Vaccines Cannot Overcome Subversion of the T-cell Response by HCV during Chronic Infection

Vaccines, Vol 4, Iss 3, p

2016 Volume 27

Abstract: An effective therapeutic vaccine for the treatment of chronic hepatitis C virus (HCV) infection, as an adjunct to newly developed directly-acting antivirals (DAA), or for the prevention of reinfection, would significantly reduce the global burden of ... ...

Abstract	An effective therapeutic vaccine for the treatment of chronic hepatitis C virus (HCV) infection, as an adjunct to newly developed directly-acting antivirals (DAA), or for the prevention of reinfection, would significantly reduce the global burden of disease associated with chronic HCV infection. A recombinant chimpanzee adenoviral (ChAd3) vector and a modified vaccinia Ankara (MVA), encoding the non-structural proteins of HCV (NSmut), used in a heterologous prime/boost regimen induced multi-specific, high-magnitude, durable HCV-specific CD4+ and CD8+ T-cell responses in healthy volunteers, and was more immunogenic than a heterologous Ad regimen. We now assess the immunogenicity of this vaccine regimen in HCV infected patients (including patients with a low viral load suppressed with interferon/ribavirin therapy), determine T-cell cross-reactivity to endogenous virus, and compare immunogenicity with that observed previously in both healthy volunteers and in HCV infected patients vaccinated with the heterologous Ad regimen. Vaccination of HCV infected patients with ChAd3-NSmut/MVA-NSmut was well tolerated. Vaccine-induced HCV-specific T-cell responses were detected in 8/12 patients; however, CD4+ T-cell responses were rarely detected, and the overall magnitude of HCV-specific T-cell responses was markedly reduced when compared to vaccinated healthy volunteers. Furthermore, HCV-specific cells had a distinct partially-functional phenotype (lower expression of activation markers, granzyme B, and TNFα production, weaker in vitro proliferation, and higher Tim3 expression, with comparable Tbet and Eomes expression) compared to healthy volunteers. Robust anti-vector T-cells and antibodies were induced, showing that there is no global defect in immunity. The level of viremia at the time of vaccination did not correlate with the magnitude of the vaccine-induced T-cell response. Full-length, next-generation sequencing of the circulating virus demonstrated that T-cells were only induced by vaccination when there was a ...
Keywords	therapeutic vaccination ; adenovirus ; modified vaccinia Ankara ; immunotherapy ; HCV ; T-cells ; exhaustion ; Medicine ; R
Subject code	570
Language	English
Publishing date	2016-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

Full text online

Full text

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article ; Online: Chronic hepatitis C viral infection subverts vaccine-induced T-cell immunity in humans.

Kelly, Christabel / Swadling, Leo / Capone, Stefania / Brown, Anthony / Richardson, Rachel / Halliday, John / von Delft, Annette / Oo, Ye / Mutimer, David / Kurioka, Ayako / Hartnell, Felicity / Collier, Jane / Ammendola, Virginia / Del Sorbo, Mariarosaria / Grazioli, Fabiana / Esposito, Maria Luisa / Di Marco, Stefania / Siani, Loredana / Traboni, Cinzia /

Hill, Adrian V S / Colloca, Stefano / Nicosia, Alfredo / Cortese, Riccardo / Folgori, Antonella / Klenerman, Paul / Barnes, Eleanor

Hepatology (Baltimore, Md.)

2016 Volume 63, Issue 5, Page(s) 1455–1470

Abstract: Unlabelled: Adenoviral vectors encoding hepatitis C virus (HCV) nonstructural (NS) proteins induce multispecific, high-magnitude, durable CD4(+) and CD8(+) T-cell responses in healthy volunteers. We assessed the capacity of these vaccines to induce ... ...

Abstract	Unlabelled: Adenoviral vectors encoding hepatitis C virus (HCV) nonstructural (NS) proteins induce multispecific, high-magnitude, durable CD4(+) and CD8(+) T-cell responses in healthy volunteers. We assessed the capacity of these vaccines to induce functional HCV-specific immune responses and determine T-cell cross-reactivity to endogenous virus in patients with chronic HCV infection. HCV genotype 1-infected patients were vaccinated using heterologous adenoviral vectors (ChAd3-NSmut and Ad6-NSmut) encoding HCV NS proteins in a dose escalation, prime-boost regimen, with and without concomitant pegylated interferon-α/ribavirin therapy. Analysis of immune responses ex vivo used human leukocyte antigen class I pentamers, intracellular cytokine staining, and fine mapping in interferon-γ enzyme-linked immunospot assays. Cross-reactivity of T cells with population and endogenous viral variants was determined following viral sequence analysis. Compared to healthy volunteers, the magnitude of HCV-specific T-cell responses following vaccination was markedly reduced. CD8(+) HCV-specific T-cell responses were detected in 15/24 patients at the highest dose, whereas CD4(+) T-cell responses were rarely detectable. Analysis of the host circulating viral sequence showed that T-cell responses were rarely elicited when there was sequence homology between vaccine immunogen and endogenous virus. In contrast, T cells were induced in the context of genetic mismatch between vaccine immunogen and endogenous virus; however, these commonly failed to recognize circulating epitope variants and had a distinct partially functional phenotype. Vaccination was well tolerated but had no significant effect on HCV viral load. Conclusion: Vaccination with potent HCV adenoviral vectored vaccines fails to restore T-cell immunity except where there is genetic mismatch between vaccine immunogen and endogenous virus; this highlights the major challenge of overcoming T-cell exhaustion in the context of persistent antigen exposure with implications for cancer and other persistent infections.
MeSH term(s)	Adenoviridae/genetics ; Adult ; Aged ; Amino Acid Sequence ; Epitopes, T-Lymphocyte ; Hepacivirus/immunology ; Hepatitis C, Chronic/drug therapy ; Hepatitis C, Chronic/immunology ; Hepatitis C, Chronic/virology ; Humans ; Interferon-alpha/administration & dosage ; Male ; Middle Aged ; Molecular Sequence Data ; Polyethylene Glycols/administration & dosage ; Recombinant Proteins/administration & dosage ; Riboflavin/administration & dosage ; T-Lymphocytes/immunology ; Vaccination ; Viral Hepatitis Vaccines/immunology
Chemical Substances	Epitopes, T-Lymphocyte ; Interferon-alpha ; Recombinant Proteins ; Viral Hepatitis Vaccines ; Polyethylene Glycols (3WJQ0SDW1A) ; peginterferon alfa-2a (Q46947FE7K) ; Riboflavin (TLM2976OFR)
Language	English
Publishing date	2016-01-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1002/hep.28294
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 1660: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾

Article: Highly-Immunogenic Virally-Vectored T-cell Vaccines Cannot Overcome Subversion of the T-cell Response by HCV during Chronic Infection.

Vaccines

2016 Volume 4, Issue 3

Abstract	An effective therapeutic vaccine for the treatment of chronic hepatitis C virus (HCV) infection, as an adjunct to newly developed directly-acting antivirals (DAA), or for the prevention of reinfection, would significantly reduce the global burden of disease associated with chronic HCV infection. A recombinant chimpanzee adenoviral (ChAd3) vector and a modified vaccinia Ankara (MVA), encoding the non-structural proteins of HCV (NSmut), used in a heterologous prime/boost regimen induced multi-specific, high-magnitude, durable HCV-specific CD4+ and CD8+ T-cell responses in healthy volunteers, and was more immunogenic than a heterologous Ad regimen. We now assess the immunogenicity of this vaccine regimen in HCV infected patients (including patients with a low viral load suppressed with interferon/ribavirin therapy), determine T-cell cross-reactivity to endogenous virus, and compare immunogenicity with that observed previously in both healthy volunteers and in HCV infected patients vaccinated with the heterologous Ad regimen. Vaccination of HCV infected patients with ChAd3-NSmut/MVA-NSmut was well tolerated. Vaccine-induced HCV-specific T-cell responses were detected in 8/12 patients; however, CD4+ T-cell responses were rarely detected, and the overall magnitude of HCV-specific T-cell responses was markedly reduced when compared to vaccinated healthy volunteers. Furthermore, HCV-specific cells had a distinct partially-functional phenotype (lower expression of activation markers, granzyme B, and TNFα production, weaker in vitro proliferation, and higher Tim3 expression, with comparable Tbet and Eomes expression) compared to healthy volunteers. Robust anti-vector T-cells and antibodies were induced, showing that there is no global defect in immunity. The level of viremia at the time of vaccination did not correlate with the magnitude of the vaccine-induced T-cell response. Full-length, next-generation sequencing of the circulating virus demonstrated that T-cells were only induced by vaccination when there was a sequence mismatch between the autologous virus and the vaccine immunogen. However, these T-cells were not cross-reactive with the endogenous viral variant epitopes. Conversely, when there was complete homology between the immunogen and circulating virus at a given epitope T-cells were not induced. T-cell induction following vaccination had no significant impact on HCV viral load. In vitro T-cell culture experiments identified the presence of T-cells at baseline that could be expanded by vaccination; thus, HCV-specific T-cells may have been expanded from pre-existing low-level memory T-cell populations that had been exposed to HCV antigens during natural infection, explaining the partial T-cell dysfunction. In conclusion, vaccination with ChAd3-NSmut and MVA-NSmut prime/boost, a potent vaccine regimen previously optimized in healthy volunteers was unable to reconstitute HCV-specific T-cell immunity in HCV infected patients. This highlights the major challenge of overcoming T-cell exhaustion in the context of persistent antigen exposure.
Language	English
Publishing date	2016-08-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines4030027
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

To top

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

Inter-library loan at ZB MED

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito