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Article ; Online: Antigen-independent, autonomous B cell receptor signaling drives activated B cell DLBCL.

Eken, Janneke A / Koning, Marvyn T / Kupcova, Kristyna / Sepúlveda Yáñez, Julieta H / de Groen, Ruben A L / Quinten, Edwin / Janssen, Jurriaan / van Bergen, Cornelis A M / Vermaat, Joost S P / Cleven, Arjen / Navarrete, Marcelo A / Ylstra, Bauke / de Jong, Daphne / Havranek, Ondrej / Jumaa, Hassan / Veelken, Hendrik

The Journal of experimental medicine

2024 Volume 221, Issue 5

Abstract: Diffuse large B cell lymphoma of activated B cell type (ABC-DLBCL), a major cell-of-origin DLBCL subtype, is characterized by chronic active B cell receptor (BCR) signaling and NF-κB activation, which can be explained by activating mutations of the BCR ... ...

Abstract	Diffuse large B cell lymphoma of activated B cell type (ABC-DLBCL), a major cell-of-origin DLBCL subtype, is characterized by chronic active B cell receptor (BCR) signaling and NF-κB activation, which can be explained by activating mutations of the BCR signaling cascade in a minority of cases. We demonstrate that autonomous BCR signaling, akin to its essential pathogenetic role in chronic lymphocytic leukemia (CLL), can explain chronic active BCR signaling in ABC-DLBCL. 13 of 18 tested DLBCL-derived BCR, including 12 cases selected for expression of IgM, induced spontaneous calcium flux and increased phosphorylation of the BCR signaling cascade in murine triple knockout pre-B cells without antigenic stimulation or external BCR crosslinking. Autonomous BCR signaling was associated with IgM isotype, dependent on somatic BCR mutations and individual HCDR3 sequences, and largely restricted to non-GCB DLBCL. Autonomous BCR signaling represents a novel immunological oncogenic driver mechanism in DLBCL originating from individual BCR sequences and adds a new dimension to currently proposed genetics- and transcriptomics-based DLBCL classifications.
MeSH term(s)	Animals ; Mice ; B-Lymphocytes ; Lymphoma, Large B-Cell, Diffuse/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell ; Receptors, Antigen, B-Cell ; Immunoglobulin M
Chemical Substances	Receptors, Antigen, B-Cell ; Immunoglobulin M
Language	English
Publishing date	2024-03-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20230941
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Article ; Online: Acquisition of a glycosylated B-cell receptor drives follicular lymphoma toward a dark zone phenotype.

van Bergen, Cornelis A M / Kloet, Susan L / Quinten, Edwin / Sepúlveda Yáñez, Julieta H / Menafra, Roberta / Griffioen, Marieke / Jansen, Patty M / Koning, Marvyn T / Knijnenburg, Jeroen / Navarrete, Marcelo A / Kiełbasa, Szymon M / Veelken, Hendrik

Blood advances

2023 Volume 7, Issue 19, Page(s) 5812–5816

Language	English
Publishing date	2023-07-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023010725
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Zs.A 7153: Show issues

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Article ; Online: Autonomous B-cell receptor signaling and genetic aberrations in chronic lymphocytic leukemia-phenotype monoclonal B lymphocytosis in siblings of patients with chronic lymphocytic leukemia.

Haematologica

2024 Volume 109, Issue 3, Page(s) 824–834

Abstract: Clonal expansion of CD5-expressing B cells, commonly designated as monoclonal B lymphocytosis (MBL), is a precursor condition for chronic lymphocytic leukemia (CLL). The mechanisms driving subclinical MBL B-cell expansion and progression to CLL, ... ...

Abstract	Clonal expansion of CD5-expressing B cells, commonly designated as monoclonal B lymphocytosis (MBL), is a precursor condition for chronic lymphocytic leukemia (CLL). The mechanisms driving subclinical MBL B-cell expansion and progression to CLL, occurring in approximately 1% of affected individuals, are unknown. An autonomously signaling B-cell receptor (BCR) is essential for the pathogenesis of CLL. The objectives of this study were functional characterization of the BCR of MBL in siblings of CLL patients and a comparison of genetic variants in MBL-CLL sibling pairs. Screening of peripheral blood by flow cytometry detected 0.2-480 clonal CLL-phenotype cells per microliter (median: 37/μL) in 34 of 191 (17.8%) siblings of CLL patients. Clonal BCR isolated from highly purified CLL-phenotype cells induced robust calcium mobilization in BCR-deficient murine pre-B cells in the absence of external antigen and without experimental crosslinking. This autonomous BCR signal was less intense than the signal originating from the CLL BCR of their CLL siblings. According to genotyping by single nucleotide polymorphism array, whole exome, and targeted panel sequencing, CLL risk alleles were found with high and similar prevalence in CLL patients and MBL siblings, respectively. Likewise, the prevalence of recurrent CLL-associated genetic variants was similar between CLL and matched MBL samples. However, copy number variations and small variants were frequently subclonal in MBL cells, suggesting their acquisition during subclinical clonal expansion. These findings support a stepwise model of CLL pathogenesis, in which autonomous BCR signaling leads to a non-malignant (oligo)clonal expansion of CD5+ B cells, followed by malignant progression to CLL after acquisition of pathogenic genetic variants.
MeSH term(s)	Humans ; Animals ; Mice ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Siblings ; DNA Copy Number Variations ; Lymphocytosis/genetics ; Leukemia ; Receptors, Antigen, B-Cell/genetics ; Phenotype
Chemical Substances	Receptors, Antigen, B-Cell
Language	English
Publishing date	2024-03-01
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2022.282542
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Article ; Online: Prognosis of IGLV3-21

Hengeveld, Paul J / Veelken, Hendrik / van Bergen, Cornelis A M / Quinten, Edwin / Vervoordeldonk, Mischa Y L / Ismailzada, Wahija / Barendse, Rob S / Dubois, Julie M N / van Oers, Marinus H J / Geisler, Christian H / Kater, Arnon P / Westerweel, Peter E / Langerak, Anton W / Levin, Mark-David

Leukemia

2023 Volume 37, Issue 9, Page(s) 1929–1932

MeSH term(s)	Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Prognosis
Language	English
Publishing date	2023-07-21
Publishing country	England
Document type	Letter
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-023-01975-0
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Zs.A 2295: Show issues

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Article ; Online: Acquired N-Linked Glycosylation Motifs in B-Cell Receptors of Primary Cutaneous B-Cell Lymphoma and the Normal B-Cell Repertoire.

Koning, Marvyn T / Quinten, Edwin / Zoutman, Willem H / Kiełbasa, Szymon M / Mei, Hailiang / van Bergen, Cornelis A M / Jansen, Patty / Vergroesen, Rochelle D / Willemze, Rein / Vermeer, Maarten H / Tensen, Cornelis P / Veelken, Hendrik

The Journal of investigative dermatology

2019 Volume 139, Issue 10, Page(s) 2195–2203

Abstract: Primary cutaneous follicle center lymphoma (PCFCL) is a rare mature B-cell lymphoma with an unknown etiology. PCFCL resembles follicular lymphoma (FL) by cytomorphologic and microarchitectural criteria. FL B cells are selected for N-linked glycosylation ... ...

Abstract	Primary cutaneous follicle center lymphoma (PCFCL) is a rare mature B-cell lymphoma with an unknown etiology. PCFCL resembles follicular lymphoma (FL) by cytomorphologic and microarchitectural criteria. FL B cells are selected for N-linked glycosylation motifs in their B-cell receptors (BCRs) that are acquired during continuous somatic hypermutation. The stimulation of mannosylated BCR by lectins on the tumor microenvironment is therefore a candidate driver in FL pathogenesis. We investigated whether the same mechanism could play a role in PCFCL pathogenesis. Full-length functional variable, diversity, and joining gene sequences of 18 PCFCL and 8 primary cutaneous diffuse large B-cell lymphoma, leg-type were identified by unbiased Anchoring Reverse Transcription of Immunoglobulin Sequences and Amplification by Nested PCR and BCR reconstruction from RNA sequencing data. Low BCR variation demonstrated negligible ongoing somatic hypermutation in PCFCL and primary cutaneous diffuse large B-cell lymphoma, leg-type, and indicated that the PCFCL microarchitecture does not act as a functional germinal center. Similar to FL but in contrast to primary cutaneous diffuse large B-cell lymphoma, leg-type, BCR genes of 15 PCFCLs (83%) had acquired N-linked glycosylation motifs. These motifs were located at the BCR positions converted to N-linked glycosylation motifs in normal B-cell repertoires with low prevalence but mostly at different positions than those found in FL. The cutaneous localization of PCFCL might suggest a role for lectins from commensal skin bacteria in PCFCL lymphomagenesis.
MeSH term(s)	Aged ; Aged, 80 and over ; Biopsy, Needle ; Cohort Studies ; DNA Mutational Analysis ; Diagnosis, Differential ; Female ; Gene Expression Regulation ; Germinal Center/metabolism ; Glycosylation ; Humans ; Immunohistochemistry ; Lymphoma, Follicular/genetics ; Lymphoma, Follicular/pathology ; Lymphoma, Large B-Cell, Diffuse/genetics ; Lymphoma, Large B-Cell, Diffuse/pathology ; Male ; Middle Aged ; Molecular Sequence Data ; Prognosis ; Receptors, Antigen, B-Cell/genetics ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology ; Tumor Microenvironment/genetics
Chemical Substances	Receptors, Antigen, B-Cell
Language	English
Publishing date	2019-04-28
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2019.04.005
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Article ; Online: Transcriptomic signatures induced by the Ebola virus vaccine rVSVΔG-ZEBOV-GP in adult cohorts in Europe, Africa, and North America: a molecular biomarker study.

Vianello, Eleonora / Gonzalez-Dias, Patricia / van Veen, Suzanne / Engele, Carmen G / Quinten, Edwin / Monath, Thomas P / Medaglini, Donata / Santoro, Francesco / Huttner, Angela / Dubey, Sheri / Eichberg, Michael / Ndungu, Francis M / Kremsner, Peter G / Essone, Paulin N / Agnandji, Selidji Todagbe / Siegrist, Claire-Anne / Nakaya, Helder I / Ottenhoff, Tom H M / Haks, Mariëlle C

The Lancet. Microbe

2021 Volume 3, Issue 2, Page(s) e113–e123

Abstract: Background: A recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP) vaccine has been reported as safe, immunogenic, and highly protective in a ring vaccination trial. We aimed to identify ... ...

Abstract	Background: A recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP) vaccine has been reported as safe, immunogenic, and highly protective in a ring vaccination trial. We aimed to identify transcriptomic immune response biomarker signatures induced by vaccination and associated signatures with its immunogenicity and reactogenicity to better understand the potential mechanisms of action of the vaccine. Methods: 354 healthy adult volunteers were vaccinated in randomised, double-blind, placebo-controlled trials in Europe (Geneva, Switzerland [November, 2014, to January, 2015]) and North America (USA [Dec 5, 2014, to June 23, 2015]), and dose-escalation trials in Africa (Lambaréné, Gabon [November, 2014, to January, 2015], and Kilifi, Kenya [December, 2014, to January, 2015]) using different doses of the recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP; 3 × 10 Findings: Our results indicated that perturbation of gene expression peaked on day 1 and returned to baseline levels between day 7 and day 28. The magnitude of the response was dose-dependent, with vaccinees receiving a high dose (≥9 × 10 Interpretation: Collectively, our results identify and cross-validate immune-related transcriptomic signatures induced by rVSVΔG-ZEBOV-GP vaccination in four cohorts of adult participants from different genetic and geographical backgrounds. These signatures will aid in the rational development, testing, and evaluation of novel vaccines and will allow evaluation of the effect of host factors such as age, co-infection, and comorbidity on responses to vaccines. Funding: Innovative Medicines Initiative 2 Joint Undertaking.
MeSH term(s)	Adult ; Africa ; Antibodies, Viral ; Biomarkers ; Ebola Vaccines/adverse effects ; Ebolavirus/genetics ; Europe ; Glycoproteins/genetics ; Hemorrhagic Fever, Ebola/prevention & control ; Humans ; North America ; Randomized Controlled Trials as Topic ; Transcriptome ; Vesicular Stomatitis/chemically induced ; Vesiculovirus/genetics
Chemical Substances	Antibodies, Viral ; Biomarkers ; Ebola Vaccines ; Glycoproteins
Language	English
Publishing date	2021-12-06
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ISSN	2666-5247
ISSN (online)	2666-5247
DOI	10.1016/S2666-5247(21)00235-4
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Article ; Online: Retinal Pigment Epithelial Cells Control Early Mycobacterium tuberculosis Infection via Interferon Signaling.

La Distia Nora, Rina / Walburg, Kimberley V / van Hagen, P Martin / Swagemakers, Sigrid M A / van der Spek, Peter J / Quinten, Edwin / van Velthoven, Mirjam / Ottenhoff, Tom H M / Dik, Willem A / Haks, Mariëlle C

Investigative ophthalmology & visual science

2018 Volume 59, Issue 3, Page(s) 1384–1395

Abstract: Purpose: Mycobacterium tuberculosis (Mtb) bacilli have been found in retinal pigment epithelial (RPE) cells from uveitis patients without signs of systemic tuberculosis (TB) infection. RPE cells are important for ocular immune privilege and uveitis ... ...

Abstract	Purpose: Mycobacterium tuberculosis (Mtb) bacilli have been found in retinal pigment epithelial (RPE) cells from uveitis patients without signs of systemic tuberculosis (TB) infection. RPE cells are important for ocular immune privilege and uveitis development. Methods: To address a potential role for Mtb-infected RPE cells in the development of uveitis, we delineated the response to Mtb infection in human RPE cells and primary human macrophages, the main target cell of Mtb. Primary human RPE cells, the human RPE cell line ARPE-19, and monocyte-derived proinflammatory M1 and anti-inflammatory M2 macrophages were infected with DsRed-expressing Mtb strain H37Rv. Infection rates and clearance were addressed along with RNA sequencing analysis, a confirmation analysis by dual-color reverse-transcriptase multiplex ligation-dependent probe amplification (dcRT-MLPA) and cytokine secretion. Results: RPE cells robustly controlled intracellular outgrowth of Mtb early after infection. The response in RPE cells to control Mtb survival was dominated by interferon (IFN) signaling and further characterized by prominent regulation of cell death/survival-associated genes and low-level production of Th1-associated cytokines. In contrast, macrophages engaged a plethora of responses including IFN signaling and communication between innate and adaptive immune cells to induce granuloma formation. Conclusions: Together, our data demonstrate that RPE cells display a strong response to Mtb infection that appears, however, incomplete in comparison to the macrophage response to Mtb. The RPE response might reflect a balance between mechanisms aimed at Mtb eradication and mechanisms that limit retinal inflammation.
MeSH term(s)	Cells, Cultured ; Cytokines/metabolism ; Epithelial Cells/physiology ; Host-Pathogen Interactions/immunology ; Humans ; Interferon-gamma/metabolism ; Macrophage Activation ; Macrophages/immunology ; Macrophages/microbiology ; Mycobacterium tuberculosis/growth & development ; Mycobacterium tuberculosis/immunology ; Retinal Pigment Epithelium/cytology ; Retinal Pigment Epithelium/immunology ; Retinal Pigment Epithelium/microbiology ; Signal Transduction/physiology ; Tuberculosis, Ocular/immunology ; Tuberculosis, Ocular/microbiology ; Uveitis/microbiology
Chemical Substances	Cytokines ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2018-02-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.17-23246
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Zs.A 45: Show issues

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Article ; Online: Host Gene Expression Kinetics During Treatment of Tuberculosis in HIV-Coinfected Individuals Is Independent of Highly Active Antiretroviral Therapy.

Gebremicael, Gebremedhin / Kassa, Desta / Quinten, Edwin / Alemayehu, Yodit / Gebreegziaxier, Atsbeha / Belay, Yohannes / van Baarle, Debbie / Ottenhoff, Tom H M / Cliff, Jacqueline M / Haks, Mariëlle C

The Journal of infectious diseases

2018 Volume 218, Issue 11, Page(s) 1833–1846

Abstract: Background: Limitations in diagnostic tools to discriminate between active tuberculosis and latent Mycobacterium tuberculosis infection and for monitoring antituberculosis treatment responses are major challenges in tuberculosis control, especially in ... ...

Abstract	Background: Limitations in diagnostic tools to discriminate between active tuberculosis and latent Mycobacterium tuberculosis infection and for monitoring antituberculosis treatment responses are major challenges in tuberculosis control, especially in human immunodeficiency virus (HIV)-coinfected individuals. Methods: Expression levels of 105 immune-related genes were determined in 131 HIV-infected patients with active tuberculosis (n = 48), patients with latent M. tuberculosis infection (LTBI; n = 37), and controls with no M. tuberculosis infection (n = 46) in Addis Ababa, Ethiopia, using focused gene expression profiling with a dual-color reverse-transcription multiplex ligation-dependent probe amplification assay. Results: Within the cohort of HIV-positive subjects, the expression profiles of 7 genes at baseline (FCGR1A, RAB24, TLR1, TLR4, MMP9, NLRC4, and IL1B) could accurately discriminate between active tuberculosis and both latent and no M. tuberculosis infection, largely independently of (in)eligibility for highly active antiretroviral therapy (HAART). Six months after antituberculosis treatment, biomarker profiles of patients with tuberculosis became indistinguishable from those of patients with LTBI and controls. Importantly, host gene expression kinetics during antituberculosis treatment in HIV-coinfected individuals was found to be independent of HAART use. Conclusions: Blood transcriptomic profiles can potentially be used as biomarkers to discriminate the different clinical stages of tuberculosis in HIV-coinfected individuals and to monitor tuberculosis treatment responses in both HAART recipients and untreated individuals.
MeSH term(s)	Adult ; Anti-HIV Agents/therapeutic use ; Antiretroviral Therapy, Highly Active/statistics & numerical data ; Biomarkers/analysis ; Coinfection/genetics ; Coinfection/immunology ; Cytokines/analysis ; Cytokines/genetics ; Cytokines/metabolism ; Female ; HIV Infections/complications ; HIV Infections/drug therapy ; HIV Infections/genetics ; HIV Infections/immunology ; Humans ; Longitudinal Studies ; Male ; Transcriptome/genetics ; Transcriptome/immunology ; Tuberculosis/complications ; Tuberculosis/genetics ; Tuberculosis/immunology ; Young Adult
Chemical Substances	Anti-HIV Agents ; Biomarkers ; Cytokines
Language	English
Publishing date	2018-07-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiy404
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Article ; Online: Host Immune Responses Differ between M. africanum- and M. tuberculosis-Infected Patients following Standard Anti-tuberculosis Treatment.

Tientcheu, Leopold D / Haks, Mariëlle C / Agbla, Schadrac C / Sutherland, Jayne S / Adetifa, Ifedayo M / Donkor, Simon / Quinten, Edwin / Daramy, Mohammed / Antonio, Martin / Kampmann, Beate / Ottenhoff, Tom H M / Dockrell, Hazel M / Ota, Martin O

PLoS neglected tropical diseases

2016 Volume 10, Issue 5, Page(s) e0004701

Abstract: Epidemiological differences exist between Mycobacterium africanum (Maf)- and Mycobacterium tuberculosis (Mtb)-infected patients, but to date, contributing host factors have not been characterised. We analysed clinical outcomes, as well as soluble markers ...

Abstract	Epidemiological differences exist between Mycobacterium africanum (Maf)- and Mycobacterium tuberculosis (Mtb)-infected patients, but to date, contributing host factors have not been characterised. We analysed clinical outcomes, as well as soluble markers and gene expression profiles in unstimulated, and ESAT6/CFP-10-, whole-Maf- and Mtb-stimulated blood samples of 26 Maf- and 49 Mtb-HIV-negative tuberculosis patients before, and after 2 and 6 months of anti-tuberculosis therapy. Before treatment, both groups had similar clinical parameters, but differed in few cytokines concentration and gene expression profiles. Following treatment the body mass index, skinfold thickness and chest X-ray scores showed greater improvement in the Mtb- compared to Maf-infected patients, after adjusting for age, sex and ethnicity (p = 0.02; 0.04 and 0.007, respectively). In addition, in unstimulated blood, IL-12p70, IL12A and TLR9 were significantly higher in Maf-infected patients, while IL-15, IL-8 and MIP-1α were higher in Mtb-infected patients. Overnight stimulation with ESAT-6/CFP-10 induced significantly higher levels of IFN-γ and TNF-α production, as well as gene expression of CCL4, IL1B and TLR4 in Mtb- compared to Maf-infected patients. Our study confirms differences in clinical features and immune genes expression and concentration of proteins associated with inflammatory processes between Mtb- and Maf-infected patients following anti-tuberculosis treatment These findings have public health implications for treatment regimens, and biomarkers for tuberculosis diagnosis and susceptibility.
MeSH term(s)	Adolescent ; Adult ; Aged ; Antigens, Bacterial/immunology ; Antitubercular Agents/therapeutic use ; Biomarkers/blood ; Cytokines/blood ; Female ; Gambia ; Gene Expression ; Host-Pathogen Interactions ; Humans ; Interferon-gamma/blood ; Interleukin-5/blood ; Interleukin-8/blood ; Male ; Middle Aged ; Mycobacterium/drug effects ; Mycobacterium/immunology ; Mycobacterium/isolation & purification ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/immunology ; Mycobacterium tuberculosis/isolation & purification ; Tuberculosis/drug therapy ; Tuberculosis/ethnology ; Tuberculosis/immunology ; Tuberculosis/microbiology ; Tumor Necrosis Factor-alpha/drug effects ; Young Adult
Chemical Substances	Antigens, Bacterial ; Antitubercular Agents ; Biomarkers ; Cytokines ; ESAT-6 antigen, Mycobacterium leprae ; IL5 protein, human ; Interleukin-5 ; Interleukin-8 ; Tumor Necrosis Factor-alpha ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2016-05-18
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2735
ISSN (online)	1935-2735
ISSN	1935-2735
DOI	10.1371/journal.pntd.0004701
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Article ; Online: A dose-dependent plasma signature of the safety and immunogenicity of the rVSV-Ebola vaccine in Europe and Africa.

Huttner, Angela / Combescure, Christophe / Grillet, Stéphane / Haks, Mariëlle C / Quinten, Edwin / Modoux, Christine / Agnandji, Selidji Todagbe / Brosnahan, Jessica / Dayer, Julie-Anne / Harandi, Ali M / Kaiser, Laurent / Medaglini, Donata / Monath, Tom / Roux-Lombard, Pascale / Kremsner, Peter G / Ottenhoff, Tom H M / Siegrist, Claire-Anne

Science translational medicine

2017 Volume 9, Issue 385

Abstract: The 2014-2015 Ebola epidemic affected several African countries, claiming more than 11,000 lives and leaving thousands with ongoing sequelae. Safe and effective vaccines could prevent or limit future outbreaks. The recombinant vesicular stomatitis virus- ... ...

Abstract	The 2014-2015 Ebola epidemic affected several African countries, claiming more than 11,000 lives and leaving thousands with ongoing sequelae. Safe and effective vaccines could prevent or limit future outbreaks. The recombinant vesicular stomatitis virus-vectored Zaire Ebola (rVSV-ZEBOV) vaccine has shown marked immunogenicity and efficacy in humans but is reactogenic at higher doses. To understand its effects, we examined plasma samples from 115 healthy volunteers from Geneva who received low-dose (LD) or high-dose (HD) vaccine or placebo. Fifteen plasma chemokines/cytokines were assessed at baseline and on days 1, 2 to 3, and 7 after injection. Significant increases in monocyte-mediated MCP-1/CCL2, MIP-1β/CCL4, IL-6, TNF-α, IL-1Ra, and IL-10 occurred on day 1. A signature explaining 68% of cytokine/chemokine vaccine-response variability was identified. Its score was higher in HD versus LD vaccinees and was associated positively with vaccine viremia and negatively with cytopenia. It was higher in vaccinees with injection-site pain, fever, myalgia, chills, and headache; higher scores reflected increasing severity. In contrast, HD vaccinees who subsequently developed arthritis had lower day 1 scores than other HD vaccinees. Vaccine dose did not influence the signature despite its influence on specific outcomes. The Geneva-derived signature associated strongly (ρ = 0.97) with that of a cohort of 75 vaccinees from a parallel trial in Lambaréné, Gabon. Its score in Geneva HD vaccinees with subsequent arthritis was significantly lower than that in Lambaréné HD vaccinees, none of whom experienced arthritis. This signature, which reveals monocytes' critical role in rVSV-ZEBOV immunogenicity and safety across doses and continents, should prove useful in assessments of other vaccines.
MeSH term(s)	Africa ; Ebola Vaccines/adverse effects ; Ebola Vaccines/immunology ; Europe ; Female ; Hemorrhagic Fever, Ebola/blood ; Hemorrhagic Fever, Ebola/immunology ; Humans ; Macrophages/metabolism ; Male
Chemical Substances	Ebola Vaccines
Language	English
Publishing date	2017-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.aaj1701
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