17 results on '"Lena Wehlin"'
Search Results
2. A phase I clinical study of a live attenuated Bordetella pertussis vaccine--BPZE1; a single centre, double-blind, placebo-controlled, dose-escalating study of BPZE1 given intranasally to healthy adult male volunteers.
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Rigmor Thorstensson, Birger Trollfors, Nabil Al-Tawil, Maja Jahnmatz, Jakob Bergström, Margaretha Ljungman, Anna Törner, Lena Wehlin, Annie Van Broekhoven, Fons Bosman, Anne-Sophie Debrie, Nathalie Mielcarek, and Camille Locht
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Medicine ,Science - Abstract
Acellular pertussis vaccines do not control pertussis. A new approach to offer protection to infants is necessary. BPZE1, a genetically modified Bordetella pertussis strain, was developed as a live attenuated nasal pertussis vaccine by genetically eliminating or detoxifying 3 toxins.We performed a double-blind, placebo-controlled, dose-escalating study of BPZE1 given intranasally for the first time to human volunteers, the first trial of a live attenuated bacterial vaccine specifically designed for the respiratory tract. 12 subjects per dose group received 10³, 10⁵ or 10⁷ colony-forming units as droplets with half of the dose in each nostril. 12 controls received the diluent. Local and systemic safety and immune responses were assessed during 6 months, and nasopharyngeal colonization with BPZE1 was determined with repeated cultures during the first 4 weeks after vaccination.Colonization was seen in one subject in the low dose, one in the medium dose and five in the high dose group. Significant increases in immune responses against pertussis antigens were seen in all colonized subjects. There was one serious adverse event not related to the vaccine. Other adverse events were trivial and occurred with similar frequency in the placebo and vaccine groups.BPZE1 is safe in healthy adults and able to transiently colonize the nasopharynx. It induces immune responses in all colonized individuals. BPZE1 can thus undergo further clinical development, including dose optimization and trials in younger age groups.ClinicalTrials.gov NCT01188512.
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- 2014
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3. rBCG induces strong antigen-specific T cell responses in rhesus macaques in a prime-boost setting with an adenovirus 35 tuberculosis vaccine vector.
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Isabelle Magalhaes, Donata R Sizemore, Raija K Ahmed, Stefanie Mueller, Lena Wehlin, Charles Scanga, Frank Weichold, Giulia Schirru, Maria Grazia Pau, Jaap Goudsmit, Sharon Kühlmann-Berenzon, Mats Spångberg, Jan Andersson, Hans Gaines, Rigmor Thorstensson, Yasir A W Skeiky, Jerry Sadoff, and Markus Maeurer
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Medicine ,Science - Abstract
BACKGROUND: BCG vaccination, combined with adenoviral-delivered boosts, represents a reasonable strategy to augment, broaden and prolong immune protection against tuberculosis (TB). We tested BCG (SSI1331) (in 6 animals, delivered intradermally) and a recombinant (rBCG) AFRO-1 expressing perfringolysin (in 6 animals) followed by two boosts (delivered intramuscullary) with non-replicating adenovirus 35 (rAd35) expressing a fusion protein composed of Ag85A, Ag85B and TB10.4, for the capacity to induce antigen-specific cellular immune responses in rhesus macaques (Macaca mulatta). Control animals received diluent (3 animals). METHODS AND FINDINGS: Cellular immune responses were analyzed longitudinally (12 blood draws for each animal) using intracellular cytokine staining (TNF-alpha, IL-2 and IFN-gamma), T cell proliferation was measured in CD4(+), CD8alpha/beta(+), and CD8alpha/alpha(+) T cell subsets and IFN-gamma production was tested in 7 day PBMC cultures (whole blood cell assay, WBA) using Ag85A, Ag85B, TB10.4 recombinant proteins, PPD or BCG as stimuli. Animals primed with AFRO-1 showed i) increased Ag85B-specific IFN-gamma production in the WBA assay (median >400 pg/ml for 6 animals) one week after the first boost with adenoviral-delivered TB-antigens as compared to animals primed with BCG (
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- 2008
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4. Safety and immunogenicity of the live attenuated intranasal pertussis vaccine BPZE1: a phase 1b, double-blind, randomised, placebo-controlled dose-escalation study
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Alex Assuied, Izabella Zarea, Loïc Coutte, Ken Solovay, Jann Storsaeter, Delphine Jean, Keith Rubin, Åsa Linde, Claire Bauduin, Sonia Gueguen, Nina Ekholm, Dominique Raze, Teghesti Tecleab, Erla Sigurdardottir, Noémie Mercier, Laetitia Moinot, Margaretha Ljungman, Margareta Gustafsson, Florence Allais, Cecilia Lång, Nathalie Mielcarek, Gabrielle Derocle, Eva Hanson Pihlainen, Inga-Lill Reinholdsson, Marcel Thalen, Cédrick Wallet, Camille Locht, Philippe Reboud, Nabil Al-Tawil, Geneviève Chêne, Hélène Espérou, Alpha Diallo, Maja Jahnmatz, Ludivine Taïeb, Emilie Rousseau, Teodora Aktas, Fabien Le Marec, Camille Gilbert, Ingrid Andersson, Céline Colin, Céline Roy, Christine Schwimmer, Maria Nastase, Lena Dager, Maj Ringman, Rigmor Thorstensson, Anne-Sophie Debrie, Lena Wehlin, Anneli Wahlberg, Claire Lévy-Marchal, Laura Richert, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biophotonique et Pharmacologie - UMR 7213 (LBP), Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), BPZE1 study team : Lena Dager, Nina Ekholm, Margareta Gustafsson, Åsa Linde, Cecilia Lång, Maria Nastase, Inga-Lill Reinholdsson, Erla Sigurdardottir, Anneli Wahlberg, Izabella Zarea, Teodora Aktas, Ingrid Andersson, Eva Hanson Pihlainen, Margaretha Ljungman, Maj Ringman, Teghesti Tecleab, Lena Wehlin, Florence Allais, Alex Assuied, Geneviève Chêne, Camille Gilbert, Delphine Jean, Fabien Le Marec, Laetitia Moinot, Philippe Reboud, Emilie Rousseau, Céline Roy, Christine Schwimmer, Ludivine Taïeb, Cédrick Wallet, Gabrielle Derocle, Sonia Gueguen, Claire Lévy-Marchal, Hélène Esperou, Anne-Sophie Debrie, Dominique Raze, Loïc Coutte, Alpha Diallo, Noémie Mercier., CCSD, Accord Elsevier, Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA)), Epidémiologie et Biostatistique [Bordeaux], and Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Whooping Cough ,[SDV]Life Sciences [q-bio] ,Booster dose ,Nasal congestion ,Vaccines, Attenuated ,Placebo ,Bordetella pertussis ,Herd immunity ,Young Adult ,03 medical and health sciences ,Immunogenicity, Vaccine ,0302 clinical medicine ,[SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Adverse effect ,Administration, Intranasal ,Pertussis Vaccine ,Antigens, Bacterial ,business.industry ,Immunogenicity ,Vaccination ,Healthy Volunteers ,Immunoglobulin A ,3. Good health ,SISTM ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,Infectious Diseases ,Immunoglobulin G ,Pertussis vaccine ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,medicine.symptom ,[SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology ,business ,Follow-Up Studies ,medicine.drug - Abstract
Summary Background Long-term protection and herd immunity induced by existing pertussis vaccines are imperfect, and a need therefore exists to develop new pertussis vaccines. This study aimed to investigate the safety, colonisation, and immunogenicity of the new, live attenuated pertussis vaccine, BPZE1, when given intranasally. Methods This phase 1b, double-blind, randomised, placebo-controlled, dose-escalation study was done at the phase 1 unit, Karolinska Trial Alliance, Karolinska University Hospital, Stockholm, Sweden. Healthy adults (18–32 years) were screened and included sequentially into three groups of increasing BPZE1 dose strength (107 colony-forming units [CFU], 108 CFU, and 109 CFU), and were randomly assigned (3:1 within each group) to receive vaccine or placebo. Vaccine and placebo were administered in phosphate-buffered saline contained 5% saccharose as 0·4 mL in each nostril. The primary outcome was solicited and unsolicited adverse events between day 0 and day 28. The analysis included all randomised participants who received a vaccine dose. Colonisation with BPZE1 was determined by repeatedly culturing nasopharyngeal aspirates at day 4, day 7, day 11, day 14, day 21, and day 28 after vaccination. Immunogenicity, as serum IgG and IgA responses were assessed at day 0, day 7, day 14, day 21, day 28, 6 months, and 12 months after vaccination. This trial is registered at Clinicaltrials.gov , NCT02453048 . Findings Between Sept 1, 2015, and Feb 3, 2016, 120 participants were assessed for eligibility, 48 of whom were enrolled and randomly assigned (3:1) to receive vaccine or placebo, with 12 participants each in a low-dose, medium-dose, and high-dose vaccine group. Adverse events between day 0 and day 28 were reported by one (8%, 95% CI 0–39) of 12 participants in both the placebo and low-dose groups, and two (17%; 2–48) of 12 participants in both the medium-dose and high-dose groups, including cough of grade 2 or more, oropharyngeal pain, and rhinorrhoea and nasal congestion. During this time, none of the participants experienced any spasmodic cough, difficulties in breathing, or adverse events following immunisation concerning vital signs. The tested doses of BPZE1 or placebo were well tolerated, with no apparent difference in solicited or unsolicited adverse events following immunisation between groups. Colonisation at least once after vaccination was observed in 29 (81%; 68–93) of 36 vaccinated participants. The tested vaccine doses were immunogenic, with increases in serum IgG and IgA titres against the four B pertussis antigens from baseline to 12 months. Interpretation The tested vaccine was safe, induced a high colonisation rate in an adult population, and was immunogenic at all doses. These findings justify further clinical development of BPZE1 to ultimately be used as a priming vaccine for neonates or a booster vaccine for adolescents and adults, or both. Funding ILiAD Biotechnologies.
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- 2020
5. Pertussis seroprevalence among adults of reproductive age (20–39 years) in fourteen European countries
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Waldemar Rastawicki, H. O. Hallander, Kris Huygen, Julie Haider, Arno Hänninen, Evi Petridou, Sabrina Bacci, Clara M. Ausiello, Margaretha Ljungman, Fernando de Ory Manchón, Tine Dalby, Vilnele Lipnickiene, Lena Wehlin, Sharon Kühlmann-Berenzon, Tove Karin Herstad, Audun Aase, Zsuzsanna Molnár, Carla Rio, Alex-Mikael Barkoff, Qiushui He, Ilias Galanis, Odette Popovici, Denis Pierard, Maria Carollo, Supporting clinical sciences, Microbiology and Infection Control, and Clinical Biology
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Adult ,Male ,Microbiology (medical) ,Veterinary medicine ,Bordetella pertussis ,Vaccination Coverage ,Whooping Cough ,Reproductive age ,Pertussis toxin ,Europe/epidemiology ,Whooping Cough/epidemiology ,Pathology and Forensic Medicine ,Young Adult ,Elisa kit ,Age groups ,Seroepidemiologic Studies ,Humans ,Immunology and Allergy ,Medicine ,Seroprevalence ,Medicine(all) ,biology ,business.industry ,Incidence ,Incidence (epidemiology) ,Antibodies, Bacterial/blood ,General Medicine ,biology.organism_classification ,Antibodies, Bacterial ,Vaccination Coverage/statistics & numerical data ,Europe ,Vaccination ,Immunoglobulin G/blood ,Immunoglobulin G ,Female ,business ,Bordetella pertussis/immunology - Abstract
The reported incidence of pertussis in European countries varies considerably. We aimed to study specific Bordetella pertussis seroprevalence in Europe by measuring serum IgG antibody levels to pertussis toxin (anti-PT IgG). Fourteen national laboratories participated in this study including Belgium, Denmark, Finland, Greece, Hungary, Italy, Lithuania, Malta, Norway, Poland, Portugal, Romania, Spain, and Sweden. Each country collected approximately 250 samples (N = 7903) from the age groups 20-29 years (N = 3976) and 30-39 years (N = 3927) during 2010-2013. Samples were anonymous residual sera from diagnostic laboratories and were analyzed at the national laboratories by a Swedish reference method, a commercial ELISA kit, or were sent to Sweden for analysis. The median anti-PT IgG concentrations ranged from 4 to 13.6 IU/mL. The proportion of samples with anti-PT IgG ≥100 IU/mL, indicating a recent infection ranged from 0.2% (Hungary) to 5.7% (Portugal). The highest proportion of sera with anti-PT IgG levels between 50 and
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- 2021
6. Widespread circulation of pertussis and poor protection against diphtheria among middle-aged adults in 18 European countries
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Guy Berbers, Pieter van Gageldonk, Jan van de Kassteele, Ursula Wiedermann, Isabelle Desombere, Tine Dalby, Julie Toubiana, Sotirios Tsiodras, Ildiko Paluska Ferencz, Kathryn Mullan, Algirdas Griskevicius, Tatjana Kolupajeva, Didrik Frimann Vestrheim, Paula Palminha, Odette Popovici, Lena Wehlin, Tamara Kastrin, Lucia Maďarová, Helen Campbell, Csaba Ködmön, Sabrina Bacci, Alex-Mikael Barkoff, and Qiushui He
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complex mixtures - Abstract
Reported incidence of pertussis in member states of the European Union (EU) and the European Economic Area (EEA) varies and may not reflect the real situation. In the EU/EEA, vaccine-induced protection against diphtheria and tetanus seems sufficient as few cases are reported even among the adult population who was vaccinated many years ago. Aim of this study was to determine the seroprevalence of pertussis, diphtheria and tetanus antibodies in EU/EEA countries within the age groups of 40-49 and 50-59 years. Eighteen countries collected around 500 samples between 2015 and 2018 (N=10,302 in total) and they were analysed for IgG-specific antibodies against pertussis toxin (PT), diphtheria toxoid (Dt) and tetanus toxin (TT). The proportion of sera with IgG-PT antibody levels ≥100 IU/mL, indicative for recent pertussis infection was comparable for 13/18 countries ranging between 4.0-6.4%. For diphtheria the proportion of sera lacking the protective level (
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- 2020
7. Pertactin-deficient Bordetella pertussis isolates
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Alex-Mikael Barkoff, Qiushui He, Tine Dalby, Margaretha Ljungman, Marjolein van Gent, Guy A. M. Berbers, Kevin Markey, Margrethe Greve-Isdahl, Denis Pierard, Jussi Mertsola, Silje Vermedal Hoegh, Lena Wehlin, Didrik F. Vestrheim, Norman K. Fry, Paola Stefanelli, Sophie Guillot, Supporting clinical sciences, Microbiology and Infection Control, and Clinical Biology
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0301 basic medicine ,Bordetella pertussis ,Time Factors ,Whooping Cough ,Epidemiology ,030106 microbiology ,Fimbria ,Enzyme-Linked Immunosorbent Assay ,Acellular pertussis vaccines ,Pertussis toxin ,pertactin ,Microbiology ,03 medical and health sciences ,Vaccines, Acellular ,0302 clinical medicine ,Virology ,Humans ,Virulence Factors, Bordetella ,030212 general & internal medicine ,Pertussis Vaccine ,Antigens, Bacterial ,High prevalence ,biology ,Research ,pertussis ,Public Health, Environmental and Occupational Health ,Outbreak ,biology.organism_classification ,Europe ,Pertussis Toxin ,acellular vaccine ,vaccination, Europe ,Pertactin ,Bacterial Outer Membrane Proteins - Abstract
Introduction Pertussis outbreaks have occurred in several industrialised countries using acellular pertussis vaccines (ACVs) since the 1990s. High prevalence of pertactin (PRN)-deficient Bordetella pertussis isolates has been found in these countries. Aims To evaluate in Europe: (i) whether proportions of PRN-deficient strains increased in consecutive collections of B. pertussis clinical isolates; (ii) if the frequency of PRN-deficient strains in countries correlated with the time since ACV introduction; (iii) the presence of pertussis toxin (PT)-, filamentous haemagglutinin (FHA)- or fimbriae (Fim)-deficient isolates. Methods B. pertussis clinical isolates were obtained from different European countries during four periods (EUpert I–IV studies): 1998 to 2001 (n = 102), 2004 to 2005 (n = 154), 2007 to 2009 (n = 140) and 2012 to 2015 (n = 265). The isolates’ selection criteria remained unchanged in all periods. PRN, PT, FHA and Fim2 and Fim3 expression were assessed by ELISA. Results In each period 1.0% (1/102), 1.9% (3/154), 6.4% (9/140) and 24.9% (66/265) of isolates were PRN-deficient. In EUpert IV, PRN-deficient isolates occurred in all countries sampled and in six countries their frequency was higher than in EUpert III (for Sweden and the United Kingdom, p Conclusion Results suggest that the longer the period since the introduction of ACVs containing PRN, the higher the frequency of circulating PRN-deficient isolates.
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- 2019
8. Surveillance of Circulating Bordetella pertussis Strains in Europe during 1998 to 2015
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Paola Stefanelli, Silje Vermedal Hoegh, Qiushui He, Lena Wehlin, Marjolein van Gent, Jussi Mertsola, Sophie Guillot, Kari Auranen, Margrethe Greve-Isdahl, Norman K. Fry, Didrik F. Vestrheim, Margaretha Ljungman, Alex-Mikael Barkoff, Denis Pierard, Guy A. M. Berbers, Kevin Markey, Tine Dalby, Supporting clinical sciences, Microbiology and Infection Control, and Clinical Biology
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DNA, Bacterial ,0301 basic medicine ,Microbiology (medical) ,Serotype ,Genotyping ,Bordetella pertussis ,Genotype ,Whooping Cough ,030106 microbiology ,Population ,Bordetella pertussis/genetics ,Multiple Loci VNTR Analysis ,Serogroup ,Whooping Cough/epidemiology ,Europe/epidemiology ,Microbiology ,Pertussis Vaccine/immunology ,03 medical and health sciences ,Journal Article ,medicine ,Pulsed-field gel electrophoresis ,Humans ,Serotyping ,education ,Whooping cough ,Pertussis Vaccine ,education.field_of_study ,biology ,MLVA ,Genetic Variation ,Bacteriology ,Genome, Bacterial/genetics ,Sequence Analysis, DNA ,PFGE ,medicine.disease ,biology.organism_classification ,Molecular Typing ,Europe ,DNA, Bacterial/genetics ,Genes, Bacterial ,Epidemiological Monitoring ,Genes, Bacterial/genetics ,Pertussis vaccine ,Genome, Bacterial ,medicine.drug - Abstract
One reason for increased pertussis incidence is the adaptation of Bordetella pertussis to vaccine-induced immunity by modulating its genomic structure. This study, EUpert IV, includes 265 isolates collected from nine European countries during 2012 to 2015 ( n = 265) and compares the results to previous EUpert I to III studies (1998 to 2009). The analyses included genotyping, serotyping, pulsed-field gel electrophoresis (PFGE), and multilocus variable-number tandem-repeat analysis (MLVA). Genotyping results showed only small variations among the common virulence genes of B. pertussis . The frequencies of serotypes Fim2 and Fim3 varied among the four collections. Genomic analyses showed that MLVA type 27 increased to 80% between the periods of 1998 to 2001 and 2012 to 2015. Two PFGE profiles, BpSR3 (29.4%) and BpSR10 (27.2%), constituted more than 50% of the circulating isolates in the present collection. Our study indicates that the European B. pertussis population is changing and became more homogenous after the introduction of acellular pertussis vaccines.
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- 2018
9. Activation of complement and leukocyte receptors during on- and off pump coronary artery bypass surgery
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Joachim Lundahl, Jenny Vedin, Lena Wehlin, and Jarle Vaage
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Male ,Pulmonary and Respiratory Medicine ,Extracorporeal Circulation ,medicine.medical_specialty ,medicine.medical_treatment ,Inflammation ,Neutrophil Activation ,Leukocyte Count ,Surgical anastomosis ,Humans ,Medicine ,Prospective Studies ,Derivation ,Coronary Artery Bypass ,Complement Activation ,Aged ,Off-pump coronary artery bypass ,Receptors, Leukocyte-Adhesion ,biology ,business.industry ,Interleukins ,Extracorporeal circulation ,Complement C5 ,Interleukin ,General Medicine ,Middle Aged ,Flow Cytometry ,Surgery ,Complement system ,Eosinophils ,Integrin alpha M ,biology.protein ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Objective: The aim of this prospective, randomised study was to investigate the influence of extracorporeal circulation on the inflammatory response, our hypothesis being that off pump coronary artery bypass grafting (OFFCAB) procedures would generate less activation than on pump procedures (ONCAB). Methods: Patients admitted for elective CABG were randomised to either ONCAB or OFFCAB surgery and blood samples were taken during and up to 24 h after the operation. We measured complement factors C5a and the terminal complement complex (TCC, C59-b), and the interleukins IL-6 and IL-8. Leukocytes were studied for cellular counts and adhesion molecules (CD11b, CD35 and CD62L) by flow cytometry. We included a combination of activity markers with different aspects of neutrophil function and combined these with in vitro activation. Results: The complement factors C5a and TCC showed a more rapid (P ¼ 0:02, P , 0:001) and TCC a more profound (P , 0:001) increase in the ONCAB group than in the OFFACB group during the operation, after that there were no inter-group differences. Cellular markers, cell counts and interleukin levels were activated by surgery but with no difference between groups. Conclusion: This prospective, randomised study showed less complement activation in low risk OFFCAB, compared to ONCAB patients. q 2003 Elsevier B.V. All rights reserved.
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- 2004
10. B-cell responses after intranasal vaccination with the novel attenuated Bordetella pertussis vaccine strain BPZE1 in a randomized phase I clinical trial
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Nathalie Mielcarek, Rigmor Thorstensson, Lena Wehlin, Sylvie Amu, Camille Locht, Maja Jahnmatz, Francesca Chiodi, and Margaretha Ljungman
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Male ,Bordetella pertussis ,Whooping Cough ,0302 clinical medicine ,Medicine ,BPZE1 ,Pertussis Vaccine ,0303 health sciences ,B-Lymphocytes ,biology ,ELISPOT ,Antibodies, Bacterial ,3. Good health ,Vaccination ,Infectious Diseases ,Molecular Medicine ,Pertactin ,medicine.drug ,Adult ,Plasma Cells ,B-Lymphocyte Subsets ,Pertussis toxin ,Vaccines, Attenuated ,03 medical and health sciences ,Antigen ,Pertussis ,Immunology and Microbiology(all) ,Humans ,Administration, Intranasal ,030304 developmental biology ,B cells ,General Veterinary ,General Immunology and Microbiology ,business.industry ,Public Health, Environmental and Occupational Health ,biology.organism_classification ,Virology ,veterinary(all) ,Live attenuated nasal vaccine ,Novel human vaccine ,Immunoglobulin G ,Immunology ,Antibody Formation ,Phase I clinical trial ,Pertussis vaccine ,Nasal administration ,business ,Immunologic Memory ,030215 immunology - Abstract
Despite high vaccination coverage, pertussis is still a global concern in infant morbidity and mortality, and improved pertussis vaccines are needed. A live attenuated Bordetella pertussis strain, named BPZE1, was designed as an intranasal vaccine candidate and has recently been tested in man in a phase I clinical trial. Here, we report the evaluation of the B-cell responses after vaccination with BPZE1. Forty-eight healthy males with no previous pertussis-vaccination were randomized into one of three dose-escalating groups or into a placebo group. Plasma blast- and memory B-cell responses were evaluated by ELISpot against three different pertussis antigens: pertussis toxin, filamentous haemagglutinin and pertactin. Seven out of the 36 subjects who had received the vaccine were colonized by BPZE1, and significant increases in the memory B-cell response were detected against all three tested antigens in the culture-positive subjects between days 0 and 28 post-vaccination. The culture-positive subjects also mounted a significant increase in the filamentous haemagglutinin-specific plasma blast response between days 7 and 14 post-vaccination. No response could be detected in the culture-negatives or in the placebo group post-vaccination. These data show that BPZE1 is immunogenic in humans and is therefore a promising candidate for a novel pertussis vaccine. This trial is registered at ClinicalTrials.gov (NCT01188512).
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- 2014
11. A Phase I Clinical Study of a Live Attenuated Bordetella pertussis Vaccine - BPZE1; A Single Centre, Double-Blind, Placebo-Controlled, Dose-Escalating Study of BPZE1 Given Intranasally to Healthy Adult Male Volunteers
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Anna Törner, Birger Trollfors, Rigmor Thorstensson, Nabil Al-Tawil, Fons Bosman, Maja Jahnmatz, Nathalie Mielcarek, Margaretha Ljungman, Annie Van Broekhoven, Anne-Sophie Debrie, Lena Wehlin, Jakob Bergström, and Camille Locht
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Bacterial Diseases ,Male ,Bordetella pertussis ,Whooping Cough ,Colony Count, Microbial ,lcsh:Medicine ,Placebos ,0302 clinical medicine ,Clinical trials ,Nasopharynx ,Medicine ,030212 general & internal medicine ,lcsh:Science ,Immune Response ,Pertussis Vaccine ,0303 health sciences ,Vaccines ,Multidisciplinary ,Attenuated vaccine ,biology ,Vaccination ,Healthy Volunteers ,3. Good health ,Bacterial Pathogens ,Bacterial vaccine ,Infectious Diseases ,medicine.drug ,Research Article ,Adult ,Infectious Disease Control ,Dose-Response Relationship, Immunologic ,Vaccines, Attenuated ,Microbiology ,03 medical and health sciences ,Young Adult ,Phase I ,Pertussis ,Double-Blind Method ,Vaccine Development ,Humans ,Adverse effect ,Biology ,Whooping cough ,Administration, Intranasal ,030304 developmental biology ,Demography ,business.industry ,lcsh:R ,Immunity ,medicine.disease ,biology.organism_classification ,Immunoglobulin G ,Immunology ,Pertussis vaccine ,lcsh:Q ,Nasal administration ,Clinical Immunology ,business ,Clinical research design - Abstract
Background Acellular pertussis vaccines do not control pertussis. A new approach to offer protection to infants is necessary. BPZE1, a genetically modified Bordetella pertussis strain, was developed as a live attenuated nasal pertussis vaccine by genetically eliminating or detoxifying 3 toxins. Methods We performed a double-blind, placebo-controlled, dose-escalating study of BPZE1 given intranasally for the first time to human volunteers, the first trial of a live attenuated bacterial vaccine specifically designed for the respiratory tract. 12 subjects per dose group received 103, 105 or 107 colony-forming units as droplets with half of the dose in each nostril. 12 controls received the diluent. Local and systemic safety and immune responses were assessed during 6 months, and nasopharyngeal colonization with BPZE1 was determined with repeated cultures during the first 4 weeks after vaccination. Results Colonization was seen in one subject in the low dose, one in the medium dose and five in the high dose group. Significant increases in immune responses against pertussis antigens were seen in all colonized subjects. There was one serious adverse event not related to the vaccine. Other adverse events were trivial and occurred with similar frequency in the placebo and vaccine groups. Conclusions BPZE1 is safe in healthy adults and able to transiently colonize the nasopharynx. It induces immune responses in all colonized individuals. BPZE1 can thus undergo further clinical development, including dose optimization and trials in younger age groups. Trial Registration ClinicalTrials.gov NCT01188512
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- 2014
12. High content cellular immune profiling reveals differences between rhesus monkeys and men
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Jan Andersson, Jerry Sadoff, Mats Spångberg, Markus Maeurer, Sharon Kühlmann-Berenzon, Frank Weichold, Donata Sizemore, Yasir A. W. Skeiky, Rigmor Thorstensson, Lena Wehlin, Nalini K. Vudattu, Raija K. Ahmed, Isabelle Magalhaes, Yen Ngo, and Hans Gaines
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Adult ,CD3 ,Immunology ,Population ,chemical and pharmacologic phenomena ,Biology ,T-Lymphocytes, Regulatory ,Young Adult ,Immune system ,T-Lymphocyte Subsets ,STAT5 Transcription Factor ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Humans ,IL-2 receptor ,Phosphorylation ,education ,education.field_of_study ,Immunity, Cellular ,Tumor Necrosis Factor-alpha ,Interleukin-7 ,FOXP3 ,CD28 ,hemic and immune systems ,Original Articles ,Flow Cytometry ,Macaca mulatta ,biology.protein ,Cytokines ,Female ,CD8 - Abstract
A better understanding of similarities and differences in the composition of the cellular immune system in non-human primates (NHPs) compared with human subjects will improve the interpretation of preclinical studies. It will also aid in addressing the usefulness of NHPs as subjects for studying chronic diseases, vaccine development and immune reconstitution. We employed high content colour flow cytometry and analysed simultaneously the expression of CD3, CD4, CD8alpha, CD8beta, CD16/CD56, CD45RA, CCR7, CD27, CD28, CD107a and the interleukin-7 receptor alpha-chain (IL-7Ralpha) in peripheral blood mononuclear cells (PBMCs) of 27 rhesus macaques and 16 healthy human subjects. Regulatory T cells (Tregs) were identified using anti-CD3, -CD4, -CD25, -FoxP3, and -IL-7Ralpha monoclonal antibodies. Responsiveness to IL-7 was gauged in a signal transducer and activation of transcription 5 (STAT-5) phosphorylation assay. Human and NHP PBMCs showed a similar T-cell composition pattern with some remarkable differences. Similarities: human and NHP CD4(+) and CD8(+) cells showed a similar STAT-5 phosphorylation pattern in response to IL-7. Multicolour flow cytometric analysis identified a CD4(+) CD8alphaalpha(+) CD8alphabeta(+) T-cell population in NHPs as well as in human subjects that expressed the degranulation marker CD107a and may represent a unique CD4(+) T-cell subset endowed with cytotoxic capacity. Differences: we identified in PBMCs from NHPs a higher proportion (5.16% in CD3(+) T cells) of CD8alphaalpha(+) T cells when compared with human donors (1.22% in CD3(+) T cells). NHP CD8alphaalpha(+) T cells produced tumour necrosis factor-alpha / interferon-gamma (TNF-alpha/IFN-gamma) or TNF-alpha, whereas human CD8alphaalpha(+) T cells produced simultaneously TNF-alpha/IFN-gamma and IL-2. A minor percentage of human CD8(+) T cells expressed CD25(bright) and FoxP3 (0.01%). In contrast, 0.07% of NHP CD8(+) T cells exhibited the CD25(bright) FoxP3(+) phenotype. PBMCs from NHPs showed less IL-7Ralpha-positive events in all T-cell subsets including CD4(+) Tregs (median 5%) as compared with human (median 12%). The data visualize commonalities and differences in immune cell subsets in humans and NHPs, most of them in long-lived memory cells and cells with suppressive functions. This provides a matrix to assess future efforts to study diseases and vaccines in NHPs.
- Published
- 2010
13. rBCG Induces Strong Antigen-Specific T Cell Responses in Rhesus Macaques in a Prime-Boost Setting with an Adenovirus 35 Tuberculosis Vaccine Vector
- Author
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Hans Gaines, Frank Weichold, Donata Sizemore, Raija K. Ahmed, Charles A. Scanga, Rigmor Thorstensson, Maria Grazia Pau, Jaap Goudsmit, Isabelle Magalhaes, Mats Spångberg, Sharon Kühlmann-Berenzon, Giulia Schirru, Jerry Sadoff, Stefanie Mueller, Lena Wehlin, Yasir A. W. Skeiky, Jan Andersson, Markus Maeurer, Amsterdam institute for Infection and Immunity, and General Internal Medicine
- Subjects
T-Lymphocytes ,T cell ,Immunology ,Bacterial Toxins ,Genetic Vectors ,Immunization, Secondary ,lcsh:Medicine ,Biology ,Lymphocyte Activation ,Peripheral blood mononuclear cell ,Adenoviridae ,Infectious Diseases/Bacterial Infections ,Hemolysin Proteins ,Interferon-gamma ,Immune system ,Immunology/Immunity to Infections ,medicine ,Animals ,Cytotoxic T cell ,Interferon gamma ,Tuberculosis Vaccines ,lcsh:Science ,Antigens, Bacterial ,Immunity, Cellular ,Vaccines, Synthetic ,Multidisciplinary ,Infectious Diseases/Respiratory Infections ,lcsh:R ,Macaca mulatta ,Virology ,Infectious Diseases ,medicine.anatomical_structure ,Immunology/Immune Response ,BCG Vaccine ,Female ,lcsh:Q ,Tuberculosis vaccines ,BCG vaccine ,Research Article ,Blood drawing ,medicine.drug - Abstract
BACKGROUND: BCG vaccination, combined with adenoviral-delivered boosts, represents a reasonable strategy to augment, broaden and prolong immune protection against tuberculosis (TB). We tested BCG (SSI1331) (in 6 animals, delivered intradermally) and a recombinant (rBCG) AFRO-1 expressing perfringolysin (in 6 animals) followed by two boosts (delivered intramuscullary) with non-replicating adenovirus 35 (rAd35) expressing a fusion protein composed of Ag85A, Ag85B and TB10.4, for the capacity to induce antigen-specific cellular immune responses in rhesus macaques (Macaca mulatta). Control animals received diluent (3 animals). METHODS AND FINDINGS: Cellular immune responses were analyzed longitudinally (12 blood draws for each animal) using intracellular cytokine staining (TNF-alpha, IL-2 and IFN-gamma), T cell proliferation was measured in CD4(+), CD8alpha/beta(+), and CD8alpha/alpha(+) T cell subsets and IFN-gamma production was tested in 7 day PBMC cultures (whole blood cell assay, WBA) using Ag85A, Ag85B, TB10.4 recombinant proteins, PPD or BCG as stimuli. Animals primed with AFRO-1 showed i) increased Ag85B-specific IFN-gamma production in the WBA assay (median >400 pg/ml for 6 animals) one week after the first boost with adenoviral-delivered TB-antigens as compared to animals primed with BCG (
- Published
- 2008
14. Reduced intracellular oxygen radical production in whole blood leukocytes from COPD patients and asymptomatic smokers
- Author
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Magnus Löfdahl, Joachim Lundahl, Lena Wehlin, and Magnus Sköld
- Subjects
Pulmonary and Respiratory Medicine ,Adult ,Male ,medicine.medical_specialty ,Free Radicals ,Copd patients ,Radical ,Population ,Critical Care and Intensive Care Medicine ,Asymptomatic ,Gastroenterology ,Endothelial activation ,Pulmonary Disease, Chronic Obstructive ,Internal medicine ,Forced Expiratory Volume ,medicine ,Leukocytes ,Humans ,education ,Whole blood ,Aged ,COPD ,education.field_of_study ,Singlet Oxygen ,Cell adhesion molecule ,business.industry ,Smoking ,Eosinophil ,Middle Aged ,medicine.disease ,Intercellular Adhesion Molecule-1 ,respiratory tract diseases ,Respiratory burst ,Surgery ,N-Formylmethionine Leucyl-Phenylalanine ,Oxygen ,medicine.anatomical_structure ,Immunology ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Intracellular ,Blood sampling - Abstract
Rationale and objectives: COPD is characterized by irreversible airflow obstruction. It has, however, become clear that COPD also is a systemic disease. In the present study, we sought to investigate its impact on different peripheral leukocyte subpopulations that are recognized as important effector cells in the lung tissue. Methods: We enrolled 20 patients with stable, moderate COPD (FEV1, 33 to 69%). Ten asymptomatic smokers and 10 nonsmokers served as control groups. Flow cytometry and whole blood analysis were used to minimize unwanted ex vivo modulation. Oxidative burst and adhesion molecule mobilization were analyzed on freshly drawn cells and after in vitro activation. Measurements and main results: We found reduced oxidative burst in neutrophils, monocytes, and eosinophils after in vitro stimulation with tumor necrosis factor (TNF) and the bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) in both COPD patients and asymptomatic smokers as compared to nonsmoking control subjects. Vascular involvement was determined as increased soluble intercellular adhesion molecule-1 (sICAM-1) in the COPD group. There were no differences in adhesion molecule expression among the three groups. However, in COPD patients who had smoked the same morning prior to blood sampling, we found a reduced ability to mobilize adhesion molecule CD11b after TNF plus fMLP activation in all investigated cell types. “Acute” smoking did not significantly alter respiratory burst measurements. Conclusions: Both COPD patients and asymptomatic smokers have increased levels of sICAM-1 and a reduced intracellular oxidative burst in vitro, indicating a vascular endothelial activation and a possible state of refractoriness in circulating phagocytes in COPD. Although expression and mobilization of adhesion molecules were similar between groups, the acute smoke effect on CD11b points out the value of information on smoking behavior when analyzing function of peripheral inflammatory cells in a smoking population. (CHEST 2005; 128:2051–2058)
- Published
- 2005
15. Peripheral blood monocyte activation during coronary artery bypass grafting with or without cardiopulmonary bypass
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Lena Wehlin, Jenny Vedin, Jarle Vaage, and Joachim Lundahl
- Subjects
Male ,medicine.medical_specialty ,CD14 ,Coronary Artery Bypass, Off-Pump ,Lipopolysaccharide Receptors ,CD16 ,Coronary Angiography ,Risk Assessment ,Sensitivity and Specificity ,Severity of Illness Index ,Monocytes ,law.invention ,Intraoperative Period ,law ,Internal medicine ,Preoperative Care ,medicine ,Cardiopulmonary bypass ,Macrophage ,Humans ,Prospective Studies ,Chemokine CCL4 ,Aged ,Probability ,Postoperative Care ,Cardiopulmonary Bypass ,biology ,business.industry ,Coronary Stenosis ,Macrophage Inflammatory Proteins ,Middle Aged ,Flow Cytometry ,Prognosis ,Peripheral ,Respiratory burst ,Survival Rate ,medicine.anatomical_structure ,Treatment Outcome ,Integrin alpha M ,biology.protein ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,Artery - Abstract
The aim of this prospective, randomized study was to investigate the impact of coronary artery bypass grafting (CABG) on peripheral monocytes and to evaluate the additional effect of cardiopulmonary bypass (CPB).Twenty patients admitted for elective CABG were randomized to either on-pump (ONCAB, n = 9) or off-pump (OFFCAB, n = 11) surgery and blood samples were drawn before, during and 24 h after the operation. The total number of monocytes and the proportion of the more mature CD16+/CD14+ monocytes were measured. Expression of activation markers (CD11b, CD35 and CD62L) and oxidative burst were determined using flow cytometry on both resting and in vitro stimulated cells. Serum concentrations of soluble CD14 and monocytes/macrophage chemotactic protein 1 (MCP-1) were analysed.During surgery there was a selective decrease in the proportion of CD16+/CD14+ monocytes compared to total monocytes. These had returned to preoperative values 24 h after surgery while the total number of monocytes had increased more than 100%. Intracellular production of oxygen free radical H2O2 was increased in the ONCAB group during surgery compared to OFFCAB. Monocyte expression and in vitro mobilization of complement receptors, CD11b and CD35, were similar in both study groups during and after surgery as was the expression of CD62L. Serum levels of MCP-1 decreased during surgery as did soluble CD14, both with increased levels again the day after surgery.It is concluded that the circulating monocyte population is activated during and as a consequence of CABG. There were few apparent additional effects of CPB found in this study. In this setting the inflammation caused by the surgery procedure per se probably surpasses the impact of the CPB on circulating blood monocytes.
- Published
- 2005
16. beta2-Integrin and lipid modifications indicate a non-antioxidant mechanism for the anti-atherogenic effect of dietary coenzyme Q10
- Author
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Joachim Lundahl, Mats Sjöberg, Kerstin Brismar, Lena Wehlin, Mikael Turunen, Pavel J. Sindelar, and Gustav Dallner
- Subjects
Male ,medicine.medical_specialty ,Antioxidant ,Ubiquinone ,medicine.medical_treatment ,alpha-Tocopherol ,Biophysics ,Coenzymes ,Macrophage-1 Antigen ,Complement receptor ,Biochemistry ,Peripheral blood mononuclear cell ,Antioxidants ,chemistry.chemical_compound ,Phospholipase A2 ,Internal medicine ,medicine ,Leukocytes ,Animals ,Humans ,Molecular Biology ,Phospholipids ,Aged ,Coenzyme Q10 ,chemistry.chemical_classification ,biology ,food and beverages ,Fatty acid ,Cell Biology ,Middle Aged ,Endocrinology ,chemistry ,Integrin alpha M ,Cytoprotection ,CD18 Antigens ,Dietary Supplements ,biology.protein ,Receptors, Complement 3b ,Diet, Atherogenic ,Arachidonic acid ,Female - Abstract
Dietary supplementation with coenzyme Q (CoQ) has been proposed to have anti-atherogenic effects by virtue of its antioxidant capacity. To investigate this question, the leukocyte status of 5 males and 5 females (52–68 years) was evaluated before and after supplementation with 200 mg CoQ/day for 5 and 10 weeks. CoQ was selectively taken up by mononuclear cells and α-tocopherol increased in polynuclear and mononuclear cells. The expression of β2-integrin CD11b and complement receptor CD35 on the plasma membrane of resting and stimulated monocytes was significantly decreased upon dietary CoQ. Fatty acid and aldehyde analysis revealed that there was a selective increase of arachidonic acid and plasmalogens in only mononuclear cells. These selective lipid changes are not consistent with a general improvement in antioxidant status and indicate that CoQ most likely inhibits a phospholipase A2. Thus, these results strongly suggest that the anti-atherogenic effects of CoQ be mediated by other mechanisms beside its antioxidant protection.
- Published
- 2002
17. Reply to Raja
- Author
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Joachim Lundahl, Lena Wehlin, Jenny Vedin, and Jarle Vaage
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Raja ,biology ,business.industry ,General Medicine ,biology.organism_classification ,Internal medicine ,medicine ,Cardiology ,Surgery ,Religious studies ,Cardiology and Cardiovascular Medicine ,business - Published
- 2004
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