G F Rimmelzwaan

Erasmus MC, Rotterdam, South Holland, Netherlands

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Publications (319)1770.99 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Animal and human studies have demonstrated the importance of influenza A virus (IAV)-specific CD8(+) cytotoxic T lymphocytes (CTLs) in heterosubtypic cross-protective immunity. Using peripheral blood mononuclear cells (PBMCs) obtained intermittently from healthy HLA-typed blood donors between 1999 and 2012, we were able to demonstrate that IAV-specific CTLs are long-lived. Intercurrent IAV infections transiently increase the frequency of functionally distinct subsets of IAV-specific CTLs, in particular effector and effector memory T cells. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    The Journal of infectious diseases. 01/2015;
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    ABSTRACT: To elucidate the pathogenesis and transmission of influenza virus, the ferret model is typically used. To investigate protective immune responses, the use of inbred mouse strains has proven invaluable. Here, we describe a study with isogenic guinea pigs, which would uniquely combine the advantages of the mouse and ferret models for influenza virus infection. Strain 2 isogenic guinea pigs were inoculated with H1N1pdm09 influenza virus A/Netherlands/602/09 by the intranasal or intratracheal route. Viral replication kinetics were assessed by determining virus titers in nasal swabs and respiratory tissues, which were also used to assess histopathologic changes and the number of infected cells. In all guinea pigs, virus titers peaked in nasal secretions at day 2 after inoculation. Intranasal inoculation resulted in higher virus excretion via the nose and higher virus titers in the nasal turbinates than intratracheal inoculation. After intranasal inoculation, infectious virus was recovered only from nasal epithelium; after intratracheal inoculation, it was recovered also from trachea, lung, and cerebrum. Histopathologic changes corresponded with virus antigen distribution, being largely limited to nasal epithelium for intranasally infected guinea pigs and more widespread in the respiratory tract for intratracheally infected guinea pigs. In summary, isogenic guinea pigs show promise as a model to investigate the role of humoral and cell-mediated immunity to influenza and its effect on virus transmission. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
    American Journal Of Pathology 12/2014; · 4.60 Impact Factor
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    ABSTRACT: BACKGROUND: Modified vaccinia virus Ankara (MVA) is a promising viral vector platform for the development of an H5N1 influenza vaccine. Preclinical assessment of MVA-based H5N1 vaccines showed their immunogenicity and safety in different animal models. We aimed to assess the safety and immunogenicity of the MVA-haemagglutinin-based H5N1 vaccine MVA-H5-sfMR in healthy individuals. METHODS: In a single-centre, double-blind phase 1/2a study, young volunteers (aged 18-28 years) were randomly assigned with a computer-generated list in equal numbers to one of eight groups and were given one injection or two injections intramuscularly at an interval of 4 weeks of a standard dose (10(8) plaque forming units [pfu]) or a ten times lower dose (10(7) pfu) of the MVA-H5-sfMR (vector encoding the haemagglutinin gene of influenza A/Vietnam/1194/2004 virus [H5N1 subtype]) or MVA-F6-sfMR (empty vector) vaccine. Volunteers and physicians who examined and administered the vaccine were masked to vaccine assignment. Individuals who received the MVA-H5-sfMR vaccine were eligible for a booster immunisation 1 year after the first immunisation. Primary endpoint was safety. Secondary outcome was immunogenicity. The trial is registered with the Dutch Trial Register, number NTR3401. FINDINGS: 79 of 80 individuals who were enrolled completed the study. No serious adverse events were identified. 11 individuals reported severe headache and lightheadedness, erythema nodosum, respiratory illness (accompanied by influenza-like symptoms), sore throat, or injection-site reaction. Most of the volunteers had one or more local (itch, pain, redness, and swelling) and systemic reactions (rise in body temperature, headache, myalgia, arthralgia, chills, malaise, and fatigue) after the first, second, and booster immunisations. Individuals who received the 10(7) dose had fewer systemic reactions. The MVA-H5-sfMR vaccine at 10(8) pfu induced significantly higher antibody responses after one and two immunisations than did 10(7) pfu when assessed with haemagglutination inhibition geometric mean titre at 8 weeks against H5N1 A/Vietnam/1194/2004 (30.2 [SD 3.8] vs 9.2 [2.3] and 108.1 [2.4] vs 15.8 [3.2]). 27 of 39 eligible individuals were enrolled in the booster immunisation study. A single shot of MVA-H5-sfMR 10(8) pfu prime immunisation resulted in higher antibody responses after the booster immunisation than did two shots of MVA-H5-sfMR at the ten times lower dose. INTERPRETATION: The MVA-based H5N1 vaccine was well tolerated and immunogenic and therefore the vaccine candidates arising from the MVA platform hold great promise for rapid development in response to a future influenza pandemic threat. However, the immunogenicity of this vaccine needs to be compared with conventional H5N1 inactivated non-adjuvanted vaccine candidates in head-to-head clinical trials. FUNDING: European Research Council.
    The Lancet Infectious Diseases 12/2014; 14(12):1196-207. · 19.45 Impact Factor
  • Arwen F Altenburg, Guus F Rimmelzwaan, Rory D de Vries
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    ABSTRACT: Since inactivated influenza vaccines mainly confer protective immunity by inducing strain-specific antibodies to the viral hemagglutinin, these vaccines only afford protection against infection with antigenically matching influenza virus strains. Due to the continuous emergence of antigenic drift variants of seasonal influenza viruses and the inevitable future emergence of pandemic influenza viruses, there is considerable interest in the development of influenza vaccines that induce broader protective immunity. It has long been recognized that influenza virus-specific CD8(+) T cells directed to epitopes located in the relatively conserved internal proteins can cross-react with various subtypes of influenza A virus. This implies that these CD8(+) T cells, induced by prior influenza virus infections or vaccinations, could afford heterosubtypic immunity. Furthermore, influenza virus-specific CD4(+) T cells have been shown to be important in protection from infection, either via direct cytotoxic effects or indirectly by providing help to B cells and CD8(+) T cells. In the present paper, we review the induction of virus-specific T cell responses by influenza virus infection and the role of virus-specific CD4(+) and CD8(+) T cells in viral clearance and conferring protection from subsequent infections with homologous or heterologous influenza virus strains. Furthermore, we discuss vector-based vaccination strategies that aim at the induction of a cross-reactive virus-specific T cell response. Copyright © 2014. Published by Elsevier Ltd.
    Vaccine 12/2014; · 3.49 Impact Factor
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    ABSTRACT: Background The Autotransporter pathway, ubiquitous in Gram-negative bacteria, allows the efficient secretion of large passenger proteins via a relatively simple mechanism. Capitalizing on its crystal structure, we have engineered the Escherichia coli autotransporter Hemoglobin protease (Hbp) into a versatile platform for secretion and surface display of multiple heterologous proteins in one carrier molecule.ResultsAs proof-of-concept, we demonstrate efficient secretion and high-density display of the sizeable Mycobacterium tuberculosis antigens ESAT6, Ag85B and Rv2660c in E. coli simultaneously. Furthermore, we show stable multivalent display of these antigens in an attenuated Salmonella Typhimurium strain upon chromosomal integration. To emphasize the versatility of the Hbp platform, we also demonstrate efficient expression of multiple sizeable antigenic fragments from Chlamydia trachomatis and the influenza A virus at the Salmonella cell surface.Conclusions The successful efficient cell-surface display of multiple antigens from various pathogenic organisms highlights the potential of Hbp as a universal platform for the development of multivalent recombinant bacterial vector vaccines.
    Microbial Cell Factories 11/2014; 13(1):162. · 4.25 Impact Factor
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    ABSTRACT: 996 (2014); 346 Science et al. J. M. Fonville Antibody landscapes after influenza virus infection or vaccination This copy is for your personal, non-commercial use only. clicking here. colleagues, clients, or customers by , you can order high-quality copies for your If you wish to distribute this article to others here. following the guidelines can be obtained by Permission to republish or repurpose articles or portions of articles): November 20, 2014 www.sciencemag.org (this information is current as of The following resources related to this article are available online atepidemiology Epidemiology subject collections: This article appears in the following registered trademark of AAAS. is a Science 2014 by the American Association for the Advancement of Science; all rights reserved. The title Copyright American Association for the Advancement of Science,
    Science 11/2014; 346(6212):996-1000. · 31.48 Impact Factor
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    ABSTRACT: Activated CD8(+) T cells choose between terminal effector cell (TEC) or memory precursor cell (MPC) fates. We found that the signaling receptor Notch controls this 'choice'. Notch promoted the differentiation of immediately protective TECs and was correspondingly required for the clearance of acute infection with influenza virus. Notch activated a major portion of the TEC-specific gene-expression program and suppressed the MPC-specific program. Expression of Notch was induced on naive CD8(+) T cells by inflammatory mediators and interleukin 2 (IL-2) via pathways dependent on the metabolic checkpoint kinase mTOR and the transcription factor T-bet. These pathways were subsequently amplified downstream of Notch, creating a positive feedback loop. Notch thus functions as a central hub where information from different sources converges to match effector T cell differentiation to the demands of an infection.
    Nature Immunology 10/2014; · 24.97 Impact Factor
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    ABSTRACT: Vaccines used against seasonal influenza are poorly effective against influenza A viruses of novel subtypes that may have pandemic potential. Furthermore, pre(pandemic) influenza vaccines are poorly immunogenic, which can be overcome by the use of adjuvants. A limited number of adjuvants has been approved for use in humans, however there is a need for alternative safe and effective adjuvants that can enhance the immunogenicity of influenza vaccines and that promote the induction of broad-protective T cell responses. Here we evaluated a novel nanoparticle, G3, as an adjuvant for a seasonal trivalent inactivated influenza vaccine in a mouse model. The G3 adjuvant was formulated with or without steviol glycosides (DT, for diterpenoid). The use of both formulations enhanced the virus-specific antibody response to all three vaccine strains considerably. The adjuvants were well tolerated without any signs of discomfort. To assess the protective potential of the vaccine-induced immune responses, an antigenically distinct influenza virus strain, A/Puerto Rico/8/34 (A/PR/8/34), was used for challenge infection. The vaccine-induced antibodies did not cross-react with strain A/PR/8/34 in HI and VN assays. However, mice immunized with the G3/DT-adjuvanted vaccine were partially protected against A/PR/8/34 infection, which correlated with the induction of anamnestic virus-specific CD8+ T cell responses that were not observed with the use of G3 without DT. Both formulations induced maturation of human dendritic cells and promoted antigen presentation to a similar extent. In conclusion, G3/DT is a promising adjuvant formulation that not only potentiates the antibody response induced by influenza vaccines, but also induces T cell immunity which could afford broader protection against antigenically distinct influenza viruses.
    Vaccine 09/2014; 32(43):5614–5623. · 3.49 Impact Factor
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    ABSTRACT: Since the first reports in early 2013, over 440 human cases of infection with avian influenza A viruses of the H7N9 subtype have been reported including 122 fatalities. After the isolation of the first H7N9 viruses the nucleotide sequences became publically available. Based on the coding sequence of the influenza virus A/Shanghai/2/2013 HA gene, a codon-optimized gene was synthesized and cloned into a recombinant Modified Vaccinia virus Ankara (MVA). This MVA-H7-Sh2 viral vector was used to immunize ferrets and proved to be immunogenic, even after a single immunization. Subsequently, ferrets were challenged with influenza virus A/Anhui/1/2013 via the intratracheal route. Unprotected animals that were mock-vaccinated or that received empty vector, developed interstitial pneumonia characterized by a marked alveolitis, accompanied by loss of appetite, weight loss and heavy breathing. In contrast, MVA-H7-Sh2 immunized animals were protected from severe disease.
    The Journal of infectious diseases. 09/2014;
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    ABSTRACT: Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype are genetically highly variable and have diversified into multiple phylogenetic clades over the past decade. Antigenic drift is a well-studied phenomenon for seasonal human influenza viruses, but much less is known about the antigenic evolution of HPAI H5N1 viruses that circulate in poultry. In this study, we focused on HPAI H5N1 viruses that are enzootic to Indonesia. We selected representative viruses from genetically distinct lineages that are currently circulating and determined their antigenic properties by hemagglutination inhibition assays. At least six antigenic variants have circulated between 2003, when H5N1 clade 2.1 viruses were first detected in Indonesia, and 2011. During this period, multiple antigenic variants cocirculated in the same geographic regions. Mutant viruses were constructed by site-directed mutagenesis to represent each of the circulating antigenic variants, revealing that antigenic differences between clade 2.1 viruses were due to only one or very few amino acid substitutions immediately adjacent to the receptor binding site. Antigenic variants of H5N1 virus evaded recognition by both ferret and chicken antibodies. The molecular basis for antigenic change in clade 2.1 viruses closely resembled that of seasonal human influenza viruses, indicating that the hemagglutinin of influenza viruses from different hosts and subtypes may be similarly restricted to evade antibody recognition.
    mBio 07/2014; 5(3). · 6.88 Impact Factor
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    ABSTRACT: Influenza virus infections yearly cause high morbidity and mortality burdens in humans, and the development of a new influenza pandemic continues to threaten mankind as a Damoclean sword. Influenza vaccines have been produced by using egg-based virus growth and passaging techniques that were developed more than 60 years ago, following the identification of influenza A virus as an etiological agent of seasonal influenza. These vaccines aimed mainly at eliciting neutralizing antibodies targeting antigenically variable regions of the hemagglutinin (HA) protein, which requires regular updates to match circulating seasonal influenza A and B virus strains. Given the relatively limited protection induced by current seasonal influenza vaccines, a more universal influenza vaccine that would protect against more-if not all-influenza viruses is among the largest unmet medical needs of the 21st century. New insights into correlates of protection from influenza and into broad B- and T-cell protective anti-influenza immune responses offer promising avenues for innovative vaccine development as well as manufacturing strategies or platforms, leading to the development of a new generation of vaccines. These aim at the rapid and massive production of influenza vaccines that provide broad protective and long-lasting immunity. Recent advances in influenza vaccine research demonstrate the feasibility of a wide range of approaches and call for the initiation of preclinical proof-of-principle studies followed by clinical trials in humans.
    F1000prime reports. 06/2014; 6:47.
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    ABSTRACT: Recently, A/H5N1 influenza viruses were shown to acquire airborne transmissibility between ferrets upon targeted mutagenesis and virus passage. The critical genetic changes in airborne A/Indonesia/5/05 were not yet identified. Here, five substitutions proved to be sufficient to determine this airborne transmission phenotype. Substitutions in PB1 and PB2 collectively caused enhanced transcription and virus replication. One substitution increased HA thermostability and lowered the pH of membrane fusion. Two substitutions independently changed HA binding preference from α2,3-linked to α2,6-linked sialic acid receptors. The loss of a glycosylation site in HA enhanced overall binding to receptors. The acquired substitutions emerged early during ferret passage as minor variants and became dominant rapidly. Identification of substitutions that are essential for airborne transmission of avian influenza viruses between ferrets and their associated phenotypes advances our fundamental understanding of virus transmission and will increase the value of future surveillance programs and public health risk assessments.
    Cell 04/2014; 157(2):329-39. · 31.96 Impact Factor
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    ABSTRACT: To assess the efficacy of novel antiviral drugs against influenza in clinical trials it is necessary to quantify infectious virus titers in patients' respiratory tract samples. Typically, this is achieved by inoculating virus-susceptible cells with serial dilutions of clinical specimens, and detecting the production of progeny virus by hemagglutination since influenza viruses generally have the capacity to bind and agglutinate erythrocytes of various species through their hemagglutinin (HA). This readout method is no longer adequate, since an increasing number of currently circulating A(H3) influenza viruses display reduced capacity to agglutinate erythrocytes.Here, we report the magnitude of this problem by analyzing the frequency of HA deficient A(H3) viruses detected in the Netherlands from 1999-2012. Furthermore, we report development and validation of an alternative method to monitor the production of progeny influenza virus in quantitative virus cultures, which is independent of the capacity to agglutinate erythrocytes. This method is based on detection of viral nucleoprotein (NP) in virus culture plates by ELISA, and it produced similar results compared to the hemagglutination assay using strains with good HA activity, including A/Brisbane/059/07 (H1N1), A/Victoria/210/09 (H3N2) and other seasonal A(H1N1), A(H1N1)pdm09 and the majority of A(H3) virus strains isolated in 2009. In contrast, many A(H3) viruses that circulate since 2010 failed to display HA activity and infectious virus titers could only be determined by detecting NP. The virus culture ELISA described here will enable efficacy testing of new antiviral compounds in clinical trials during seasons in which non-hemagglutinating influenza A viruses circulate.
    Journal of clinical microbiology 03/2014; · 4.23 Impact Factor
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    ABSTRACT: Influenza A virus-specific T cells are highly cross-reactive and contribute to heterosubtypic immunity, which may afford protection against novel pandemic strains of influenza virus. However, the magnitude and nature of virus-specific T-cell responses induced by natural infections and/or vaccination in young children is poorly understood. Host factors, such as the development of the immune system during childhood and environmental factors such as exposure rates to influenza viruses and interference by vaccination contribute to shaping the magnitude and specificity of the T-cell response. Here, the authors review several of these factors, including the differences between T-cell responses of young children and adults, the age-dependent frequency of virus-specific T cells and the impact of annual childhood influenza vaccination. In addition, the authors summarize all currently available studies in which influenza vaccine-induced T-cell responses were evaluated. The authors discuss these findings in the light of developing vaccines and vaccination strategies aiming at the induction of protective immunity to seasonal and pandemic influenza viruses of antigenically distinct subtypes.
    Expert Review of Vaccines 01/2014; 11(8). · 4.22 Impact Factor
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    ABSTRACT: The armamentarium of antiviral drugs against influenza viruses is limited. Furthermore, influenza viruses emerge that are resistant to existing antiviral drugs like the M2 and NA inhibitors. Therefore, there is an urgent need for the development of novel classes of antiviral drugs. Here we investigated the antiviral properties of recombinant porcine surfactant protein D (RpSP-D), an innate defense molecule with lectin properties, against influenza B viruses. We have previously shown that porcine SP-D has more potent neutralizing activity against influenza A viruses than human SP-D. Here we show that RpSP-D neutralizes influenza B viruses efficiently and inhibited the binding of these viruses to epithelial cells of the human trachea.
    Virus Research 01/2014; · 2.83 Impact Factor
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    ABSTRACT: Respiratory viruses infections caused by influenza viruses, human parainfluenza virus (hPIV), respiratory syncytial virus (RSV) and coronaviruses are an eminent threat for public health. Currently, there are no licensed vaccines available for hPIV, RSV and coronaviruses, and the available seasonal influenza vaccines have considerable limitations. With regard to pandemic preparedness, it is important that procedures are in place to respond rapidly and produce tailor made vaccines against these respiratory viruses on short notice. Moreover, especially for influenza there is great need for the development of a universal vaccine that induces broad protective immunity against influenza viruses of various subtypes. Modified Vaccinia Virus Ankara (MVA) is a replication-deficient viral vector that holds great promise as a vaccine platform. MVA can encode one or more foreign antigens and thus functions as a multivalent vaccine. The vector can be used at biosafety level 1, has intrinsic adjuvant capacities and induces humoral and cellular immune responses. However, there are some practical and regulatory issues that need to be addressed in order to develop MVA-based vaccines on short notice at the verge of a pandemic. In this review, we discuss promising novel influenza virus vaccine targets and the use of MVA for vaccine development against various respiratory viruses.
    Viruses. 01/2014; 6(7):2735-2761.
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    ABSTRACT: Influenza is a major burden to public health. Due to high mutation rates and selection pressure, mutant viruses emerge which are resistant to currently used antiviral drugs. Therefore, there is a need for the development of novel classes of antiviral drugs that suffer less from the emergence of resistant viruses. Antiviral drugs based on collectin-like surfactant protein D (SP-D) may fulfil these requirements. Especially porcine SP-D displays strong antiviral activity to influenza A viruses. In the present study the antiviral activity of recombinant porcine SP-D was investigated in ex vivo cultures of respiratory tract tissue infected with human influenza A virus of the H3N2 subtype. Porcine SP-D has antiviral activity in these test systems. It is suggested that porcine SP-D may be used as a venue to develop a novel class of antiviral drugs.
    Virus Research 12/2013; · 2.83 Impact Factor
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    ABSTRACT: Influenza A(H3N2) viruses became widespread in humans during the 1968 H3N2 virus pandemic and have been a major cause of influenza epidemics ever since. The viruses evolve continuously by reassortment and genomic evolution. Antigenic drift is the cause for the need to update the influenza vaccine frequently. Using two datasets that span the entire period of circulation of human influenza A(H3N2) viruses, it was shown that the influenza A(H3N2) virus evolution could be mapped into thirteen antigenic clusters. Here, we have analyzed the full genome of 286 influenza A(H3N2) viruses from these two datasets to investigate the genomic evolution and reassortment patterns. Numerous reassortment events, scattered over the entire period of virus circulation, were found, but most prominently in viruses circulating between 1991 and 1998. Some of these reassortment events persisted over time, and one of these coincided with an antigenic cluster transition. Further, selection pressures and nucleotide and amino acid substitution rates of all proteins were studied, including the recently discovered PB1-N40, PA-X, PA-N155, and PA-N182 proteins. Rates of nucleotide and amino acid substitution were most pronounced for hemagglutinin, neuraminidase, and PB1-F2 proteins. Selection pressures were highest in hemagglutinin, neuraminidase, matrix 1 and non-structural protein 1. This study of genotype in relation to the antigenic phenotype throughout the entire period of circulation of human influenza A(H3N2) viruses leads to a better understanding of its evolution.
    Journal of Virology 12/2013; · 4.65 Impact Factor
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    ABSTRACT: The molecular basis of antigenic drift was determined for the hemagglutinin (HA) of human influenza A/H3N2 virus. From 1968 to 2003, antigenic change was caused mainly by single amino acid substitutions, which occurred at only seven positions in HA immediately adjacent to the receptor binding site. Most of these substitutions were involved in antigenic change more than once. Equivalent positions were responsible for the recent antigenic changes of influenza B and A/H1N1 viruses. Substitution of a single amino acid at one of these positions substantially changed the virus-specific antibody response in infected ferrets. These findings have potentially far-reaching consequences for understanding the evolutionary mechanisms that govern influenza viruses.
    Science 11/2013; 342(6161):976-979. · 31.48 Impact Factor
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    ABSTRACT: In February 2013 zoonotic transmission of a novel influenza A virus of the H7N9 subtype was reported in China. Although at present no sustained human-to-human transmission has been reported, a pandemic outbreak of this H7N9 virus is feared. Since neutralizing antibodies to the hemagglutinin (HA) globular head domain of this virus are virtually absent in the human population, there is interest in identifying other correlates of protection, such as cross-reactive CD8(+) T cells (cytotoxic T lymphocytes (CTLs)) elicited during seasonal influenza A virus infections. These virus-specific CD8(+) T cells are known to recognize conserved internal proteins of influenza A viruses predominantly, but it is unknown to what extent they cross-react with the newly emerging H7N9 virus. Here, we assessed the cross-reactivity of seasonal H3N2, H1N1 and pandemic H1N1 influenza A virus-specific polyclonal CD8(+) T cells, obtained from HLA-typed study subjects, with the novel H7N9 virus. The cross-reactivity of CD8(+) T cells to H7N9 variants of known influenza A epitopes and H7N9 virus infected cells was determined by their IFN-γ response and lytic activity. It was concluded that, apart from recognition of individual H7N9 variant epitopes, CD8(+) T cells to seasonal influenza viruses display considerable cross-reactivity with the novel H7N9 virus. The presence of these cross-reactive CD8(+) T cells may afford some protection against infection with this new virus.
    Journal of Virology 11/2013; · 4.65 Impact Factor

Publication Stats

13k Citations
1,770.99 Total Impact Points


  • 2000–2014
    • Erasmus MC
      • Department of Virology
      Rotterdam, South Holland, Netherlands
  • 2013
    • Claude Bernard University Lyon 1
      Villeurbanne, Rhône-Alpes, France
    • University of Melbourne
      • Department of Microbiology and Immunology
      Melbourne, Victoria, Australia
  • 1994–2013
    • Erasmus Universiteit Rotterdam
      • Department of Virology
      Rotterdam, South Holland, Netherlands
  • 2010
    • Icahn School of Medicine at Mount Sinai
      Manhattan, New York, United States
  • 2009
    • Princeton University
      • Department of Ecology and Evolutionary Biology
      Princeton, NJ, United States
  • 2004–2008
    • University of Cambridge
      • Department of Zoology
      Cambridge, ENG, United Kingdom
    • Rode Kruis Ziekenhuis Beverwijk
      Berverwyk, North Holland, Netherlands
  • 2002
    • Swedish Institute for Communicable Disease Control
      Tukholma, Stockholm, Sweden
  • 1987
    • National Veterinary Institute, Sweden
      Uppsala, Uppsala, Sweden