Guus F Rimmelzwaan

Erasmus MC, Rotterdam, South Holland, Netherlands

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Publications (330)1867.63 Total impact

  • The Journal of Infectious Diseases 07/2015; DOI:10.1093/infdis/jiv367 · 5.78 Impact Factor
  • Rory D de Vries, Arwen F Altenburg, Guus F Rimmelzwaan
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    ABSTRACT: Currently used influenza vaccines are only effective when the vaccine strains match the epidemic strains antigenically. To this end, seasonal influenza vaccines must be updated almost annually. Furthermore, seasonal influenza vaccines fail to afford protection against antigenically distinct pandemic influenza viruses. Because of an ever-present threat of the next influenza pandemic and the continuous emergence of drift variants of seasonal influenza A viruses, there is a need for an universal influenza vaccine that induces protective immunity against all influenza A viruses. Here, we summarize some of the efforts that are ongoing to develop universal influenza vaccines.
    Expert Review of Vaccines 06/2015; DOI:10.1586/14760584.2015.1060860 · 4.22 Impact Factor
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    ABSTRACT: Background. Influenza-related morbidity and mortality remain high. Seasonal vaccination is the backbone of influenza management but does not always result in protective antibody titres. Non-specific effects of BCG-vaccination related to enhanced function of myeloid antigen-presenting cells have been reported. We hypothesized that BCG vaccination could also enhance immune responses to influenza vaccination. Methods. Healthy volunteers received either live attenuated BCG vaccine (n=20) or placebo (n=20) in a randomized fashion, followed by intra-muscular injection of trivalent influenza vaccine 14 days later. Hemaglutination inhibiting (HI) antibodies and cellular immunity measured by ex-vivo leukocyte responses were assessed. Results. In BCG-vaccinated subjects, HI antibody responses against the 2009 pandemic H1N1 vaccine strain were significantly enhanced compared with the placebo group, and there is a trend towards more rapid seroconversion. Additionally, apart from enhanced pro-inflammatory leukocyte responses following BCG vaccination, nonspecific effects of influenza vaccination were also observed, with modulation of cytokine responses against unrelated pathogens. Conclusion. BCG vaccination prior to vaccination with influenza vaccine results in a more pronounced increase and accelerated induction of functional antibody responses against the 2009 pandemic H1N1 influenza vaccine strain. These results may have implications for the design of vaccination strategies and could lead to improvement of vaccination efficacy.
    The Journal of Infectious Diseases 06/2015; DOI:10.1093/infdis/jiv332 · 5.78 Impact Factor
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    Emerging Infectious Diseases 06/2015; 21(6):1086-8. DOI:10.3201/eid2106.150021 · 7.33 Impact Factor
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    ABSTRACT: Influenza B viruses fall in two antigenically distinct lineages (B/Victoria/2/1987 and B/Yamagata/16/1988 lineage) that co-circulate with influenza A viruses of the H3N2 and H1N1 subtype during seasonal epidemics. Infections with influenza B viruses contribute considerably to morbidity and mortality in the human population. Influenza B virus neutralizing antibodies, elicited by natural infections or vaccination, poorly cross-react with viruses of the opposing influenza B lineage. Therefore, there is an increased interest in identifying other correlates of protection which could aid the development of broadly-protective vaccines. BLAST analysis revealed high sequence identity of all viral proteins. With two online epitope prediction algorithms, putative conserved epitopes relevant for study subjects used in the present study, were predicted. The cross-reactivity of influenza B virus-specific polyclonal CD8+ T lymphocyte populations, obtained from HLA-typed healthy study subjects, with intra-lineage drift variants and viruses of the opposing lineage was determined by assessing their in vitro interferon gamma (IFN-γ) response and lytic activity. Here, we show for the first time, that CD8+ T lymphocytes directed to viruses of the B/Victoria lineage cross-react with viruses of the B/Yamagata lineage and vice versa.
    Journal of General Virology 04/2015; DOI:10.1099/vir.0.000156 · 3.53 Impact Factor
  • Carolien E van de Sandt, Guus F Rimmelzwaan
    Proceedings of the National Academy of Sciences 04/2015; 112(19). DOI:10.1073/pnas.1503245112 · 9.81 Impact Factor
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    ABSTRACT: The influenza season 2014/15 started in Europe in week 50 2014 with influenza A(H3N2) viruses predominating. The majority of the A(H3N2) viruses characterised antigenically and/or genetically differ from the northern hemisphere vaccine component which may result in reduced vaccine effectiveness for the season. We therefore anticipate that this season may be more severe than the 2013/14 season. Treating influenza with antivirals in addition to prevention with vaccination will be important. --------------------------------------------------------------------------------
    Eurosurveillance: bulletin europeen sur les maladies transmissibles = European communicable disease bulletin 01/2015; 20(4):1-5. · 4.66 Impact Factor
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    ABSTRACT: The majority of currently circulating influenza A(H1N1) viruses are antigenically similar to the virus that caused the 2009 influenza pandemic. However, antigenic variants are expected to emerge as population immunity increases. Amino acid substitutions in the hemagglutinin protein can result in escape from neutralizing antibodies, affect viral fitness, and change receptor preference. Here we constructed mutants with substitutions in the hemagglutinin of A/Netherlands/602/09 in an attenuated backbone to explore amino acid changes that may contribute to emergence of antigenic variants in the human population. Our analysis revealed that single substitutions affecting the 151 - 159 loop located adjacent to the receptor binding site caused escape from ferret and human antibodies elicited after primary A(H1N1)pdm09 virus infection. The majority of these substitutions resulted in similar or increased replication efficiency in vitro compared to the virus carrying the wildtype hemagglutinin, and did not result in a change of receptor preference. However, none of the substitutions was sufficient to escape from the antibodies in sera from individuals that experienced both seasonal and pandemic A(H1N1) virus infections. These results suggest that antibodies directed against epitopes on seasonal A(H1N1) viruses contribute to neutralization of A(H1N1)pdm09 antigenic variants, thereby limiting the number of possible substitutions that could lead to escape from population immunity. Influenza A viruses can cause significant morbidity and mortality in humans. Amino acid substitutions in the hemagglutinin protein can result in escape from antibody-mediated neutralization. This allows the virus to re-infect individuals that have acquired immunity to previously circulating strains through infection or vaccination. To date, the vast majority of A(H1N1)pdm09 strains remain antigenically similar to the virus that caused the 2009 influenza pandemic. However, antigenic variants are expected to emerge as a result of increasing population immunity. We show that single amino acid substitutions near the receptor binding site were sufficient to escape from antibodies specific for A(H1N1)pdm09 viruses, but not from antibodies elicited in response to infections with seasonal A(H1N1) and A(H1N1)pdm09 viruses. This study identifies substitutions in A(H1N1)pdm09 viruses that support escape from population immunity, but also suggests that the number of potential escape variants is limited by previous exposure to seasonal A(H1N1) viruses. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 01/2015; 89(7). DOI:10.1128/JVI.02962-14 · 4.65 Impact Factor
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    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:
    The Journal of Infectious Diseases 01/2015; 212(1). DOI:10.1093/infdis/jiv018 · 5.78 Impact Factor
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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; 185(3). DOI:10.1016/j.ajpath.2014.11.012 · 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. DOI:10.1016/S1473-3099(14)70963-6 · 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; 33(4). DOI:10.1016/j.vaccine.2014.11.054 · 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. DOI:10.1186/s12934-014-0162-8 · 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 (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. DOI:10.1126/science.1256427 · 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; 15(12). DOI:10.1038/ni.3027 · 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. DOI:10.1016/j.vaccine.2014.08.003 · 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; 211(5). DOI:10.1093/infdis/jiu528 · 5.78 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 07/2014; 6(7):2735-2761. DOI:10.3390/v6072735 · 3.28 Impact Factor
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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). DOI:10.1128/mBio.01070-14 · 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.
    06/2014; 6:47. DOI:10.12703/P6-47

Publication Stats

15k Citations
1,867.63 Total Impact Points


  • 2000–2015
    • Erasmus MC
      • Department of Virology
      Rotterdam, South Holland, Netherlands
  • 1994–2013
    • Erasmus Universiteit Rotterdam
      • Department of Virology
      Rotterdam, South Holland, Netherlands
  • 2011
    • Novartis Vaccines
      Cambridge, Massachusetts, United States
    • National Institute for Public Health and the Environment (RIVM)
      • Laboratory for Infectious Diseases and Perinatal Screening
      Utrecht, Utrecht, 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
  • 2008
    • French National Institute for Agricultural Research
      Lutetia Parisorum, Île-de-France, France
  • 2004
    • University of Cambridge
      • Department of Zoology
      Cambridge, ENG, United Kingdom
  • 1991
    • Netherlands Cancer Institute
      Amsterdamo, North Holland, Netherlands