Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

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    On the role of vaccine dose and antigenic distance in the transmission dynamics of Highly Pathogenic Avian Influenza (HPAI) H5N1 virus and its selected mutants in vaccinated animals
    Sitaras, Ioannis - \ 2017
    Wageningen University. Promotor(en): M.C.M. Jong, co-promotor(en): B. Peeters. - Wageningen : Wageningen University - ISBN 9789463438063 - 209
    avian influenza viruses - avian influenza - disease transmission - vaccines - vaccination - dosage - antigenic variation - mutants - mutations - immunity - vaccine development - virology - epidemiology - aviaire influenzavirussen - aviaire influenza - ziekteoverdracht - vaccins - vaccinatie - dosering - antigene variatie - mutanten - mutaties - immuniteit - vaccinontwikkeling - virologie - epidemiologie

    Influenza virus infections can cause high morbidity and mortality rates among animals and humans, and result in staggering direct and indirect financial losses amounting to billions of US dollars. Ever since it emerged in 1996 in Guangdong province, People’s Republic of China, one particular highly pathogenic avian influenza (HPAI) H5N1 virus has spread globally, and is responsible for massive losses of poultry, as well as human infections. For these reasons, HPAI H5N1 is considered as one of the viruses possible to cause a future influenza pandemic.

    One of the main reasons why influenza is a recurring problem is its ability to constantly evolve through the selection of mutants that are able to avoid immunity (be it natural or acquired). Due to the accumulation of mutations during genome replication, diverse/variant influenza genome sequences co-exist in a virus pool (quasispecies). These sequences can contain mutations that are able to confer selective advantages to the influenza virus given the opportunity. As a consequence, whenever a situation arises that places the virus under any type of pressure that the dominant virus sequence cannot cope with (i.e. immune pressure, selective receptor binding, etc.), the virus with the genome sequence that allows it to better adapt to that particular pressure becomes selected and takes over.

    Because of the influenza virus’s high rate of mutations, a global surveillance network is in place to monitor changes in circulating strains among humans that would warrant an update of the vaccines used. For human influenza strains, vaccines are updated frequently (every one or two years) and a similar situation holds true for racehorse vaccination. For avian influenza vaccination, however, the situation is different. In most countries, vaccination against avian influenza is not used, and in the countries where vaccines are used (either as routine or emergency measures), they are not updated as frequently as human vaccines are. In addition, in many instances vaccination against avian influenza viruses has met with some spectacular failures, since it failed to produce a level of immunity that would protect against circulating field strains. These vaccination failures have often been attributed to the fact that without constant vaccine updating (as is done for human influenza), the vaccines used are not able to keep up with continuously evolving antigenic variants selected in the field, and thus to protect poultry against them. In addition, since it is known that immune pressure resulting from vaccination can be a driving force in the evolution of influenza viruses and the selection of immune-escape mutants, there is a school of thought that posits that vaccination against avian influenza is not only a very expensive affair (especially if vaccines need to be frequently updated), but can also lead to selection of mutants that are able to avoid vaccination-induced immunity.

    The research reported in this thesis started with addressing the gaps in the knowledge regarding the role of vaccination-induced immunity in the selection of immune-escape mutants of HPAI H5N1, and if there is a way for vaccines to still be able to protect against antigenically-distant variants of the vaccine seed strain, without the need for frequent vaccine updates.

    Our first step in studying influenza virus evolution and selection of immune-escape mutants was to investigate how antigenic pressure may drive the selection of such mutants, and what the effect of the selected mutations on the pathogenicity and transmissibility of the mutants may be. Although there exist a variety of methods to select for influenza virus mutations (i.e. monoclonal antibodies, site-directed mutagenesis, reverse genetics, etc.), none of them is representative of selection as it happens in a vaccinated animal. In Chapter 2, we discuss in detail a laboratory-based system we have developed, in which immune-escape mutants are selected using homologous polyclonal chicken sera, similar to how they are selected in the field due to vaccination- induced immune pressure. We find that selection takes place early on, and additional mutations are selected when immune pressure is increased. Antigenic distances between the selected mutants and their parent strains are also increased throughout the selection process, but not in a linear fashion. Our selection system proved to be robust and replicable, and to be representative of selection in the field, since the mutations we selected for are also found in naturally-selected field isolates, and the antigenic distances between our selected mutants and their parent strains are similar to antigenic distances between vaccine strains and field isolates.

    We continued our research by addressing the roles played by vaccine dose (and resulting immunity) and antigenic distance between vaccine and challenge strains, in the transmission of HPAI H5N1 viruses, by employing transmission experiments using vaccinated chickens (Chapter 3). To our surprise, we found that the effect of antigenic distances between vaccine and challenge strains on transmission is very small compared to the effect of vaccine dose. We then quantified, for the first time, the minimum level of immunity and minimum percentage of the vaccinated population exhibiting said immunity, in order for vaccines to be able to protect against transmission even of strains that are antigenically distant to the vaccine seed strain. Transmission of such strains in well-vaccinated populations would allow for a scenario where vaccination- induced immunity may drive the selection of immune-escape mutants. Our results show that in order for vaccines to prevent transmission of antigenically distant strains (such as the ones resulting from selection due to immune pressure), the threshold level of immunity against these strains should be ≥23 haemagglutination inhibition units (HIU), in at least 86.5% of the vaccinated population. This level of immunity can be estimated by knowing the antigenic distance between the vaccine and challenge (field) strain, and the HI titre against the vaccine strain, which would then allow the approximate level of immunity against the field strain to be deduced. For example, assuming the HI titre against a vaccine strain is 210 HIU, and the distance with the challenge (field) strain is 24 HIU, according to our results the vaccine should be able to protect against the challenge strain, because the difference in HI titres should be around 26 HIU (i.e. above 23 HIU). These results, taken together with our previous work on selection of mutants, where we showed that the antigenic distances between our mutants and their parent strains are representative of distances found in the field, point to the fact that it is unlikely that vaccination-induced immunity can lead to selection of mutants able to escape it, given that a threshold level of immunity in a minimum percentage of the vaccinated population is achieved. As a consequence, we believe that constant vaccine updating may not be necessary for avian influenza viruses, as long as a threshold level of immunity is maintained. This makes vaccination a more attractive control measure, both from a health perspective and a financial one, than just applying biosecurity measures.

    To examine the effect the mutations in the haemagglutinin protein of our selected mutants may have in their transmission among chickens vaccinated with the parent strain, we used reverse genetics techniques to insert the HA gene of our most antigenically distant mutant into the parent strain backbone (Chapter 4). We vaccinated animals with a sub-optimal dose of vaccine, and we concluded that the mutations we selected for did not allow the mutant to avoid even low levels of immunity, such as the ones resulting from a sub-optimal vaccine dose (which resembles a poor field vaccination scenario). At the same time, the HA mutations we selected for did not appear to have a negative effect either on the pathogenicity of the mutant, or its ability to transmit to unvaccinated animals, since both parameters were comparable to the parent strain.

    Finally, we studied the role inter-animal variation in immunity – as measured by HI titres – has in the accuracy of antigenic cartography calculations (Chapter 5). We found that using sera from more than one animal significantly increased the accuracy of antigenic distance calculations, since it takes into account individual differences in immune responses to vaccination, an inevitable phenomenon documented in both humans and animals. In addition, we increased the accuracy of antigenic maps by avoiding the use of dimension-reducing algorithms as is currently done. By not reducing the dimensionality of virus positioning in space, our maps retain the original geometry between strains or sera, leading to more accurate positioning (Chapters 2 and 5). We hope that improving the accuracy of antigenic cartography can lead to a more precise surveillance of influenza evolution and better informed decisions regarding the need to update vaccines.

    Taken collectively, our results can improve field vaccination outcomes, since they provide guidelines on how to increase vaccination efficiency in stopping transmission of even antigenically-distant strains. In addition, our method for selecting for immune- escape mutants can be a valuable addition to research on influenza virus evolution. Moreover, policy making decisions regarding vaccination against any type of influenza can also benefit from our improvement on antigenic cartography accuracy, saving unnecessary costs in vaccine updating, and reducing morbidity and mortality of both animals and humans.

    Handelingsperspectief voor pluimveehouders in de preventie van laag- en hoogpathogene vogelgriep (AI)
    Bokma, Martien ; Bergevoet, Ron ; Elbers, Armin ; Goot, Jeanet van der; Neijenhuis, Francesca ; Niekerk, Thea van; Leenstra, Ferry - \ 2016
    Wageningen : Wageningen Livestock Research (Wageningen Livestock Research rapport 998) - 42
    aviaire influenza - hennen - pluimveehouderij - boeren - dierziektepreventie - risicofactoren - avian influenza - hens - poultry farming - farmers - animal disease prevention - risk factors
    Committed by the Dutch poultry sector research is carried out concerning acting perspective for prevention of AI-introduction on poultry farms, based on existing knowledge. The findings are shown in two parts: part I with practical advices for poultry farmers, and part II with its underpinning with a summary of existing knowledge of risk factors, preventive measures, early detection and possibilities for promoting desired (preventive) behaviour.
    H5N8 in Nederland in 2014 : Een nadere blik op de uitbraken
    Velkers, F.C. ; Elbers, A.R.W. ; Bouwstra, R.J. ; Stegeman, A. - \ 2015
    dierenwelzijn - dierlijke productie - pluimvee - dierziekten - diergezondheid - aviaire influenza - pluimveehouderij - animal welfare - animal production - poultry - animal diseases - animal health - avian influenza - poultry farming
    In opdracht van het Ministerie van Economische Zaken (EZ) is een analyse uitgevoerd van de H5N8 uitbraken om nader inzicht in binnenkomst, verspreiding en symptomen van het virus op pluimveebedrijven te krijgen. De bevindingen zijn tussentijds gerapporteerd via het overleg van de deskundigengroep dierziekten. De volledige
    rapportage is eind 2014 aangeboden aan het Ministerie van EZ. Dit document is een samenvatting hiervan.
    Dierenlab beschermt mensen
    Sikkema, A. ; Bianchi, A.T.J. - \ 2015
    WageningenWorld (2015)1. - ISSN 2210-7908 - p. 24 - 27.
    dierziekten - infectieziekten - zoönosen - virusziekten - onderzoek - diergezondheid - vaccins - aviaire influenza - q-koorts - animal diseases - infectious diseases - zoonoses - viral diseases - research - animal health - vaccines - avian influenza - q fever
    Nederland krijgt steeds meer te maken met besmettelijke dierziektes die ook mensen ziek kunnen maken, zoals vogelgriep. Om daar goed onderzoek naar te doen is een lab gebouwd waarin levende, besmette landbouwhuisdieren gehouden worden. Geen virus kan eruit ontsnappen. ‘Zelfs het DNA wordt vernietigd.’
    Vogelgriepvirus kwam aanvliegen uit Azië
    Sikkema, A. ; Bouwstra, R.J. - \ 2014
    Resource: weekblad voor Wageningen UR 9 (2014)8. - ISSN 1874-3625 - p. 8 - 8.
    aviaire influenza - aviaire influenzavirussen - besmetting - pluimveehouderij - pluimvee - diergezondheid - dierenwelzijn - ziekteoverdracht - dierlijke productie - avian influenza - avian influenza viruses - contamination - poultry farming - poultry - animal health - animal welfare - disease transmission - animal production
    CVI acht besmetting via trekvogels 'waarschijnlijk.' Het virus komt oorspronkelijk uit China.
    Risk of poultry compartments for transmission of High Pathogenic Avian Influenza
    Boender, G.J. ; Hagenaars, T.H.J. ; Backer, J.A. ; Nodelijk, G. ; Asseldonk, M.A.P.M. van; Bergevoet, R.H.M. ; Roermund, H.J.W. van - \ 2014
    Lelystad : CVI en LEI (Report number CVI: 14/I00028 ) - 28
    aviaire influenza - pluimveeziekten - pluimveehouderij - compartimenten - ziekteoverdracht - pathogeniteit - eu regelingen - wetgeving - diergezondheid - dierenwelzijn - pluimvee - avian influenza - poultry diseases - poultry farming - compartments - disease transmission - pathogenicity - eu regulations - legislation - animal health - animal welfare - poultry
    The application for a poultry compartment by VPI and the prospect of further ones motivates the Dutch Ministry of Economic Affairs and the Netherlands Food and Consumer Product Safety Authority to raise the following three questions: 1) What are the additional transmission risks that the (specific) VPI compartment poses during an HPAI epidemic, compared to a situation without compartment?; 2) What are the additional transmission risks that a compartment in general poses during an HPAI epidemic, depending on its characteristics?; 3) What are relevant evaluation criteria for granting the compartment status? In this study we addressed these questions by quantitatively assessing the veterinary risks based on mathematical model calculations, and by qualitatively discussing the (socio) economic aspects.
    Laag pathogene aviaire influenza virus infecties op pluimveebedrijven in Nederland
    Goot, J.A. van der; Verhagen, J. ; Gonzales, J. ; Backer, J.A. ; Bongers, J.H. ; Boender, G.J. ; Fouchier, R.A.M. ; Koch, G. - \ 2013
    Tijdschrift voor Diergeneeskunde 138 (2013)6. - ISSN 0040-7453 - p. 24 - 29.
    pluimveehouderij - pluimveeziekten - aviaire influenza - hennen - kippen - ziekte-incidentie - huisvesting, dieren - agrarische productiesystemen - uitloop - risicofactoren - poultry farming - poultry diseases - avian influenza - hens - fowls - disease incidence - animal housing - agricultural production systems - outdoor run - risk factors
    Dit artikel is een samenvatting van het rapport "Laag pathogene aviaire influenza virus iInfecties op pluimveebedrijven in Nederland" (CVI 2012). Dit rapport is geschreven naar aanleiding van vragen van het toenmalige Ministerie van Economische zaken, Landbouw en Innovatie. De vragen die werden gesteld zijn: - hebben pluimveebedrijven met vrije uitloop een grotere kans op introductie van LPAI virus infecties?; - is de kans op introductie gerelateerd aan wilde vogels?; - is er een periode in het jaar waarin het risico op infectie groter is? - kunnen er factoren geidentificeerd worden die de kans op introductie verminderen?
    Vogelgriep ontrafeld : resultaten FES-AI onderzoeksprogramma
    Luijkx, D.L.M. ; Scholtens, B. ; Nijland, H.R. - \ 2012
    Lelystad : CVI - ISBN 9789461734907 - 62
    aviaire influenza - aviaire influenzavirussen - vogels - pluimveehouderij - epidemieën - dierziektepreventie - ziektebestrijding - vaccinatie - diagnostiek - virologie - nederland - avian influenza - avian influenza viruses - birds - poultry farming - epidemics - animal disease prevention - disease control - vaccination - diagnostics - virology - netherlands
    Vogelgriep en mensengriep zijn nauwe verwanten: beide worden meestal veroorzaakt door zogeheten Influenza-A-virussen. Zo'n griepvirus is een mini-kikkertje van hooguit honderd nanometer (0,0001 milimeter) doorsnede met eiwituitstulpingen aan de buitenkant. Daarmee klampt het virusbolletje zich vast aan de cellen van zijn gastheer. Die hechting heeft het nodig om de cel te infecteren en zichzelf daarna te kunnen vermenigvuldigen. Dit boekje heeft de vogelgriepuitbraak van 2003 in Nederland als startpunt. Welke dilemma's deden zich toen voor en welke bestrijdingsmogelijkheden waren er voorhanden? Vanwege de twijfels, vragen en onzekerheden werd het FES-AI onderzoeksprogramma in het leven geroepen. Het FES-AI programma is opgedeeld in 7 verschillende kennisvelden. Voor de samenstelling van dit boekje is gesproken met de onderzoekleiders, die het onderzoek vorm hebben gegeven.
    Cell culture based production of avian influenza vaccines
    Wielink, R. van - \ 2012
    Wageningen University. Promotor(en): Rene Wijffels; Rob Moormann, co-promotor(en): Michael Harmsen; Dirk Martens. - S.l. : s.n. - ISBN 9789461733535 - 141
    aviaire influenza - aviaire influenza a-virussen - celcultuur vaccins - vaccins - celkweek - virologie - bioproceskunde - veeartsenijkunde - avian influenza - avian influenza a viruses - cell culture vaccines - vaccines - cell culture - virology - bioprocess engineering - veterinary medicine

    Vaccination of poultry can be used as a tool to control outbreaks of avian influenza, including that of highly pathogenic H5 and H7 strains. Influenza vaccines are traditionally produced in embryonated chicken eggs. Continuous cell lines have been suggested as an alternative substrate to produce influenza vaccines, as they are more robust and lack the long lead times associated with the production of large quantities of embryonated eggs. In the study that is described in this thesis, the production of influenza virus in cell culture was explored. Therefore, several cell lines were assessed for their ability to propagate influenza virus. Furthermore, adaptations to both cell line and seed virus were suggested that increased virus yield, thereby allowing the production of attenuated influenza virus strains.

    Laag pathogene aviaire influenza virus infecties op pluimveebedrijven in Nederland
    Goot, J.A. van der; Verhagen, J. ; Gonzales, J. ; Backer, J.A. ; Bongers, J.H. ; Boender, G.J. ; Koch, G. - \ 2012
    Wageningen [etc.] : Wageningen Universiteit en Researchcentrum, Centraal Veterinair Instituut [etc.] (CVI rapport / Centraal Veterinair Instituut 12/CVI0036) - 31
    pluimveehouderij - aviaire influenza - dierenwelzijn - diergezondheid - huisvesting, dieren - pluimvee - hennen - kippen - dierlijke productie - dierziekten - uitloop - influenzavirussen - poultry farming - avian influenza - animal welfare - animal health - animal housing - poultry - hens - fowls - animal production - animal diseases - outdoor run - influenza viruses
    Laag Pathogene Aviaire Influenza (LPAI) is een aandoening bij pluimvee die wordt veroorzaakt door LPAI virussen. In Nederland worden elk jaar meer infecties met LPAI virussen op pluimveebedrijven gedetecteerd. In dit rapport is gekeken naar een aantal mogelijke oorzaken voor deze toename. Het vermoeden bestaat dat serologisch en/of virologisch positieve bedrijven vaker dan gemiddeld bedrijven zijn met vrije uitloop. De vraag is of dit werkelijk zo is, en zo ja welke maatregelen dan genomen kunnen worden om de kans op een introductie op een bedrijf met vrije uitloop te verminderen.
    The role of Mallard (Anas platyrhynchos) in the spread of avian influenza: genomics, population genetics, and flyways
    Kraus, R.H.S. - \ 2011
    Wageningen University. Promotor(en): Herbert Prins; Ron Ydenberg, co-promotor(en): Pim van Hooft. - [S.l.] : S.n. - ISBN 9789461730282 - 143
    aviaire influenzavirussen - aviaire influenza - anas platyrhynchos - ziekteoverdracht - vogeltrek - genomica - populatiegenetica - evolutionaire genetica - zoögeografie - bioveiligheid - ziekteoverzichten - epidemiologie - avian influenza viruses - avian influenza - anas platyrhynchos - disease transmission - bird migration - genomics - population genetics - evolutionary genetics - zoogeography - biosafety - disease surveys - epidemiology

    Birds, in particular poultry and ducks, are a source of many infectious diseases, such as those caused by influenza viruses. These viruses are a threat not only to the birds themselves but also to poultry farming and human health, as forms that can infect humans are known to have evolved. It is believed that migratory birds in general play an important role in the global spread of avian influenza (AI). However, it is still debated how large this role precisely is and whether other modes of spread may be more important. The mallard (Anas platyrhynchos) is the world’s most abundant and well-studied waterfowl species. Besides being an important game and agricultural species, it is also a flagship species in wetland conservation and restoration. Waterfowl (Anseriformes: Anatidae) and especially ducks currently are the focal bird group in long distance dispersal of Avian Influenza in the wild, and the mallard has been identified as the most likely species to transport this virus.

    In my thesis I report aspects of the biology of this important host species of AI by molecular ecological means. As molecular marker system I established a genome-wide set of more than 100,000 SNPs of which I developed a subset of 384 SNPs into an assay to genotype about 1,000 ducks. This subset was employed to study the evolutionary history and speciation processes in the Anas genus. Further investigations into the world-wide mallard population structure on a species level were based not only on this set of 384 SNPs but also on mitochondrial DNA sequences. Last but not last, I investigated an option of AI sampling and detection from duck faeces by technology that is safe from a biohazard perspective, and solves transportation issues related to cold chains.

    The main results of my thesis include the development of a generally applicable improved analysis pipeline to develop genome-wide SNP sets for non-model organisms. Further, my results show that, from a migration system perspective, mallard flyways/populations can hardly be delineated from a biological point of view. Detailed phylogenetic, population genetic and coalescent analyses of a data set of samples spanning the whole northern hemisphere leads me to conclude that the only firm population boundaries that I can draw are between Eurasia and North America, within which panmixia is almost achieved. Mallards’ and other Anas-ducks’ whole continental to global distribution brings them together in sympatry. I can show that a combination of sympatric distribution, conflicting genetically determined and learned mate recognition mechanisms, and genomic compatibility between species helps to explain the long-standing puzzle of waterfowl hybridisation and introgression of genes from one duck species into another. Besides obvious management implications I propose that this fact can be part of the explanation why ducks are so well adaptable and successful, as well as why they show extraordinary abilities to withstand AI infections, or its consequences for health status.

    Verzekeren van broedeieren bij een uitbraak van vogelgriep
    Horne, P.L.M. van; Asseldonk, M.A.P.M. van; Bergevoet, R.H.M. - \ 2011
    Den Haag : LEI, onderdeel van Wageningen UR (LEI-rapport : Onderzoeksveld Markt & ketens ) - ISBN 9789086154968 - 58
    pluimveehouderij - aviaire influenza - kuikenproductie - nadelige gevolgen - landbouwverzekering - poultry farming - avian influenza - chick production - adverse effects - agricultural insurance
    Bij een uitbraak aviaire influenza (AI) hebben pluimveevermeerderingsbedrijven grote economische schade. Voor bedrijven gelegen in een gebied met beperkende maatregelen kan de schade zo hoog oplopen dat de continuïteitspositie in het geding is. In deze studie is de schade voor de vermeerderingsbedrijven gekwantificeerd. Vervolgens is aangegeven hoe de sector kan komen tot een verzekering of collectieve fondsvorming om de schade van de bedrijven bij een uitbraak van AI te compenseren.
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