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Titel:Untersuchungen zur Optimierung der genetischen Konstellation von Influenzaimpfstoff-Saatviren unter Verwendung einer attenuierten Mutante des Virusisolats A/FPV/Rostock/1934 (H7N1)
Autor:Alex, Nina
Weitere Beteiligte: Bölker, Michael (Prof. Dr.)
Veröffentlicht:2013
URI:https://archiv.ub.uni-marburg.de/diss/z2014/0224
URN: urn:nbn:de:hebis:04-z2014-02241
DOI: https://doi.org/10.17192/z2014.0224
DDC:570 Biowissenschaften, Biologie
Publikationsdatum:2014-10-21
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Antigen, Influenza-A-Viren, Reassortanten, Reassortanten, Impfstoffsaatviren, Influenza-A-virus, Impfstoffsaatviren, reassortants, Influenza-A-Viren, vaccine-seed, Antigen, antigen

Zusammenfassung:
Influenza-A-Viren lösen beim Menschen hochansteckende Infektionen der Atemwege aus, die in Abhängigkeit des Immunstatus der Person und der Pathogenität des Virus unterschiedlich schwere Krankheitsverläufe nehmen können. Eine Impfung bietet hierbei den effektivsten Schutz vor einer Infektion und den damit einhergehenden gesundheitlichen Komplikationen. Zum jetzigen Zeitpunkt erfolgt die Herstellung der Impfstoffe überwiegend in embryonierten Hühnereiern, jedoch zunehmend auch in zellkulturbasierten Vermehrungssystemen (MDCK- und Vero-Zellen). Einer der wichtigsten limitierenden Faktoren für die ausreichende Impfstoffversorgung der Bevölkerung stellt dabei die erzeugbare Antigenausbeute dar, die abhängig von dem eingesetzten Saatvirus stark variabel sein kann. Insbesondere bei neu auftretenden pandemischen Viren, wie z.B. denen der H1N1-Pandemie 2009 sowie den H5N1-Isolaten, sind die erzielbaren Antigenmengen häufig sehr niedrig. In dieser Arbeit wurde mit dem Fokus höhere Antigenausbeuten zu erzielen, die Eignung der apathogenen, attenuierten Variante FPVmut des hochpathogenen aviären Influenzastammes A/Huhn/Rostock/1934 (H7N1) als neuer, alternativer Akzeptorstamm für die Generierung der Impfstoffsaatviren im Vergleich zu dem gegenwärtig durch die WHO empfohlenen humanen H1N1-Stamm A/Puerto Rico/8/1934 (PR8) analysiert. Zusätzlich wurde der Einfluss der Inkorporation des zu den Oberflächenantigenen Hämagglutinin und Neuraminidase (HA und NA) homologen M-Gens in die Saatviren untersucht. Hierzu wurden mittels des Reversen-Genetik-Systems Doppel-Reassortanten (HA+NA) sowie Triple-Reassortanten (HA+NA+M) in den beiden zu vergleichenden Akzeptorstämmen hergestellt. Bei dieser Reassortierungsmethode kann die genetische Zusammensetzung der zu erzeugenden rekombinanten Viren vorab gezielt festgelegt werden, da die Virusgenerierung ausschließlich ausgehend von klonierter cDNA erfolgt. Hierzu werden acht für die Gensegmente kodierenden Plasmide in Zellen transfiziert. Als Donorviren wurden sowohl saisonale Viren der Subtypen H1N1 und H3N2 als auch (potenziell) pandemische Isolate der Subtypen H1N1pdm09, H5N1 und H9N2 eingesetzt. FPVmut zeichnet sich bei Vermehrung in embryonierten Hühnereiern sowie MDCK- und Vero-Zellen durch identische Ausbeuten im Vergleich mit dem aufgrund seiner guten Wachstumseigenschaften für die Erzeugung von Influenzasaatviren standardmäßig eingesetzten PR8-Isolat aus. Zusätzlich erwiesen sich beide Hintergrundstämme grundsätzlich als gleichermaßen geeignet für die Erzeugung rekombinanter Viren, da mit ihnen im selben Zeitrahmen ein identischer Satz an Reassortanten erzeugt werden konnte. Bei der Untersuchung der Replikationseigenschaften zeigte sich, dass bei den Viren mit dem FPVmut-Hintergrund eine produktive MDCK-Zellinfektion zu früheren Zeitpunkten einsetzte und ergänzend bei den aviären Donor-Isolaten eine gesteigerte Infektionsausbreitung beobachtet werden konnte. Kein wesentlicher Unterschied war in der NA-Ausbeute oder der Virusmorphologie in Abhängigkeit von dem Hintergrundstamm oder der genetischen Zusammensetzung festzustellen. Bei Verwendung des aviären H5N1 konnte eine deutliche Steigerung der Antigenausbeute im Hühnerei- und noch signifikanter im Vero-Anzuchtsystem erzielt werden, wodurch sich für dieses potenziell pandemische Isolat das FPVmut als ein leistungsfähigerer Akzeptorstamm im Vergleich zu dem PR8-Standardsystem herausstellte. Hierbei wurden sowohl höhere gemittelte als auch maximal erreichbare HA-Titer sowie höhere absolute HA-Antigenmengen in der Allantoisflüssigkeit infizierter Hühnereier gemessen. Bei der Vermehrung in Vero-Zellen wurden in den Doppel-Reassortanten nach einer 72-stündigen Inkubation 3fach höhere HA-Antigenmengen im FPVmut Akzeptorstamm erhalten. Im Falle des H9N2-Isolates bewirkte die Inkorporation des homologen M-Gensegmentes im FPVmut-Hintergrund eine Steigerung der Antigenausbeute um den Faktor 1,5. Auch bei dem H1N1pdm09-Isolat wurden die höchsten Einzelwerte der HA-Ausbeuten nach Inkorporation des M-Gensegmentes im PR8-Hintergrund gemessen. Somit konnte gezeigt werden, dass sich isolatabhängig Triple-Reassortanten als sinnvolle Variation der genetischen Zusammensetzung der Saatviren eignen können und die Verwendung eines aviären Akzeptorstammes zu einer deutlichen Steigerung der erzielbaren HA-Antigenausbeute in unterschiedlichen Vermehrungssystemen führen kann.

Summary:
Influenza-A-viruses cause highly contagious respiratory infections in different species against which vaccination provides the most effective protection. Presently the majority of influenza vaccines are still produced in embryonated chicken eggs but the development of cell culture-based systems is increasing (e.g. MDCK- and Vero-cells). The producible antigen yield that is highly dependent on the seed virus growth capacities is the major limiting factor for sufficient vaccine supply. In particular for emerging pandemic viruses the recoverable amounts of antigen are often very low (such as those of the H1N1 pandemic of 2009 and potentially pandemic H5N1 isolates). The focus of this work was to generate higher antigen yields by using an alternative acceptor strain for the generation of the reassortant seed viruses to be used for vaccine production. Usually the human H1N1-subtype isolate A/Puerto Rico/8/1934 (PR8) is the recommended high-yield acceptor strain for the integration of the surface antigen proteins of circulating viruses. In this study the suitability of the non-pathogenic, attenuated variant FPVmut of the avian influenza strain A/chicken/Rostock/1934 (H7N1) to serve as an alternative background strain was explored. For this purpose recombinant reassortant viruses were generated in both acceptor strain backgrounds that contained the antigenic surface proteins hemagglutinin and neuraminidase (HA and NA) of selected seasonal and (potentially) pandemic donor viruses (subtypes H1N1, H1N1pdm, H3N2, H5N1, H9N2). Further, due to its established function in promoting viral particle formation the potential influence of the incorporation of the HA- and NA-homologous M1 protein was analyzed. Both acceptor strains, FPVmut and PR8, produced almost identical viral yields when propagated in embryonated chicken eggs, MDCK- and Vero-cells. However, we found that the onset of virus production and growth to high titers in MDCK cells was faster for FPVmut than for PR8. Both acceptor strains were equally suitable for the generation of recombinant reassortant viruses applying a “reverse genetics” approach. For reassortants carrying HA and NA from an avian donor strain a more rapid and pronounced cell-to-cell spread was detectable in the FPVmut acceptor background. No significant differences were observed in the NA yields or the virus morphology depending on the background strain or the genetic composition. When using a potentially pandemic avian H5N1 strain as HA and NA donor a significant increase in the antigen yield was obtained in chicken eggs with FPVmut-reassortants. Both, higher average and maximum HA-titers and higher absolute amounts of HA-antigen were reached in the allantoic fluid of infected eggs in the FPVmut-background. This finding was even more pronounced in the Vero cell production system where the HA-antigen yields achievable with the FPVmut-reassortants were threefold higher than those of the PR8-reassortants. For the H9N2 isolate the incorporation of the surface proteins homologous M gene segment within the FPVmut genetic background resulted in an 1,5-fold increase in antigen yield. Similarly, for the H1N1pdm09 donor virus the highest individual values of the HA yields were measured in the PR8 background with the homologous M gene segment. Taken together, these data show that depending on the donor virus the use of the alternative acceptor strain FPVmut and/or the integration of the homologous M1 protein are effective approaches to optimize the composition of influenza vaccine seed viruses to achieve higher HA antigen yields. Therefore, both approaches could be of good value for the production of future seasonal and pandemic vaccines.

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