Publikationsserver der Universitätsbibliothek Marburg
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
DOI: https://doi.org/10.17192/z2014.0224
URN: urn:nbn:de:hebis:04-z2014-02241
DDC: Biowissenschaften, Biologie
Titel (trans.):Studies to optimize the genetic constellation of influenza vaccine seed viruses using an attenuated mutant of the virus isolate A/FPV/Rostock/1934 (H7N1)
Publikationsdatum:2014-10-21
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

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

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.

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