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Title: Modifications in the Polymerase Genes of a Swine-Like Triple Reassortant Influenza Virus to Generate Live Attenuated Vaccines Against 2009 Pandemic H1N1 Viruses

Author
item PENA, LINDOMAR - University Of Maryland
item Baker, Amy
item YE, JIANQIANG - University Of Maryland
item CIACCI-ZANELLA, JANICE - Labex - Embrapa
item ANGEL, MATTHEW - University Of Maryland
item GAUGER, PHILIP - Iowa State University
item JANKE, BRUCE - Iowa State University
item Loving, Crystal
item PEREZ, DANIEL - University Of Maryland

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/13/2010
Publication Date: 1/1/2011
Citation: Pena, L., Vincent, A.L., Ye, J., Ciacci-Zanella, J.R., Angel, M., Lorusso, A., Gauger, P.C., Janke, B.H., Loving, C.L., Perez, D.R. 2011. Modifications in the polymerase genes of a swine-like triple reassortant influenza virus to generate live attenuated vaccines against 2009 pandemic H1N1 Viruses. Journal of Virology. 85(1):456-469.

Interpretive Summary: Pandemic influenza (H1N1) 2009 virus has infected people in over 200 countries and also spread to animal species such as pigs. The development of effective pandemic H1N1 vaccines for use in multiple species would mitigate the impact of the evolving flu pandemic. We generated and tested the safety and the efficacy of live attenuated (att) H1N1 viruses that had been weakened by laboratory methods as vaccines in both mice and pigs. The mouse model sought to represent the severe H1N1 pneumonia seen in some human patients, while swine are important livestock species in which the H1N1pdm virus has caused outbreaks of varying intensity. The live att H1N1 vaccines were shown to be weakened in mice and pigs and provided complete protection against the 2009 H1N1 pandemic virus. This was the first testing of live att vaccines based on mutations in the polymerase complex in pigs. Our vaccine approach highlights its potential for the prevention of influenza across species, a key requirement for the One Health Initiative endorsed by FAO, OIE and WHO whose major goal is to improve the lives of all species through the integration of human and veterinary medicine.

Technical Abstract: On June 11, 2009 the World Health Organization (WHO) declared that the outbreaks caused by novel swine-origin influenza A (H1N1) virus had reached pandemic proportions. The pandemic H1N1 (H1N1pdm) is the predominant influenza strain in the human population. It has also crossed the species barriers and infected turkeys and swine in several countries. Thus, the development of a vaccine that is effective in multiple animal species is urgently needed. We have previously demonstrated that introduction of temperature-sensitive mutations in the PB2 and PB1 genes of an avian H9N2 combined with the insertion of an HA tag in PB1 resulted in an attenuated (att) vaccine backbone for both chickens and mice. Because the new pandemic strain is a triple reassortant (TR) virus, we chose a swine-like TR virus isolate, A/turkey/OH/313053/04 (H3N2) (ty/04), to introduce the double attenuating modifications with the goal of producing live attenuated influenza vaccines (LAIV). This genetically modified backbone had impaired polymerase activity and restricted virus growth at elevated temperatures. In vivo characterization of two H1N1 vaccine candidates generated using the ty/04 att backbone demonstrated that this vaccine is highly attenuated in mice as indicated by the absence of signs of disease, limited replication and minimum histopathological alterations in the respiratory tract. A single immunization with the ty/04 att-based vaccines conferred complete protection against a lethal H1N1pdm infection in mice. More importantly, vaccination of pigs with a ty/04 att-H1N1 vaccine candidate resulted in sterilizing immunity upon an aggressive intratracheal challenge with the 2009 H1N1 pandemic virus. Our studies highlight the safety of the ty/04 att vaccine platform and its potential as a master donor strain for the generation of live attenuated vaccines for humans and livestock.