Modifications in the polymerase genes of a swine-like triple-reassortant influenza virus to generate live attenuated vaccines against 2009 pandemic H1N1 viruses.
On 11 June 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) virus is the predominant influenza virus 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 the introduction of temperature-sensitive mutations into the PB2 and PB1 genes of an avian H9N2 virus, combined with the insertion of a hemagglutinin (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 to introduce the double attenuating modifications into a swine-like TR virus isolate, A/turkey/OH/313053/04 (H3N2) (ty/04), 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 virus 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.
Pena
Lindomar
L
Department of Veterinary Medicine, University of Maryland, VA-MD Regional College of Veterinary Medicine, 8075 Greenmean Dr., College Park, MD 20742, USA.
Vincent
Amy L
AL
Ye
Jianqiang
J
Ciacci-Zanella
Janice R
JR
Angel
Matthew
M
Lorusso
Alessio
A
Gauger
Philip C
PC
Janke
Bruce H
BH
Loving
Crystal L
CL
Perez
Daniel R
DR
D000818:Animals; D002460:Cell Line; D006801:Humans; D007114:Immunization; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics* / Q000276:immunology; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics* / Q000276:immunology; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000517:prevention & control / Q000662:veterinary; D058873:Pandemics; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics*; D016865:Reassortant Viruses / Q000201:enzymology / Q000235:genetics; D013552:Swine; D013553:Swine Diseases / Q000276:immunology / Q000517:prevention & control; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics* / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics*
D007252:Influenza Vaccines; C057027:PB2 protein, Influenzavirus A; D014613:Vaccines, Attenuated; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; D012324:RNA-Dependent RNA Polymerase