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Journal of Virology, February 2009, p. 1742-1753, Vol. 83, No. 4
0022-538X/09/$08.00+0     doi:10.1128/JVI.01920-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Live Attenuated Influenza Viruses Containing NS1 Truncations as Vaccine Candidates against H5N1 Highly Pathogenic Avian Influenza {triangledown}

John Steel,1 Anice C. Lowen,1 Lindomar Pena,4 Matthew Angel,4 Alicia Solórzano,4 Randy Albrecht,1 Daniel R. Perez,4 Adolfo García-Sastre,1,2,3 and Peter Palese1,2*

Department of Microbiology,1 Department of Medicine, Division of Infectious Diseases,2 Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, 1 Gustave Levy Pl., New York, New York 10029-6574,3 Department of Veterinary Medicine, University of Maryland, College Park, and Virginia-Maryland Regional College of Veterinary Medicine, 8075 Greenmead Drive, College Park, Maryland 20742-37114

Received 11 September 2008/ Accepted 17 November 2008

Due to the high mortality associated with recent, widely circulating strains of H5N1 influenza virus in poultry, the recurring introduction of H5N1 viruses from birds to humans, and the difficulties in H5N1 eradication by elimination of affected flocks, an effective vaccine against HPAI (highly pathogenic avian influenza) is highly desirable. Using reverse genetics, a set of experimental live attenuated vaccine strains based on recombinant H5N1 influenza virus A/Viet Nam/1203/04 was generated. Each virus was attenuated through expression of a hemagglutinin protein in which the polybasic cleavage site had been removed. Viruses were generated which possessed a full-length NS1 or a C-terminally truncated NS1 protein of 73, 99, or 126 amino acids. Viruses with each NS genotype were combined with a PB2 polymerase gene which carried either a lysine or a glutamic acid at position 627. We predicted that glutamic acid at position 627 of PB2 would attenuate the virus in mammalian hosts, thus increasing the safety of the vaccine. All recombinant viruses grew to high titers in 10-day-old embryonated chicken eggs but were attenuated in mammalian cell culture. Induction of high levels of beta interferon by all viruses possessing truncations in the NS1 protein was demonstrated by interferon bioassay. The viruses were each found to be highly attenuated in a mouse model. Vaccination with a single dose of any virus conferred complete protection from death upon challenge with a mouse lethal virus expressing H5N1 hemagglutinin and neuraminidase proteins. In a chicken model, vaccination with a single dose of a selected virus encoding the NS1 1-99 protein completely protected chickens from lethal challenge with homologous HPAI virus A/Viet Nam/1203/04 (H5N1) and provided a high level of protection from a heterologous virus, A/egret/Egypt/01/06 (H5N1). Thus, recombinant influenza A/Viet Nam/1203/04 viruses attenuated through the introduction of mutations in the hemagglutinin, NS1, and PB2 coding regions display characteristics desirable for live attenuated vaccines and hold potential as vaccine candidates in poultry as well as in mammalian hosts.

* Corresponding author. Mailing address: Department of Microbiology, Mount Sinai School of Medicine, 1 Gustave Levy Pl., New York, NY 10029-6574. Phone: (212) 241-7318. Fax: (212) 722-3634. E-mail: peter.palese{at}mssm.edu

{triangledown} Published ahead of print on 10 December 2008.

Journal of Virology, February 2009, p. 1742-1753, Vol. 83, No. 4
0022-538X/09/$08.00+0     doi:10.1128/JVI.01920-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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  • Plotkin, S. A. (2009). Vaccines: the Fourth Century. CVI 16: 1709-1719 [Abstract] [Full Text]  


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