Pathogenicity and immunogenicity of influenza viruses with genes from the 1918 pandemic virus

Terrence M. Tumpey ^* , Adolfo García-Sastre , Jeffery K. Taubenberger , Peter Palese , David E. Swayne ^* and Christopher F. Basler 

^*Southeast Poultry Research Laboratory, Agricultural Research Service, U.S. Department of Agriculture, Athens, GA 30605; Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029; and Division of Molecular Pathology, Department of Cellular Pathology and Genetics, Armed Forces Institute of Pathology, Rockville, MD 20850

Contributed by Peter Palese, December 16, 2003

The 1918 influenza A H1N1 virus caused the worst pandemic of influenza ever recorded. To better understand the pathogenesis and immunity to the 1918 pandemic virus, we generated recombinant influenza viruses possessing two to five genes of the 1918 influenza virus. Recombinant influenza viruses possessing the hemagglutinin (HA), neuraminidase (NA), matrix (M), nonstructural (NS), and nucleoprotein (NP) genes or any recombinant virus possessing both the HA and NA genes of the 1918 influenza virus were highly lethal for mice. Antigenic analysis by hemagglutination inhibition (HI) tests with ferret and chicken H1N1 antisera demonstrated that the 1918 recombinant viruses antigenically most resembled A/Swine/Iowa/30 (Sw/Iowa/30) virus but differed from H1N1 viruses isolated since 1930. HI and virus neutralizing (VN) antibodies to 1918 recombinant and Sw/Iowa/30 viruses in human sera were present among individuals born before or shortly after the 1918 pandemic. Mice that received an intramuscular immunization of the homologous or Sw/Iowa/30-inactivated vaccine developed HI and VN antibodies to the 1918 recombinant virus and were completely protected against lethal challenge. Mice that received A/PR/8/34, A/Texas/36/91, or A/New Caledonia/20/99 H1N1 vaccines displayed partial protection from lethal challenge. In contrast, control-vaccinated mice were not protected against lethal challenge and displayed high virus titers in respiratory tissues. Partial vaccine protection mediated by baculovirus-expressed recombinant HA vaccines suggest common cross-reactive epitopes on the H1 HA. These data suggest a strategy of vaccination that would be effective against a reemergent 1918 or 1918-like virus.

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Abbreviations: eID₅₀, egg 50% infectious dose; HA, hemagglutinin; HI, hemagglutination inhibition; i.n., intranasal(ly); M, matrix; MDCK, Madin-Darby canine kidney; NA, neuraminidase; New Cal/99, influenza A/New Caledonia/20/99 (H1N1) virus; NP, nucleoprotein; NS, nonstructural; p.c., postchallenge; p.i., postinfection; Sw/Iowa/30, influenza A/Swine/Iowa/30 (H1N1) virus; rHA, recombinant HA; WSN, influenza A/WSN/33 (H1N1) virus; VN, virus neutralization.

To whom correspondence should be addressed at: Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Mailstop G-16, 1600 Clifton Road Northeast, Atlanta, GA 30333. E-mail: tft9@cdc.gov .