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

Abstract

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.

Fig. 1.

Protective efficacy of influenza H1N1-inactivated vaccine against lethal challenge with 1918 HA/NA:WSN recombinant influenza virus. Groups of BALB/c mice received a single i.m. inoculation of H1N1 or H3N2 (X-31) vaccine. Control mice received PBS in place of vaccine. Twenty-two days after vaccination, mice were challenged i.n. with 100 LD₅₀ of 1918 HA/NA:WSN recombinant virus. Mice were monitored for survival (A) or killed 5 days later, and virus titers in individual lung, nose, and brain tissue were determined (B). Virus endpoint titers are expressed as mean log₁₀ eID₅₀/ml.

Fig. 2.

Sw/Iowa/30 vaccine provides protection against lethal challenge with a recombinant influenza virus possessing five 1918 virus genes. Groups of BALB/c mice were vaccinated as described in the legend of Fig. 1. Twenty-two days after vaccination, mice were challenged i.n. with 100 LD₅₀ of 1918 HA/NA/M/NS/NP:WSN recombinant virus. Mice were monitored for survival (A) or killed 5 days later, and virus titers in individual lung, nose, and brain tissue were determined (B). An asterisk indicates that the H1N1-vaccinated group was significantly (P < 0.05) different from the control groups by ANOVA.