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A mouse model for the evaluation of pathogenesis and immunity to influenza A (H5N1) viruses isolated from humans
1Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.
Abstract:
During 1997 in Hong Kong, 18 human cases of respiratory illness, including 6 fatalities, were caused by highly pathogenic avian influenza A (H5N1) viruses. Since H5 viruses had previously been isolated only from avian species, the outbreak raised questions about the ability of these viruses to cause severe disease and death in humans. To better understand the pathogenesis and immunity to these viruses, we have used the BALB/c mouse model. Four H5N1 viruses replicated equally well in the lungs of mice without prior adaptation but differed in lethality for mice. H5N1 viruses that were highly lethal for mice were detected in multiple organs, including the brain. This is the first demonstration of an influenza A virus that replicates systemically in a mammalian species and is neurotropic without prior adaptation. The mouse model was also used to evaluate a strategy of vaccination against the highly pathogenic avian H5N1 viruses, using an inactivated vaccine prepared from nonpathogenic A/Duck/Singapore-Q/F119-3/97 (H5N3) virus that was antigenically related to the human H5N1 viruses. Mice administered vaccine intramuscularly, with or without alum, were completely protected from lethal challenge with H5N1 virus. Protection from infection was also observed in 70% of animals administered vaccine alone and 100% of mice administered vaccine with alum. The protective effect of vaccination correlated with the level of virus-specific serum antibody. These results suggests a strategy of vaccine preparedness for rapid intervention in future influenza pandemics that uses antigenically related nonpathogenic viruses as vaccine candidates.
Insights
Highly pathogenic avian influenza A (H5N1) viruses caused severe human illness and death. A mouse model showed H5N1 can be neurotropic and systemic, and a related H5N3 vaccine protected mice from lethal H5N1 infection.
Area of Science:
- Virology
- Immunology
- Pathogenesis
Background:
- The 1997 Hong Kong outbreak of highly pathogenic avian influenza A (H5N1) demonstrated severe human disease and fatalities.
- Previous understanding limited H5 viruses to avian species, raising questions about their zoonotic potential and human pathogenicity.
Purpose of the Study:
- To investigate the pathogenesis and immune response to avian H5N1 influenza viruses in a mammalian model.
- To evaluate the efficacy of a vaccination strategy using an antigenically related, nonpathogenic H5N3 virus against H5N1 infection.
Main Methods:
- Utilized the BALB/c mouse model to study the replication and lethality of four different H5N1 viruses.
- Assessed systemic viral spread, including neurotropism, in infected mice.
- Administered an inactivated H5N3 vaccine (with or without alum) to mice and subsequently challenged them with a lethal H5N1 virus.
Main Results:
- Four H5N1 viruses replicated in mouse lungs without adaptation, exhibiting varying lethality.
- Highly lethal H5N1 viruses disseminated to multiple organs, including the brain, demonstrating systemic infection and neurotropism.
- Vaccination with the H5N3 candidate vaccine conferred complete protection against lethal H5N1 challenge in mice, especially when combined with alum.
- Vaccine efficacy correlated with virus-specific serum antibody levels.
Conclusions:
- Avian H5N1 influenza viruses can cause systemic and neurotropic infections in mammals without prior adaptation.
- An inactivated vaccine derived from an antigenically related, nonpathogenic H5N3 virus provides effective protection against lethal H5N1 avian influenza.
- This suggests a viable strategy for pandemic preparedness using related, less pathogenic viruses for vaccine development.