Related Experiment Video
Updated: Apr 12, 2026
Modeling Dysplastic and Functional Lung Alveolar Repair after Influenza Infection
Published on: September 19, 2025
Repeated Low-Dose Influenza Virus Infection Causes Severe Disease in Mice: a Model for Vaccine Evaluation
Yufeng Song1, Xiang Wang2, Hongbo Zhang1
1Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Science, Shanghai, China.
Unlabelled:
Influenza infection causes severe disease and death in humans. In traditional vaccine research and development, a single high-dose virus challenge of animals is used to evaluate vaccine efficacy. This type of challenge model may have limitations. In the present study, we developed a novel challenge model by infecting mice repeatedly in short intervals with low doses of influenza A virus. Our results show that compared to a single high-dose infection, mice that received repeated low-dose challenges showed earlier morbidity and mortality and more severe disease. They developed higher vial loads, more severe lung pathology, and greater inflammatory responses and generated only limited influenza A virus-specific B and T cell responses. A commercial trivalent influenza vaccine protected mice against a single high and lethal dose of influenza A virus but was ineffective against repeated low-dose virus challenges. Overall, our data show that the repeated low-dose influenza A virus infection mouse model is more stringent and may thus be more suitable to select for highly efficacious influenza vaccines.
Importance:
Influenza epidemics and pandemics pose serious threats to public health. Animal models are crucial for evaluating the efficacy of influenza vaccines. Traditional models based on a single high-dose virus challenge may have limitations. Here, we describe a new mouse model based on repeated low-dose influenza A virus challenges given within a short period. Repeated low-dose challenges caused more severe disease in mice, associated with higher viral loads and increased lung inflammation and reduced influenza A virus-specific B and T cell responses. A commercial influenza vaccine that was shown to protect mice from high-dose challenge was ineffective against repeated low-dose challenges. Overall, our results show that the low-dose repeated-challenge model is more stringent and may therefore be better suited for preclinical vaccine efficacy studies.
Insights
A new mouse model using repeated low-dose influenza A virus challenges reveals limitations in traditional vaccine testing. This stringent model better predicts vaccine efficacy against severe influenza, aiding the development of more effective influenza vaccines.
Area of Science:
- Virology
- Immunology
- Vaccinology
Background:
- Influenza poses a significant global health threat, necessitating robust vaccine efficacy evaluation.
- Traditional animal models using single high-dose virus challenges may not accurately reflect real-world influenza infection dynamics.
- Developing more stringent preclinical models is crucial for selecting highly effective influenza vaccines.
Purpose of the Study:
- To develop and validate a novel mouse model for influenza vaccine evaluation using repeated low-dose influenza A virus challenges.
- To compare the outcomes of repeated low-dose challenges with traditional single high-dose challenges.
- To assess the efficacy of a commercial influenza vaccine in the novel challenge model.
Main Methods:
- Mice were infected with influenza A virus using either a single high dose or repeated low doses at short intervals.
- Disease severity, viral loads, lung pathology, inflammatory responses, and adaptive immune responses (B and T cells) were assessed.
- Vaccine efficacy was evaluated by challenging vaccinated mice with both single high-dose and repeated low-dose influenza A virus infections.
Main Results:
- Repeated low-dose challenges resulted in earlier morbidity, mortality, and more severe disease compared to single high-dose challenges.
- Mice in the repeated low-dose group exhibited higher viral loads, exacerbated lung pathology, and heightened inflammatory responses.
- A commercial influenza vaccine protected against single high-dose challenge but failed to protect against repeated low-dose challenges.
- Limited influenza A virus-specific B and T cell responses were observed in the repeated low-dose challenge model.
Conclusions:
- The repeated low-dose influenza A virus challenge model is more stringent and better mimics severe influenza disease.
- This novel model may be more suitable for identifying influenza vaccines with superior protective capabilities.
- Findings highlight the need for advanced challenge models in preclinical influenza vaccine development.
