title: Repeated Low-Dose Influenza Virus Infection Causes Severe Disease in Mice: a Model for Vaccine Evaluation.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Science, Shanghai, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Song
authors.affiliation: Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Science, Shanghai, China Institute of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Science, Shanghai, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Science, Shanghai, China.
authors.forename: Xinying
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Laboratory Medicine, Ren Ji Hospital School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Animal Centre, Ren Ji Hospital School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jufang
authors.initials: J
authors.lastname: Yao
authors.affiliation: Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Science, Shanghai, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Jin
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Hildegund C J
authors.initials: HC
authors.lastname: Ertl
authors.affiliation: Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Science, Shanghai, China dmzhou@ips.ac.cn.
authors.forename: Dongming
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D002642:Chick Embryo; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000914:Antibodies, Viral; D007252:Influenza Vaccines