Kinetics of lung lesion development and pro-inflammatory cytokine response in pigs with vaccine-associated enhanced respiratory disease induced by challenge with pandemic (2009) A/H1N1 influenza virus

Vet Pathol. 2012 Nov;49(6):900-12. doi: 10.1177/0300985812439724. Epub 2012 Mar 28.


The objective of this report was to characterize the enhanced clinical disease and lung lesions observed in pigs vaccinated with inactivated H1N2 swine δ-cluster influenza A virus and challenged with pandemic 2009 A/H1N1 human influenza virus. Eighty-four, 6-week-old, cross-bred pigs were randomly allocated into 3 groups of 28 pigs to represent vaccinated/challenged (V/C), non-vaccinated/challenged (NV/C), and non-vaccinated/non-challenged (NV/NC) control groups. Pigs were intratracheally inoculated with pH1N1 and euthanized at 1, 2, 5, and 21 days post inoculation (dpi). Macroscopically, V/C pigs demonstrated greater percentages of pneumonia compared to NV/C pigs. Histologically, V/C pigs demonstrated severe bronchointerstitial pneumonia with necrotizing bronchiolitis accompanied by interlobular and alveolar edema and hemorrhage at 1 and 2 dpi. The magnitude of peribronchiolar lymphocytic cuffing was greater in V/C pigs by 5 dpi. Microscopic lung lesion scores were significantly higher in the V/C pigs at 2 and 5 dpi compared to NV/C and NV/NC pigs. Elevated TNF-α, IL-1β, IL-6, and IL-8 were detected in bronchoalveolar lavage fluid at all time points in V/C pigs compared to NV/C pigs. These data suggest H1 inactivated vaccines followed by heterologous challenge resulted in potentiated clinical signs and enhanced pulmonary lesions and correlated with an elevated proinflammatory cytokine response in the lung. The lung alterations and host immune response are consistent with the vaccine-associated enhanced respiratory disease (VAERD) clinical outcome observed reproducibly in this swine model.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Neutralizing / blood
  • Antibodies, Viral / blood
  • Antibodies, Viral / immunology
  • Bronchoalveolar Lavage Fluid
  • Cytokines / analysis
  • Cytokines / metabolism
  • Disease Models, Animal
  • Influenza A Virus, H1N1 Subtype / immunology*
  • Influenza A Virus, H1N1 Subtype / pathogenicity
  • Influenza A Virus, H1N2 Subtype / immunology*
  • Influenza Vaccines / administration & dosage
  • Influenza Vaccines / adverse effects*
  • Kinetics
  • Lung / pathology
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / pathology
  • Orthomyxoviridae Infections / veterinary*
  • Orthomyxoviridae Infections / virology
  • Pneumonia, Viral / immunology
  • Pneumonia, Viral / pathology
  • Pneumonia, Viral / veterinary*
  • Pneumonia, Viral / virology
  • Severity of Illness Index
  • Swine
  • Swine Diseases / immunology*
  • Swine Diseases / pathology
  • Swine Diseases / prevention & control
  • Swine Diseases / virology
  • Vaccines, Inactivated / administration & dosage
  • Vaccines, Inactivated / adverse effects
  • Virus Replication
  • Virus Shedding


  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Cytokines
  • Influenza Vaccines
  • Vaccines, Inactivated