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Lethality Caused by Small Particle Aerosols of H5N1 Influenza Virus in Cynomolgus Macaques Is Highly Dose Dependent
DOUGLAS REED, Katherine O'Malley, Mengying Xia, Morgan Midgett, Emily Olsen, Gwenddolen Kettenburg, Michelle Marti, Priscilla da Silva Castanha, Jacqueline Corry, Masaru Kanekiyo, Barney Graham, Simon Barratt-Boyes, University of Pittsburgh
Abstract Number: 128
Working Group: Infectious Aerosols in the Age of COVID-19
Abstract
We have previously demonstrated that exposure of cynomolgus macaques to aerosols containing high (106-107 pfu) doses of highly pathogenic H5N1 (A/Vietnam/1203/2004) avian influenza virus triggered a rapid acute respiratory distress that was lethal within 3-4 days. Fever and increased respiratory rate were noted within the first day of exposure and PET/CT imaging found evidence of an enormous inflammatory response in the lungs two days after exposure. There was a substantial depletion of the alveolar epithelium as well as elevated levels of inflammatory cytokines and chemokines in the blood and lungs. To evaluate whether the pathogenicity and lethality would be virus dose dependent, we performed a study exposing cynomolgus macaques to lower doses of H5N1. Even at the lowest dose tested, 102 pfu, macaques developed a fever response within 24 hours of infection. Substantial respiratory changes were only seen at the highest doses tested, 105 pfu. Four of the six macaques exposed at the dose in the 105 pfu range succumbed to the disease within 4-6 days. At lower doses, no macaque succumbed to infection. Surviving macaques had largely recovered by 7 days post-infection and were euthanized and necropsied at 14-15 days post-infection. Although tissues from survivors were negative for virus by plaque assay and there was no obvious gross pathology, both immunohistochemistry and PCR assays found evidence for residual viral infection in the lungs at study endpoint. In addition, all surviving macaques had anti-NP antibody at study endpoint. Analysis of these results as well as our prior data established an inhaled dose of 2.51 x 105 pfu as the LD50 for aerosolized H5N1 in the cynomolgus macaque model. This model will be useful for studying the underlying pathogenesis of lethal disease caused by H5N1 as well as evaluation of potential vaccines, prophylactics, or therapeutics.