Aerosol Exposure of Cynomolgus Macaques to SARS-CoV-2 Results in More Severe Pathology than Existing Models

Bixler, Sandra L.; Stefan, Christopher P.; Jay, Alexandra; Rossi, Franco; Ricks, Keersten M.; Shoemaker, Charles J.; Moreau, Alicia M.; Zeng, Xiankun; Hooper, Jay W.; Dyer, David; Frick, Ondraya; Koehler, Jeffrey W.; Kearney, Brian; DiPinto, Nina; Liu, Jun; Tostenson, Samantha; Clements, Tamara L.; Smith, Jeffrey M.; Johnson, Joshua A.; Berrier, Kerry; Esham, Heather; Delp, Korey L.; Coyne, Susan R.; Bloomfield, Holly; Kuehnert, Paul; Akers, Kristen; Gibson, Kathleen; Minogue, Timothy D.; Nalca, Aysegul; Pitt, Margaret L. M.

The emergence of SARS-CoV-2 pandemic has highlighted the need for animal models that faithfully recapitulate the salient features of COVID-19 disease in humans; these models are necessary for the rapid down-selection, testing, and evaluation of medical countermeasures. Here we performed a direct comparison of two distinct routes of SARS-CoV-2 exposure, combined intratracheal/intranasal and small particle aerosol, in two nonhuman primate species: rhesus and cynomolgus macaques. While all four experimental groups displayed very few outward clinical signs, evidence of mild to moderate respiratory disease was present on radiographs and at the time of necropsy. Cynomolgus macaques exposed via the aerosol route also developed the most consistent fever responses and had the most severe respiratory disease and pathology. This study demonstrates that while all four models were suitable representations of mild COVID-like illness, aerosol exposure of cynomolgus macaques to SARS-CoV-2 produced the most severe disease, which may provide additional clinical endpoints for evaluating therapeutics and vaccines.