Exposure Route Influences Disease Severity in the COVID-19 Cynomolgus Macaque Model

Abstract

The emergence of SARS-CoV-2 and the subsequent pandemic has highlighted the need for animal models that faithfully replicate the salient features of COVID-19 disease in humans. These models are necessary for the rapid selection, testing, and evaluation of potential 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 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 produced 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.

Preclinical characterization of amubarvimab and romlusevimab, a pair of non-competing neutralizing monoclonal antibody cocktail, against SARS-CoV-2

“…Plaque titrations were performed on serial dilutions of the clarified homogenate to quantify infectious virus in PFU as previously reported ( 28 ). Total RNA was extracted from clarified lung homogenates in Trizol™ LS, and the viral RNA was quantified using E gene subgenomic RT-PCR assay as previously described ( 29 ). The histopathology of the lung was evaluated based on lung tissue sections fixed with 10% neutral buffered formalin, paraffin embedded, and then hematoxylin and eosin (H&E) stained ( 30 ).…”

Risk Factors of Severe COVID-19: A Review of Host, Viral and Environmental Factors

“…The route of transmission might also influence the clinical outcome of COVID-19. Multiple studies using animal models of COVID-19 indicate that airborne and especially aerosol transmission might result in a disease with an earlier onset and higher severity compared to infections acquired by fomite, oral or gastrointestinal exposures [ 888 , 901 , 902 , 903 ].…”

Airborne Transmission and Control of Influenza and Other Respiratory Pathogens

“…The community-infected cases documented by Knight and colleagues exhibited similar symptomatology as Alford's infected volunteers, suggesting a natural tendency toward aerosol transmission. These findings were more recently borne out in ferrets where aerosol-infected animals not only presented with more severe symptoms but also shed more virus than their nasally-inoculated counterparts [57] cynomolgus macaques exposed to SARS-CoV-2 via aerosols were more likely to experience fever and severe respiratory pathology compared with those exposed via intratracheal/intranasal drops, suggesting similar anisotropy [58].…”