SARS-CoV-2 viral dynamics in non-human primates

Abstract

Non-human primates infected with SARS-CoV-2 exhibit mild clinical signs. Here we used a mathematical model to characterize in detail the viral dynamics in 31 cynomolgus macaques for which nasopharyngeal and tracheal viral load were frequently assessed. We identified that infected cells had a large burst size (>104 virus) and a within-host reproductive basic number of approximately 6 and 4 in nasopharyngeal and tracheal compartment, respectively. After peak viral load, infected cells were rapidly lost with a half-life of 9 hours, with no significant association between cytokine elevation and clearance, leading to a median time to viral clearance of 10 days, consistent with observations in mild human infections. Given these parameter estimates, we predict that a prophylactic treatment blocking 90% of viral production or viral infection could prevent viral growth. In conclusion, our results provide estimates of SARS-CoV-2 viral kinetic parameters in an experimental model of mild infection and they provide means to assess the efficacy of future antiviral treatments.

Fig 1. Nasopharyngeal and tracheal SARS-CoV-2 viral loads in infected cynomolgus macaques treated by a placebo or hydroxychloroquine ± azithromycin.

Dashed lines represent the lower limit of detection (LOD) and lower limit of quantification (LOQ).

Fig 2. Relationship between TCID₅₀ and viral loads. Each symbol corresponds to a tracheal swab obtained at 3 dpi.

A) Viral load levels in samples with no detectable infectious virus (circles) and those with detectable infectious virus (triangles). B) Correlation between the viral loads and the infectious virus, as measured by TCID₅₀. Red, green and purple dashed lines represent putative ratios of infectious virus of 10⁻⁴; 10⁻⁵ and 10⁻⁶ respectively.

Fig 3

Nasopharyngeal (blue) and tracheal (red) individual predicted dynamics by the model described in Eqs (1) to (5). Full dots are the quantifiable viral loads and crosses the observation below the limit of quantification. The dotted line represents the limit of quantification and the dashed line the limit of detection.

Fig 4. Cytokine concentrations during SARS-CoV-2 infection.

Fig 5. Correlation between the individual predicted AUC log₁₀ viral load and cytokine AUC.

None of the 6 cytokines that increased during the infection was significantly correlated with the predicted viral load AUC in the nasopharynx or the trachea.

Fig 6

Median viral kinetic profiles in the nasopharynx (blue) and the trachea (red) according to the inoculum size and the level of an antiviral initiated in prophylaxis and blocking viral entry β. Treatment efficacy of 0% (no treatment, solid line), 90% (dashed line) and 99% (dotted lines) were considered. Point-dotted line represents the threshold below which no virus could be cultured in vitro (Fig 2).