A quantitative systems pharmacology model of the pathophysiology and treatment of COVID-19 predicts optimal timing of pharmacological interventions

A quantitative systems pharmacology (QSP) model of the pathogenesis and treatment of SARS-CoV-2 infection can streamline and accelerate the development of novel medicines to treat COVID-19. Simulation of clinical trials allows in silico exploration of the uncertainties of clinical trial design and can rapidly inform their protocols. We previously published a preliminary model of the immune response to SARS-CoV-2 infection. To further our understanding of COVID-19 and treatment, we significantly updated the model by matching a curated dataset spanning viral load and immune responses in plasma and lung. We identified a population of parameter sets to generate heterogeneity in pathophysiology and treatment and tested this model against published reports from interventional SARS-CoV-2 targeting mAb and antiviral trials. Upon generation and selection of a virtual population, we match both the placebo and treated responses in viral load in these trials. We extended the model to predict the rate of hospitalization or death within a population. Via comparison of the in silico predictions with clinical data, we hypothesize that the immune response to virus is log-linear over a wide range of viral load. To validate this approach, we show the model matches a published subgroup analysis, sorted by baseline viral load, of patients treated with neutralizing Abs. By simulating intervention at different time points post infection, the model predicts efficacy is not sensitive to interventions within five days of symptom onset, but efficacy is dramatically reduced if more than five days pass post symptom onset prior to treatment.


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To account for the influence of tissue damage underlying the hyperinflammatory pathophysiological 37 outcomes associated with severe COVID-19, we explicitly account for damage and immune-mediated 38 death of alveolar cells that might occur due to both viral infection as well as the effects of 39 proinflammatory cytokines [10,11].

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The model incorporates three biomarkers commonly monitored in hospitalized cases of COVID-19: C-42 reactive protein (CRP), which is a general marker of inflammation; and ferritin and surfactant protein D

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(SP-D), which are leakage products of alveolar cell damage [12,13]. In our model, plasma IL-6 is assumed 44 to induce the production of hepatic CRP, while ferritin and SP-D are released upon the death of 45 damaged alveolar cells. All biomarkers are assumed to be released into systemic circulation from their 46 respective sites of production.

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Incorporation of anti-viral and SARS-CoV-2 neutralizing antibody cocktail 49 treatment effects

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The anti-viral, molnupiravir is the pro-drug of the pharmacologically active EIDD-1931 The virus is infects healthy type II alveolar cells (AT 2) and is productively shed by these infected cells I. Type I Interferon (IF N β) inihibits the formation of infected cells through an indirect response model. The virus is can also be phagocytosed by dendritic cells (DC) and macrophages (M 1) and is undergoes non-specific clearance at a rate β V .
2 Healthy Alveolar Type 2 Cell (AT 2) AT 2) cells are depleted due to infection by virus, apoptotic damage by (ROS) secreted by neutrophils (N ) and damage due to proinflammatory cytokines at a rate k cyt_damage . (AT 2) cells are additionally formed at a rate µ AT 2 that is dependent on the extent of (AT 2) depletion and cleared with a death rate of β AT 2 .
3 Infected Alveolar Type 2 Cells (I) Infected cells, (I) are formed by infection of (AT 2) cells and non-specifically cleared at a rate β I . Additionally, they are apoptotically cleared by cytotoxic T cells (CT L) and (ROS), and phagocytosed by (DC) and (M 1).

Healthy Alveolar Type 1 Cells
(AT 1) are resistant to infection but can undergo inflammatory cell death mediated by (ROS) and proinflammatory cytokines (k cyt_damage ). Additionally, they are formed from differentiation (AT 2) cells and undergo non-specific clearance at at a rate β AT 1 .

Neutrophil Activation
The production of (T h1) is activated by viral epitope-responsive mature (DC), and further induced by (IL12), (IL2), (IF N γ), (IF N β) and inhibited by (IL10) and (T GF β). Additionally, the ability of (IF N γ) and (IL6) to negatively regulate each other's activity is also incorporated. The clearance rate of (T h1) is determined by a nonspecific death/deactivation rate β T h1 , and inter-compartmental transport tr T h1 .

Cytotoxic T Cell Activation
The production of (CT L) is activated by viral epitope-responsive mature (DC), and further induced by (IL12), (IL2), (IF N γ), (IF N β) and inhibited by (IL10) and (T GF β). Additionally, the ability of (IF N γ) and (IL6) to negatively regulate each other's activity is also incorporated. The clearance rate of (CT L) is determined by a nonspecific death/deactivation rate β CT L , and inter-compartmental transport tr CT L .

T regulatory (Treg) Cell Activation
The production of (T reg) is activated by viral epitope-responsive mature (DC), and further induced by (T GF β) and (IL2) and inhibited by (IL17) and (IL6) . (T reg) cells can also undergo (IL12)-mediated differentiation to (T h1) cells. The clearance rate of (T reg) is determined by a nonspecific death/deactivation rate β T reg , and inter-compartmental transport tr T reg .
is secreted by (T h1), (CT L) and (DC). (IF N γ) additionally has a basal non-specific production rate α IF N γ .α IF N γ(basal) a clearance rate β IF N γ and inter-compartmental transport tr IF N γ .

Type I Interferons
is secreted by (I) and (DC). (IF N β) additionally has a basal non-specific production rate α IF N β .α IF N β(basal) , a clearance rate β IF N β and inter-compartmental transport tr IF N β .

C-reactive Protein
CRP is produced in the liver ((CRP exrtracellular )) and is induced by liver concentrations of (IL6). (CRP exrtracellular ) is tranported to blood at an inter-compartmental transit rate k tr(CRP ) . (CRP blood ) is also basally produced at a rate k basal_CRP . Both (CRP exrtracellular ) and (CRP blood ) are cleared at a rate k deg_CRP from their respective compartments.