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Modelling the impact of JNJ-1802, a first-in-class dengue inhibitor blocking the NS3-NS4B interaction, on in-vitro DENV-2 dynamics [1]

['Clare P. Mccormack', 'Mrc Centre For Global Infectious Disease Analysis', 'School Of Public Health', 'Imperial College London', 'London', 'United Kingdom', 'Olivia Goethals', 'Janssen Global Public Health', 'Janssen Pharmaceutica Nv', 'Beerse']

Date: 2024-02

Fig A. Variation in viral RNA measurements. Co-efficient of variation (CV) for the log 10 viral RNA measurement obtained from experimental infection studies in Vero cells, disaggregated by measurement type, JNJ-1802 concentration and DENV-2 strain. CV is the ratio of the standard deviation to the mean. Fig B. Model Fits (DENV-2/16681 strain, with refresh). Model fits for the measurements observed using the DENV-2/16681 strain with medium refresh on day 4 and antiviral concentrations of 0 nM, 2.56x10-03 nM, 1.28x10-02 nM, 6.40x10-02 nM, 0.32 nM, 1.6 nM, and 8 nM. Coloured points represent the data from each well (6 wells for 0 nM, 4 wells for concentrations >0 nM), the vertical red line indicates the time the viral inoculum was added to each well and the horizontal dashed black line indicates the limit of detection. The modelled dynamics of the intracellular RNA virus are in green and those of the extracellular RNA virus are in purple; solid lines represent the median and the shading represents the 95% CrI. Viral suppression is observed for concentrations 1.6 nM and 8 nM. Here, measurements below the limit of quantification (crosses in Fig 1) were included during model fitting. Measurements below the LOD were left censored at the LOD during model fitting and were plotted at the LOD for visual display. We assumed that the antiviral directly inhibits the transition process of infected cells to infectious (virion producing) cells, i.e., acts on τ. Fig C. Model Fits (DENV-2/RL strain, with refresh). Model fits for the measurements observed using the DENV-2/RL strain with medium refresh on day 4 and antiviral concentrations of 0 nM, 2.56x10-03 nM, 1.28x10-02 nM, 6.40x10-02 nM, 0.32 nM, 1.6 nM, and 8 nM. Coloured points represent the data from each well (6 wells for 0nM, 4 wells for concentrations >0nM), the vertical red line indicates the time the viral inoculum was added to each well and the horizontal dashed black line indicates the limit of detection. The modelled dynamics of the intracellular RNA virus are in green and those of the extracellular RNA virus are in purple; solid lines represent the median and the shading represents the 95% CrI. Viral suppression is observed for concentrations 1.6 nM and 8 nM. Here, measurements below the limit of quantification (crosses in Fig 1) were included during model fitting. Measurements below the LOD were left censored at the LOD during model fitting and were plotted at the LOD for visual display. We assumed that the antiviral directly inhibits the transition process of infected cells to infectious (virion producing) cells, i.e., acts on τ. Fig D. Impact of Medium Refresh. Estimated inhibition percentage (A,B), percentage reduction in the basic reproduction number R 0 (C,D) and effective reproduction number R e (E,F) as a function of concentration, for the DENV-2/RL strain (A, C, E) and DENV-2/16681 strain (B, D, F) where the well medium was refreshed or not on day 4. Estimates were calculated by substituting 1,000 parameter values sampled from the posterior distribution into Eqs (1), (6) and (7) in the main text. Solid lines represent the median, the shading represents the 95% CrI, dotted grey vertical lines indicate the concentrations tested in the in vitro experiments, and the dotted blue and red vertical lines indicate the median concentration such the R e = 1. The dotted black horizontal lines indicate the threshold for a 50% reduction (A,B,C,D), and when R e = 1 (E,F). Here, measurements below the limit of quantification (crosses in Fig 1) were included during model fitting and we assume the antiviral directly inhibits the transition process of infected cells to infectious (virion producing) cells, i.e., acts on τ. Fig E. Cell Dynamics (DENV-2/16681 strain, no refresh). Underlying modelled cell dynamics for the DENV-2/16681 strain with no medium refresh and antiviral concentrations of 0 nM, 2.56x10-03 nM, 1.28x10-02 nM, 6.40x10-02 nM, 0.32 nM, 1.6 nM, and 8 nM. The vertical red line indicates the time the viral inoculum was added to each well. The modelled dynamics of the target cells are in blue, those of the infected cells are in grey and those of the infectious (virion producing) cells are in orange; solid lines represent the median and the shading represents the 95% CrI. We assumed that the antiviral directly inhibits the transition process of infected cells to infectious (virion producing) cells, i.e., acts on τ. Fig F. Model Fits (DENV-2/RL strain, no refresh). Underlying modelled cell dynamics for the DENV-2/RL strain with no medium refresh and antiviral concentrations of 0 nM, 2.56x10-03 nM, 1.28x10-02 nM, 6.40x10-02 nM 0.32 nM, 1.6 nM, and 8 nM. The vertical red line indicates the time the viral inoculum was added to each well. The modelled dynamics of the target cells are in blue, those of the infected cells are in grey and those of the infectious (virion producing) cells are in orange; solid lines represent the median and the shading represents the 95% CrI. We assumed that the antiviral directly inhibits the transition process of infected cells to infectious (virion producing) cells, i.e., acts on τ. Fig G. Goodness of Fit. Observed vs predicted extracellular and intracellular RNA values for the experimental infection studies conducted, disaggregated by JNJ-1802 concentration and DENV-2 strain. Here, intracellular measurements below the limit of quantification (LOQ) were included during model fitting and measurements below LOD were left-censored at the LOD during model fitting. We assumed that the antiviral directly inhibits the transition process of infected cells to infectious (virion producing) cells i.e., acts on τ. For the observed values, we plot the median observed value across individual wells and the corresponding 2.5–97.5 percentiles. For the predicted values, we plot the median predicted value and corresponding 95% credible interval. For both observed and predicted values, we plot values below the LOD at the LOD (dashed red horizontal and vertical lines) to aid visual comparison between the observed and predicted values. Fig H. Model Fits (DENV-2/16681 strain, no refresh). Model fits for the measurements observed using the DENV-2/16681 strain with no medium refresh and antiviral concentrations of 0 nM, 2.56x10-03 nM, 1.28x10-02 nM, 6.40x10-02 nM, 0.32 nM, 1.6 nM, and 8 nM. Coloured points represent the data from each well (6 wells for 0 nM, 4 wells for concentrations >0 nM), the vertical red line indicates the time the viral inoculum was added to each well and the horizontal dashed black line indicates the limit of quantification. The modelled dynamics of the intracellular RNA virus are in green and those of the extracellular RNA virus are in purple; solid lines represent the median and the shading represents the 95% CrI. Viral suppression is observed for concentrations of 1.6 nM and 8 nM. Here, measurements were left-censored at the LOQ during model fitting and we plot measurements below the LOQ (crosses in Fig 1) at the LOQ for visual display. We assumed that the antiviral inhibits the transition process of infected cells to infectious (virion producing) cells, i.e. acts on τ. Fig I. Model Fits (DENV-2/RL strain, no refresh). Model fits for the measurements observed using the DENV-2/RL strain with no medium refresh and antiviral concentrations of 0 nM, 2.56x10-03 nM, 1.28x10-02 nM, 6.40x10-02 nM, 0.32 nM, 1.6 nM, and 8 nM. Coloured points represent the data from each well (6 wells for 0 nM, 4 wells for concentrations >0 nM), the vertical red line indicates the time the viral inoculum was added to each well and the horizontal dashed black line indicates the limit of quantification. The modelled dynamics of the intracellular RNA virus are in green and those of the extracellular RNA virus are in purple; solid lines represent the median and the shading represents the 95% CrI. Viral suppression is observed for concentrations of 1.6 nM and 8 nM. Here, measurements were left-censored at the LOQ during model fitting and we plot measurements below the LOQ (crosses in Fig 1) at the LOQ for visual display. We assumed that the antiviral inhibits the transition process of infected cells to infectious (virion producing) cells, i.e. acts on τ. Fig J. Limit of Quantification (No Refresh). Estimated inhibition percentage (A,B), percentage reduction in the basic reproduction number R 0 (C,D) and effective reproduction number R e (E,F) as a function of concentration for the DENV-2/RL strain (A,C,E) and DENV-2/16681 strain (B,D,F) where measurements were left-censored at either the limit of detection (LOD) or the limit of quantification (LOQ) and the well medium was not refreshed. Estimates were calculated by substituting 1,000 parameter values sampled from the posterior distribution into Eqs (1), (6) and (7) in the main text. Solid lines represent the median, the shading represents the 95% CrI, dotted grey vertical lines indicate the concentrations tested in the in vitro experiments, and the dotted blue and red vertical lines indicate the median concentration such the R e = 1. The dotted black horizontal lines indicate the threshold for a 50% reduction (A,B,C,D), and when R e = 1 (E,F). Here, we assume the antiviral directly inhibits the transition process of infected cells to infectious (virion producing) cells, i.e. acts on τ. Fig K. Model Schematic. Target cells are infected at a rate β per virion. Following a latent period of 1/τ days on average, infectious cells I synthesize intracellular viral RNA (X) at a net production rate ω (in absence of antiviral drug), a proportion p of which then gets secreted as extracellular viral RNA at a rate ε. Extracellular viral RNA decays at a rate κ V . Target cells replicate at a rate s N ; target cells and infected cells have a mean lifespan of 1/κ T and 1/(κ T + κ I ) days, respectively. Individual wells have a carrying capacity K W . The antiviral molecule acts on intracellular RNA production, following a concentration-dependent function f(C). The parameters in red are estimated, those in black are fixed. Fig L. Cell Dynamics (DENV-2/16681 strain, no refresh). Underlying modelled cell dynamics for the DENV-2/16681 strain with no medium refresh and antiviral concentrations of 0 nM, 2.56x10-03 nM, 1.28x10-02 nM, 6.40x10-02 nM, 0.32 nM, 1.6 nM, and 8 nM. The vertical red line indicates the time the viral inoculum was added to each well. The modelled dynamics of the target cells are in blue, those of the infected cells are in grey and those of the infectious (virion producing) cells are in orange; solid lines represent the median and the shading represents the 95% CrI. We assumed that the antiviral directly inhibits intracellular RNA production, i.e., acts on ω. Fig M. Cell Dynamics (DENV-2/RL strain, no refresh). Underlying modelled cell dynamics for the DENV-2/16681 strain with no medium refresh and antiviral concentrations of 0 nM, 2.56x10-03 nM, 1.28x10-02 nM, 6.40x10-02 nM, 0.32 nM, 1.6 nM, and 8 nM. The vertical red line indicates the time the viral inoculum was added to each well. The modelled dynamics of the target cells are in blue, those of the infected cells are in grey and those of the infectious (virion producing) cells are in orange; solid lines represent the median and the shading represents the 95% CrI. We assumed that the antiviral directly inhibits intracellular RNA production, i.e., acts on ω. Fig N. Model Fits (DENV-2/16681 strain, no refresh). Model fits for the measurements observed using the DENV-2/16681 strain with no medium refresh and antiviral concentrations of 0 nM, 2.56x10-03 nM, 1.28x10-02 nM, 6.40x10-02 nM 0.32 nM, 1.6 nM, and 8 nM. Coloured points represent the data from each well (6 wells for 0 nM, 4 wells for concentrations >0 nM), the vertical red line indicates the time the viral inoculum was added to each well and the horizontal dashed black line indicates the limit of detection. The modelled dynamics of the intracellular RNA virus are in green and those of the extracellular RNA virus are in purple; solid lines represent the median and the shading represents the 95% CrI. Here, measurements below the limit of quantification (crosses in Fig 1) were included during model fitting. Measurements below the LOD were left censored at the LOD during model fitting and we plot these measurements at the LOD for visual display. We assumed that the antiviral directly inhibits intracellular RNA production, i.e., acts on ω. Fig O. Model Fits (DENV-2/RL strain, no refresh). Model fits for the measurements observed using the DENV-2/RL strain with no medium refresh and antiviral concentrations of 0 nM, 2.56x10-03 nM, 1.28x10-02 nM, 6.40x10-02 nM, 0.32 nM, 1.6 nM, and 8 nM. Coloured points represent the data from each well (6 wells for 0 nM, 4 wells for concentrations >0 nM), the vertical red line indicates the time the viral inoculum was added to each well and the horizontal dashed black line indicates the limit of detection. The modelled dynamics of the intracellular RNA virus are in green and those of the extracellular RNA virus are in purple; solid lines represent the median and the shading represents the 95% CrI. Here, measurements below the limit of quantification (crosses in Fig 1) were included during model fitting. Measurements below the LOD were left censored at the LOD during model fitting and we plot these measurements at the LOD for visual display. We assumed that the antiviral directly inhibits intracellular RNA production, i.e., acts on ω. Fig P. Effect of antiviral (No Refresh). Estimated inhibition percentage (A,B), percentage reduction in the basic reproduction number R0 (C,D) and effective reproduction number Re (E,F) as a function of concentration, for the DENV-2/RL strain (A,C,E) and DENV-2/16681 strain (B,D,F) where the drug action was on intracellular RNA production in a model with/without a latent period (WL/NL) allowing for maturation of infected cells (action on ω) or the drug action was on the transition process of infected cells to infectious (virion producing) cells (action on τ) and the well medium was not refreshed. Estimates were calculated by substituting 1,000 parameter values sampled from the posterior distribution into Eqs (1), (6) and (7) in the main text and above. Solid lines represent the median, the shading represents the 95% CrI, dotted grey vertical lines indicate the concentrations tested in the in vitro experiments, and the dotted green, blue and red vertical lines indicate the median concentration such the Re = 1. The dotted black horizontal lines indicate the threshold for a 50% reduction (A,B,C,D), and when Re = 1 (E,F). Here, measurements below the limit of quantification (crosses in Fig 1) were included during model fitting. Table A. Posterior parameter estimates. Median posterior estimate and 95% credible interval (CrI) in brackets. Here the measurements below the limit of quantification (crosses in Fig 1) were included during model fitting, and we assumed that the antiviral directly inhibits transition of infected cells to infectious (virion producing) cells, i.e., acts on τ. Table B. Posterior Parameter Estimates. Posterior parameter estimates for models assuming left-censoring of the viral RNA data at the limit of detection or at the limit of quantification. The median posterior estimate is reported with the 95% credible interval (CrI) in brackets. Here, we assume the antiviral directly inhibits the transition process of infected cells to infectious (virion producing) cells, i.e., acts on τ. Table C. Posterior Parameter Estimates. Posterior parameter estimates for different modes of drug action and model structure–(1) inhibition of transition process of infected cells to infectious (virion producing) cells (action on τ), (2) direct inhibition of intracellular RNA production in a model with no latent period allowing for the transition process of infected cells to infectious cells (action on ω, no latent period) and (3) direct inhibition of intracellular RNA production in a model with a latent period allowing for the transition process of infected cells to infectious cells (action on ω, with latent period) The median posterior estimate is reported with the 95% credible interval in brackets. Here, measurements below the limit of quantification but above the limit of detection (crosses in Fig 1) were included during model fitting. Table D. Posterior Parameter Estimates (RL Strain). Posterior parameter estimates for different starting values of the initial viral inoculum (V0). Here, measurements below the limit of quantification (crosses in Fig 1) were included during model fitting. Measurements below the LOD were left censored at the LOD during model fitting and we assumed that the antiviral directly inhibits the transition process of infected cells to infectious (virion producing) cells, i.e., acts on τ. Table E. Posterior Parameter Estimates (16681 Strain). Posterior parameter estimates for different starting values of the initial viral inoculum (V0). Here, measurements below the limit of quantification (crosses in Fig 1) were included during model fitting. Measurements below the LOD were left censored at the LOD during model fitting and we assumed that the antiviral directly inhibits the transition process of infected cells to infectious (virion producing) cells, i.e., acts on τ. Table F. Posterior Parameter Estimates (RL Strain). Sensitivity of posterior parameter estimates to data excluded during model fitting. Here, measurements below the limit of quantification (crosses in Fig 1) were included during model fitting. Measurements below the LOD were left censored at the LOD during model fitting and we assumed that the antiviral directly inhibits the transition process of infected cells to infectious (virion producing) cells, i.e., acts on τ. Table G. Posterior Parameter Estimates (16681 Strain). Sensitivity of posterior parameter estimates to data excluded during model fitting. Here, measurements below the limit of quantification (crosses in Fig 1) were included during model fitting. Measurements below the LOD were left censored at the LOD during model fitting and we assumed that the antiviral directly inhibits the transition process of infected cells to infectious (virion producing) cells, i.e., acts on τ.

https://doi.org/10.1371/journal.pcbi.1011662.s002

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