Mathematical modeling explains differential SARS CoV-2 kinetics in lung and nasal passages in remdesivir treated rhesus macaques

  1. Ashish Goyal
  2. Elizabeth R. Duke
  3. E. Fabian Cardozo-Ojeda
  4. Joshua T. Schiffer

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Abstract

Remdesivir was recently demonstrated to decrease recovery time in hospitalized patients with SARS-CoV-2 infection. In rhesus macaques, early initiation of remdesivir therapy prevented pneumonia and lowered viral loads in the lung, but viral loads increased in the nasal passages five days after therapy. We developed mathematical models to explain these results. We identified that 1) drug potency is slightly higher in nasal passages than in lungs, 2) viral load decrease in lungs relative to nasal passages during therapy because of infection-dependent generation of refractory cells in the lung, 3) incomplete drug potency in the lung that decreases viral loads even slightly may allow substantially less lung damage, and 4) increases in nasal viral load may occur due to a slight blunting of peak viral load and subsequent decrease of the intensity of the innate immune response, as well as a lack of refractory cells. We also hypothesize that direct inoculation of the trachea in rhesus macaques may not recapitulate natural infection as lung damage occurs more abruptly in this model than in human infection. We demonstrate with sensitivity analysis that a drug with higher potency could completely suppress viral replication and lower viral loads abruptly in the nasal passages as well as the lung.

One Sentence Summary

We developed a mathematical model to explain why remdesivir has a greater antiviral effect on SARS CoV-2 in lung versus nasal passages in rhesus macaques.

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    SciScore for 10.1101/2020.06.21.163550: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    The experimental results highlight inherent strengths and limitations of the rhesus macaque model. Nasal passage viral kinetics and histologic lung damage appear similar between humans and rhesus macaques.8,20 We are also encouraged by the fact that a nearly equivalent mathematical model with a similar parameter set explains nasal viral loads in humans and rhesus macaques during the first week of infection,8 (though the acquired immune response is not modeled in the macaques because we do not observe complete viral elimination within the experimental timeframe). Similarly, our modeling of human data led to the prediction that a semi-potent treatment given extremely early infection might allow higher late nasal viral loads,8 which was also observed in the rhesus macaque experiments described herein. On the other hand, in rhesus macaques, extensive lung damage and clinic illness is observed within two days of infection, which is not in keeping with severe illness in humans which emerges at least a week after the initial phase of illness.5,21 We hypothesize that direct intratracheal inoculation of macaques with a high viral titer results in more immediate infection of lung. In humans, a more common pattern is for respiratory viruses to start replicating in the upper airway and then transmit to the lungs in a second stage of infection.22 An alternative, and not mutually exclusive explanation is that the degree of viral replication in the lung can also be established extremely ear...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2020.06.21.163550v1 on bioRxiv