Evolutionary safety of death by mutagenesis

  1. Gabriela Lobinska
  2. Yitzhak Pilpel
  3. Martin A Nowak

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Abstract

Nucleoside analogs are a major class of antiviral drugs. Some act by increasing the viral mutation rate causing “death by mutagenesis” of the virus. Their mutagenic capacity, however, may lead to an evolutionary safety concern. We define evolutionary safety as a probabilistic assurance that the treatment will not generate an increased number of epidemiologically concerning mutated virus progeny. We develop a mathematical framework to estimate the total mutant load produced with and without mutagenic treatment. We predict rates of appearance of virus mutants as a function of the timing of treatment and the immune competence of patients, employing various assumptions about the vulnerability of the viral genome and its potential to generate undesired phenotypes. We focus on the case study of Molnupiravir, which is an FDA-approved treatment against COVID-19. We estimate that Molnupiravir is narrowly evolutionarily safe, subject to the current estimate of parameters. Evolutionary safety can be improved by restricting treatment to individuals with a low clearance rate and by designing treatments that lead to a greater increase in mutation rate. We report a simple rule to determine the fold-increase in mutation rate required to obtain evolutionary safety which is also applicable to other pathogen-treatment combinations.

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  1. ScreenIT

    SciScore for 10.1101/2022.03.10.483790: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Experimental Models: Organisms/Strains
    SentencesResources
    We find μ* = mu* as the solution of the polynomial:Here h = bT and k = [b(2b − a0 − a1)]/[(b − a0)(a1 − b)].
    b(2b − a0 − a1)]/
    suggested: None
    b − a0)(a1 − b)]
    suggested: None

    Results from OddPub: Thank you for sharing your code.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    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.

    Results from scite Reference Check: We found no unreliable references.

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  2. Version published to 10.1101/2022.03.10.483790v1 on bioRxiv