Is Molnupiravir a Global Catastrophic Threat?

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This article was first published by TrialSiteNews behind a paywall.

Merck’s Molnupiravir (also known as EIDD-2801 and MK-4482) is a mutagenic nucleotide analogue [1]. It introduces errors in the SARS-COV-2 RNA at the time of replication after proofreading, and causes lethal mutagenesis [2]. This threatens to accelerate the evolution of the coronavirus.

Any major variant of the coronavirus represents local optimum (in mutations space), maximizing coronavirus’ fitness. One- or two-point mutations cannot accomplish this. A new variant can only rise through the change of the virus-host-conditions systems, or through larger mutations set. Even a moderate increase in the point mutations frequency causes a big increase in the frequency of multi-point mutations and dangerous recombinations. Such events are too rare to be caught in small trials, but inevitable in large populations, and might lead to catastrophic consequences. The authorization and broad use of Molnupiravir is likely to breed very dangerous SARS-COV-2 variants.

Assuming a drug causes an N times increase in frequency of non-synonymous mutations (the rate of errors), the frequency of simultaneous mutations in k points would increase by Nk. Apparently, Molnupiravir increases the rate of errors 2.5-3 times for the range of concentration from sub-toxic 1 µM to toxic 10 µM of rNHC [2]. At 3x, that increases the frequency of 4-points mutations by 81x, per replication cycle.

Additionally, Molnupiravir does not stop coronavirus replication immediately. Multiple replication cycles take place within each host under Molnupiravir. The unfit genomes are eliminated, and the fitter ones (immune escape, higher infectivity etc.) are preferred. This further increases the chances of a large mutation set increasing the virus’ fitness.

The increase in recombinations is even larger. SARS-COV-2 virions can swap parts of their genomes [3]. Usually, a host gets infected by a single strain, and all genomes are similar, differing by a small number of mutations. Recombination between genomes that differ from that strain’s genome set by 1-2 mutations is not much different than a two-point mutation. Recombination between genomes with large (k>=3) sets of different mutations can be significant. The frequency of recombinations between mutation sets of size k or more increases the proportionally to the square of the frequency of such sets, yielding N2*k. Thus, for k=4, that would yield an increase of more than 6,500 times.

Population level effects compound these numbers.

These back-of-the-envelope calculations sharply underestimate the danger because they assume average or median values, rather than probabilities’ distribution tails (i.e., the probability of 10-point mutation is increased 59,000x).

The current SARS-COV-2 Delta strain (worldwide prevalence > 80%) has 24 mutations. It was sequenced in August-September 2020 [4]. This suggests that SARS-COV-2 already mutates and evolves faster than we thought, and the sudden appearance, persistence, and recombination of sets of 5+ point mutations is a big driver of it. Can we really afford to increase the frequency of such events thousands of times?

Another possible outcome of broad use of Molnupiravir could be the appearance of SARS-COV-2 strains without proofreading, compensating for that with higher replication rates or other features. The possibility that a coronavirus can do this has been shown in-vitro, on another large RNA virus by disabling its proofreading mechanism [5].

Broad use of Molnupiravir would likely cause a catastrophic event, such as the emergence of a super-SARS-COV-2, which would evade existing immunity and have an infection fatality rate (IFR) of over 3%. In such a case, the social and infrastructure collapse would kill many more people than would die from the disease.

Even if the drug had very significant benefits for individual patients, it would not justify such a global risk. Molnupiravir is useless. Even at the advertised 50% effect, it is inferior to Ivermectin.

Of course, Molnupiravir also causes mutations in human DNA [2] [6], but those consequences (cancer, birth defects etc.) will only present themselves later, and their connection to the drug will be denied. Only one study of Molnupiravir’s side effects had been conducted [7] [8].

SARS-CoVs were shown to survive and continue to replicate with a 20-fold increase in mutation rate [3]. This casts additional doubts on Molnupiravir’s effectiveness claims. One temporary, slight benefit could be due to the possibility that the current Delta strain already has an increased mutation rate.

Nevertheless, Dr. Fauci has already promised that the FDA would review Molnupiravir as quickly as possible [9].

Conclusion

Among the FDA, NIH, and CDC, Merck is the only adult in the room and should act as such. Given the global catastrophic risks, the individual safety concerns, and the utter lack of follow-up studies for even as little as 12 months, Merck should not even consider applying for an EUA for Molnupiravir.

Reference
  1. Gordon CJ, Tchesnokov EP, Schinazi RF, Götte M. Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template. Journal of Biological Chemistry . Elsevier; 2021 https://www.jbc.org/article/S0021-9258(21)00563-9/abstract
  2. Zhou S, Hill CS, Sarkar S, et al. β-d-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells. The Journal of Infectious Diseases . 2021 https://doi.org/10.1093/infdis/jiab247
  3. Denison MR, Graham RL, Donaldson EF, Eckerle LD, Baric RS. Coronaviruses. RNA Biology . Taylor & Francis; 2011 https://doi.org/10.4161/rna.8.2.15013
  4. Mullen J, et al. outbreak.info. 2020. https://outbreak.info
  5. Graepel KW, Lu X, Case JB, Sexton NR, Smith EC, Denison MR. Proofreading-Deficient Coronaviruses Adapt for Increased Fitness over Long-Term Passage without Reversion of Exoribonuclease-Inactivating Mutations. mBio . American Society for Microbiology; 2017 https://journals.asm.org/doi/full/10.1128/mBio.01503-17
  6. Zhou S, Hill CS, Woodburn BMD, Schinazi RF, Swanstrom R. Reply to Troth et al. The Journal of Infectious Diseases . 2021 https://doi.org/10.1093/infdis/jiab363
  7. Discontent M. Molnupiravir’s Rush should Remind us to take a Cautionary Approach . Modern Discontent. 2021 https://moderndiscontent.substack.com/p/molnupiravirs-rush-should-remind
  8. Discontent M. A Possible Side Effect of Merck’s Oral COVID-19 Drug should alarm the Public . Modern Discontent. 2021 https://moderndiscontent.substack.com/p/the-possible-side-effect-of-mercks
  9. Towey R. Fauci says FDA will review Merck’s new Covid treatment “as quickly as they possibly can” . CNBC. 2021 https://www.cnbc.com/2021/10/01/fauci-says-fda-will-review-mercks-new-covid-treatment-as-quickly-as-they-possibly-can-.html

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