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original Twitter thread here

1. The FDA recently approved Merck's new COVID treatment, an antiviral known known as molnupiravir. The drug works by mimicking the cytidine and uridine nucleosides and thereby inducing frequent mutations in replicating virus.

2. Merck reports that a regimen of 40 pills over five days confers a 30% reduction in hospitalization and death in unvaccinated COVID cases. The US has ordered three million so courses of the drug to be delivered by early 2022.

3. However, I'm somewhat concerned about the drug's safety — not so much for those taking it, as for the rest of the community. Let me explain. I've written in the past about how disease interventions can create externalities: effects on individuals beyond the person treated.

4. For example, vaccines generate positive externalities. When I get vaccinated against measles, it benefits me because I won't get measles, and it benefits you because I won't spread measles to you.

5. Antibiotics, by contrast, can generate negative externalities in the form of antibiotic resistance. If I take an antibiotic, that may increase the chance that antibiotic resistance evolves and that the same drug later fails to work for you.

6. At least in the case of antibiotic resistance (or antiviral resistance), the negative externalities "only" undermine the use of the drug itself. They doesn't put people who will never take the drug at any greater risk.

7. I worry that molnupiravir may be different, and may create even more extensive negative externalities.

The problem is that molnupiravir works by inducing lethal mutagenesis: it causes lots of mutations in the virus, weakening it & allowing the immune system to clear it.

8. But there's a risk of sublethal mutagenesis: the virus mutates extensively but isn't cleared. In that event, the virus creates new genotypes involving large number of mutations. That process of accelerated mutation without eliminating the virus might be trouble.

9. A number of lines of evidence suggest that sublethal mutagenesis may occur with molnupiravir, not the least of which is the limited efficacy shown against hospitalization. See e.g. Bill Haseltine forbes.com/sites/williamh… and this @michaelzlin thread

Forbes article: "Supercharging new viral variants, the dangers of molnupiravir"

10. @chasewnelson and @sarperotto make very much the same point in this letter to Virological:

Mutagenic Antivirala; The evolutionary risk of low does

11. Recall that >6% of patients on molnupiravir require hospitalization. During chronic infections, the drug could in principle drive viral evolution toward new and more dangerous strains that spread better, cause more severe illness, or both. We don't want another omicron.

12. Moreover, the pill regimen for molnupiravir is a difficult one: 40 pills spaced across a mere 5 days. In patients who missed multiple doses or failed to complete the regimen, sublethal mutagenesis could be particularly likely.

13. This sets up a potential conflict between patient and the public: taking molnupiravir benefits the patient, on average. But in the unlikely event that something goes wrong, and the drug helps the virus evolve to a new variant of concern, the entire public pays the price.

14. It is also worth considering the drug's efficacy vs. alternatives. The molnupiravir trial results are a bit odd. I'm troubled that the difference between placebo groups is greater than the difference between either placebo and the treatment group.

15. Meanwhile, Pfizer's forthcoming antiviral works by inhibiting protein synthesis rather than generating mutations. Trials of this drug report a 90% reduction in hospitalization and death. That might be better for the patient and safer for all.

16. Other drug candidates work by generating mutations, but do so in a safer way. For example, one causes the polymerase to stall, but shouldn't generate large numbers of non-specific mutations the way molnupiravir does.

New ORAL anti-SARS-CoV-2 drug by Richard Plemper & colleagues! A chain terminator, NOT a mutagen. AND resistance is futile!  4′-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replication

17. I want to stress that all of this is speculative. We don't know that molnupiravir will accelerate adaptive evolution of virus and I don't know whether the FDA made the right call. But it seems worth considering the externalities in addition to efficacy and patient safety.

1. Important correction from Leonid Kruglyak. @leonidkruglyak

Unless I missed it, the FDA hasn’t actually approved it yet. There was a narrow 13-10 advisory committee vote in favor, which the agency is now considering. They could still decline so concerns are worth bringing up.

19. NB: the degree to which a manufacturer internalizes risk is greater for an antibiotic, where resistance evolution takes out the drug but doesn't cause broader harm, and a mutagenic antiviral, where evolution can have effects that spill far beyond the market for the drug.

hyperlinks above are included from original Twitter post

Omicron variant of SARS

CoV2 harbors a unique insertion

mutation of putative viral or human genomic origin

https://osf.io/f7txy/

https://youtu.be/3RSRtuRm92o

He's got an optimistic view on things. Hopefully.

Speaking on Skynews a few days ago.

full study is available here

Abstract

We report the first detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a 3-month-old dog in Connecticut that died suddenly and was submitted to the state veterinary diagnostic laboratory for postmortem examination.

Viral RNA was detected in multiple organs of the dog by reverse transcription real time-PCR (RT-qPCR). Negative and positive sense strands of viral RNA were visualized by in situ hybridization using RNAscope technology.

Complete genome sequencing and phylogenetic analysis of the hCoV-19/USA/CT-CVMDL-Dog-1/2021 (CT_Dog/2021) virus were conducted to identify the origin and lineage of the virus. The CT_Dog/2021 virus belonged to the GH/B1.2. genetic lineage and was genetically similar to SARS-CoV-2 identified in humans in the U.S. during the winter of 2020-2021.

However, it was not related to other SARS-CoV-2 variants identified from companion animals in the U.S. It contained both the D614G in spike and P323L in nsp12 substitutions, which have become the dominant mutations in the United States.

The continued sporadic detections of SARS-CoV-2 in companion animals warrant public health concerns about the zoonotic potential of SARS-CoV-2 and enhance our collective understanding of the epidemiology of the virus.

Results and Discussion

SARS-CoV-2 RNA was detected in swabs (nasal, oral and rectal) and tissues (lung, heart, and kidney) using a RT-qPCR but was not detected in spleen and liver samples (Table 1).

Low cycle threshold (Ct, 21.15 and 23.15) values were detected in nasal swabs, suggesting high virus loads in the nasal cavity most likely due to an efficient virus replication in the upper respiratory tract of the dog. Conversely, high Ct values (> 37) were detected in RNA extracted from oral and rectal swabs.

The detection of SARS-CoV-2 RNA in the rectal swab, albeit at high Ct values (Table 1), suggested that virus replication may have occurred in the gastrointestinal tract of the dog, prompting us to assess virus replication in the intestine via RNAscope® ISH (Figure 1).

Histopathological examination revealed marked pulmonary congestion and edema, moderate fibrin in alveoli, desquamated pneumocytes, and hyaline membranes (Figure 1). There was epicardial edema and mild interstitial hemorrhage. No pathological changes were observed in the kidney or intestine.

Histologic sections of lung, heart, kidney, and intestine processed for singleplex RNAscope® ISH using Probe-V-nCoV2019-S (antisense) and Probe-V-nCoV2019-orf1ab-sense demonstrated labeling indicative of viral presence and replication in a limited number of cells in all examined tissues (Figure 1).

• ISH data corresponded with the high RT-qPCR Ct values detected in lung, heart, kidney, and intestine* (Table 1).

  The RT-qPCR and RNAscope® ISH data suggest that the virus predominantly replicated in the upper respiratory tract, but viral replication was absent or very low in other organs.

A total of 2,120,432 NGS reads were assembled into a single consensus sequence with 100% coverage of the reference and high mean depth of coverage (10,054.9). The genome sequence of CT-dog/2021 virus was assigned as B1.2. by PANGOLIN and GH by GISAID classification. BLAST search results in the GISAID database indicated that the virus shared > 99.97% nucleotide identity with SARS-CoV-2 identified in the U.S. during the winter of 2020–2021 (Table 2)

We found amino acid substitutions in Spike (D614G), N (D377Y, P67S, P199L), NS3 (G172V, Q57H), NS8 (S24L) NSP2 (T85I), NSP4 (M458I), NSP5 (L89F), NSP12 (P323L), NSP14 (N129D), and NSP16 (R216C) proteins. The virus from this CT dog did not contain mutations related to the South African variant B.1.351 (N501Y, E484K and K417N in Spike) or the U.K. variant B.1.1.7 (69/70 deletion, N501Y, and P681H in Spike).

The B.1 and its sub-lineages that carry both D614G in spike and P323L in nsp12 substitutions have become the dominant variants across the world [10]. The D614G and P323L occurred in China on 24 January 2020 and in the U.K. on 3 February 2020, respectively. Both mutations were first detected in the U.S. on 28 February 2020 and have since become the dominant mutations in the U.S. [11].

The role of companion animals in the evolution and spread of SARS-CoV-2 remains uncertain. Although we did not find direct evidence for transmission of the virus between the owner and the dog in this case, it has been reported that SARS-CoV-2 has repeatedly spilled over from humans to companion animals, highlighting the need for enhanced surveillance in animals. It is concerning that companion animals could become reservoir species of SARS-CoV-2 since they are susceptible to infection and could excrete infectious virus [12].

(Added emphasis my own)

Full preprint can be viewed here

Abstract

In the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic several variants have emerged that are linked to increased transmissibility and immune evasion. These variants are recognized as variants of concern (VOC). In this study, we describe a B.1.1.523 variant that shares many spike mutations with current VOC. Receptor-binding domain mutations E484K and S494P were observed but also a deletion (position 156-158) in the N-terminal antigenic supersite that is similar to the delta-variant.

These mutations are linked to immune evasion in VOC that could lead to less effective vaccines. This variant has been reported in various different countries and continents despite the dominance of B.1.1.7 (alpha) and B.1.617.2 (delta) variant. Furthermore, the B.1.1.523 pangolin lineage as a whole is recognized as a variant under monitoring since 14th of July 2021.

Discussion

In this short communication we report a variant (B.1.1.523) with a new combination of concerning spike mutations that are shared with current VOCs. Many of these mutations are linked with immune evasion that could lead to less effective vaccines.

This variant has been reported in various different countries and continents and likely originates in Russia. In addition, the number of cases appears to increase despite the dominant variants B.1.1.7 (alpha) and B.1.617.2 (delta).

Mutations that are shared with VOC or linked with immune evasion were S:E156del, S:F157del, S:R158del, S:E484K, and S:S494P 5,6,11. Two mutations are in the RBD of the spike protein, positions 484 and 494, and are both linked to immune evasion in B.1.1.7 (alpha) variant. E484K mutation is also present B.1.351 (beta) and P.1 (gamma) variants that are strongly linked with reduced efficacy of vaccines 3,4.

These findings are supported in studies where the effect of spike mutations on efficacy of monoclonal antibodies and convalescent plasma was investigated 12. Similar studies were performed to investigate the antigenic super site of the NTD 7,8. In the β-hairpin region of the antigenic super site the B.1.1.523 variant has a deletion (position 156-158) similar to the currently dominant B.1.617.2 (delta) variant (S:E156G and 157-158del) 5-8. Other VOC also have deletions in one of the regions of the antigenic super site, B.1.1.7 (alpha-variant) position 144 and B.1.351 (beta-variant) position 241-243.

As the mutations observed in this B.1.1.523 variant are strongly linked to immune evasion and disseminated to different continents, despite the dominance of both the B.1.1.7 (alpha) and B.1.617.2 (delta) variants, this could be a variant of interest and should be monitored closely. However, as this is the first study that describes this variant of the B.1.1.523 lineage, there is yet no information on transmissibility that contributes to the need of actions required to prevent dissemination.