Omicron origins

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The advent of Omicron is sufficient evidence that we are not done with Covid and Covid is not done with us. To look ahead and understand where the virus is going, we need to understand the origins of Omicron. We can be relatively certain of one thing: where this variant comes from, more will come.

To begin with, Omicron is a variant like no other that is currently in circulation. Omicron is unlike any other variant currently in circulation. The variant carries 60 (50 non-synonymous, 8 synonymous and 2 non-coding) mutations compared to the original Wuhan strain. The three most likely origins are stories that Omicron emerged from an immunocompromised patient; that it emerged from reverse zoonosis – human-to-animal transmission followed by animal-to-human transmission; or that it arose from the treatment of a Covid-19 patient with the mutagenic drug molnupiravir. Here we examine the evidence to support each hypothesis.

An immunocompromised patient

It is well documented that viral variants appear in persistently infected immunocompromised Covid-19 patients treated with antiviral drugs and antibodies – the London patient, the Boston patient, Pittsburgh, and Italian patient. Given our best weapons of the time, the virus not only caught on, it got stronger and stronger and learned to escape our immune defenses.

The variations that developed and emerged in these patients showed an abundance of mutations, not just in the spike protein, but throughout the genome. In the London patient, the researchers found an H69-70 deletion in the N-terminal domain of the spike. The Boston patient had cases of the E484K spike mutation. The patients from Pittsburgh and Italy showed far more deletions in the viral genome than any previously seen and in previously unexpected locations – including an abundance of mutations in the N-terminal domain of the spike and in other proteins, including ORF1a and the N protein. Omicron carries some mutations identical and others similar to those found in these patients. Omicron could well be the latest in a long line of such variants.

Reverse zoonosis

The next hypothesis to consider is that this particular variant evolved from an inverted zoonotic event. Most now agree that SARS-CoV-2 comes from bats, a reservoir for a large number of coronaviruses. The theory with Omicron is that a human strain of the virus jumped back into animals and then reappeared from that animal to re-infect humans. The likelihood that this has occurred is entirely plausible and can even be probable. Since its appearance, this particular coronavirus has infected our entire biosphere, from mink and mice to deer and rats, not to mention ourselves. In each of these animal populations, just like humans, the virus has evolved and adapted to immune pressure so that it has survived to infect and re-infect in every population so far. As an example, a virus that was transmitted back to humans from mink contained the disturbing new spike protein N501K, which is also present in Omicron.

A study of wastewater in New York City gives us an indication of how widespread infections and mutations are in animal species. The New York research, which was carried out at 14 city sewage treatment plants, originally aimed to test human wastewater for signs of the virus, but researchers found four new combinations of virus mutations that have never been seen in humans. These variants were reasonably resistant to human antibodies, which meant that should the variants infect humans, they would likely prove more difficult to neutralize than previously known strains. Marc Johnson, the project’s lead investigator, believes the evidence points to an animal, rather than a human, reservoir for these viruses, most likely rats or possibly dogs.

A closer look at the mutations in the Omicron variant and those in rats suggests a connection (see figure below). Omicron shares numerous identical and non-identical mutations within the N and S proteins with the sewage viruses, including 13 amino acid changes in the same position or within an amino acid. Because of these similarities, some experts believe that if Omicron evolved in an animal host, it is likely a rodent.

Molnupiravir-induced

The final and perhaps most troubling theory is that Omicron is the result of our own work in treating a Covid-19 patient with the highly mutagenic antiviral drug molnupiravir. Molnupiravir works by introducing errors in the virus’ genetic code. If enough errors occur, virus replication slows down and the patient removes the virus.

Under non-ideal conditions – for example, if the full dose of molnupiravir is not taken for the entire five days – the drug could lead to the formation of highly mutated but viable strains of SARS-CoV-2. Even under ideal conditions, patients treated with molnupiravir produced viable viruses after a few days of treatment. The extent of the mutations that occurred due to molnupiravir is significant. In the FDA analysis of Merck’s clinical trial results, the authors found that patients who received molnupiravir had more virus variations than those who did not, including amino acid substitutions, deletions, or insertions in the spike gene, and amino acid changes were across the board Coding scattered order. A total of 72 spike substitutions or changes were noted in 38 molnupiravir-treated patients.

In South Africa, where Omicron was first identified, molnupiravir was used under both ideal and non-ideal conditions. Four different South African sites were used in Merck’s clinical trial of molnupiravir, which began in October 2020. The drug was administered to patients in today’s “optimal” dosage, but also in lower doses to test the effectiveness of the drug in smaller amounts. Molnupiravir and Omicron are by no means foolproof, but molnupiravir is known to induce predominantly two types of mutations: cytosine to uridine (C → U) and guanosine to adenosine (G → A). If you look at the difference in the Omicron genome and the original Wuhan variant, these C → U and G → A mutations represent the majority of the differences, with C → U mutations being more common in G → A. The same was seen with molnupiravir-induced mutations in other coronaviruses (see figure below). Agostini et al. Note that exposure to molnupiravir resulted in up to 162 mutations in MHV and 41 mutations in MERS-CoV.

Much more research needs to be done before we can be sure which of these three scenarios led to the development of Omicron. But we know enough today to make some assumptions and assertions.

First, until we can say with certainty that molnupiravir could not and will not produce a highly infectious and highly mutated variant like Omicron, it should be withdrawn from the market and any dispute over approval of the drug should be suspended.

Second, we must finally acknowledge the wide range of known and unknown tools available to this virus throughout its viral genome. While Omicron may be bad, future variants could be far worse. The United States and many other countries are still well behind what they should be in testing and genomic sequencing of viruses circulating in humans and other populations. Unless we do better on this front – until we understand what the virus has already achieved and how it has been successful – we will never have a full understanding of what else this virus can do and what lies ahead in this pandemic. Omicron tells us that now more than ever, we need to adopt a systematic, multimodal approach to Covid control, including public health interventions, vaccines, therapeutic and prophylactic drugs, and shared global engagement.

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