Could Pfizer's New Antiviral Drug Be the Source of Omicron Variant?

Wild speculation is a thing which I try to avoid. It is far to easy to fool oneself into believing that a very unlikely thing actually is possible or has happened by constructing logical or other arguments that sound good on their face, and make sense, yet quickly fall apart upon closer scrutiny. Moreover, generally speaking there is no benefit to anyone from wild speculation, but it can be a very bad thing if the speculation is accepted as true by the gullible or uninformed. Thus, as I sat down to write this article I was very much torn. Although I do believe that what I wrote in the title is possible based on what I know about how viruses transmit among, infect, and replicate in humans (a lot), and what I know about the mechanism of action of Pfizer's new antiviral Paxlovid (admittedly a very little. Only what I have read in news accounts and from a few very brief conversations and secondhand accounts from virus researchers), I have no evidence that such a thing has occurred, and in fact it may not be possible to ever generate such evidence.

So what's the point of writing this then? I have no particular beef with Pfizer and happen to believe they are a solid company with a very strong core of technically competent research scientists fully dedicated to improving the health of their fellow man with the work they do everyday. I applaud them for that and this article should in no way be taken as any sort of slight on their motives or intellects or ethics or whatever. They are doing what they believe is the right thing for all the right reasons. Moreover, they have a proven track record of success that stretches back decades in development of both vaccines and therapeutics for a host of human diseases. What I write here is most assuredly not a conspiracy theory or any sort of anti Pfizer or big pharma screed. In fact it is not a theory at all, but rather a hypothesis. A hypothesis which I happen to believe is plausible if not quite likely.

The evidence in favor of this particular hypothesis is all circumstantial, and, as I said above, that may be the only kind of evidence that is possible in a case like this. "Proof" is likely impossible as it is technically impossible for all hypotheses, though that is a question on which philosophers of science disagree, have debated for ages and continue to debate to this day. In any event the points in favor of this hypothesis run like this.

1. The South African connection- Omicron variant (B.1.1.529) apparently arose in South Africa and is one of the SARS-CoV-2 variants of South African lineage, like B.1.351.

Many cases of Covid-19 disease have clustered in an around South Africa and because of this it has been ground zero for testing of new therapeutics (if not for new vaccines). One would suspect that distribution of Paxlovid has been very high in South Africa as it would be an ideal locale for clinical trials or other non FDA regulated studies to test its real world effectiveness.

2. The timing - The emergence of Omicron tracks roughly with timeframe in which Paxlovid first began seeing use in humans during and post clinical trials.

3. The mechanism of action - At a very high level, and greatly simplified, Paxlovid works by inducing a high number of mutations in infecting SARS-CoV-2 virions. The number of mutations is such that they render the virus unable to replicate and thus non-infective (or dead for those who consider viruses alive). It is a form of virus reverse genetics. See here for more on this fascinating research tool now seeing widespread application in Covid-19 research. There has been concern among some researchers of the potential for Paxlovid to induce mutations in host cell DNA which could be detrimental to health in many ways. Pfizer says, and I believe them, they have not seen any host cell mutations and thus this is a non issue. However, Pfizer would not deny that Paxlovid causes mutations in SARS-CoV-2, this is, after all, the basis of its antiviral activity. They would argue that the number of mutations is so high as to render exposed virus non-infective. Again, I believe them.

However, what about a patient who doesn't finish the full course of Paxlovid? For example he or she splits it on the sly with a close relative who is very ill, or decides they feel better now and sells their remaining doses on the street or to friends or relatives. Or what if they just don't follow the dosing instructions correctly. They could end up with a dose level just high enough to induce some mutations, but not enough to render the exposed virus non-infective. If the wrong sorts of mutations happened the virus could in fact become more infective (more virulent, transmissible, etc.). I would note that the dosing schedule for Paxlovid is not exactly as simple as take one pill a day. Instead it reads, "The dosage for PAXLOVID is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all three tablets taken together orally twice daily for 5 days." Those sorts of instructions can be easily misunderstood or improperly followed. Or, what if the Paxlovid itself was slightly degraded by temperature abuse or some other environmental exposure such that it was administered at less than full strength? With antibiotics, incomplete dosing is a big problem. It can lead to bacterial resistance when the antibiotics in question do not reach fully lethal levels. In this case resistance would not be the outcome, but rather a whole series of randomly mutated viruses with unknown infective potential could be generated in a single person or in tens or hundreds of people. In clinical trials dosing is tightly regulated and many controls and checks are in place to make sure these sorts of things do not happen, but with desperate people, in a place like South Africa, who knows what might or could happen. I don't think anyone would say the scenarios I described above, or others I have not imagined, could be totally ruled out with 100% certainty. All it would take is one slip up and my hypothesized omicron variant emergence happens.