COVID Transmissions for 11-10-2021
One year since vaccines; also, the disappearance of an influenza virus during COVID
Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions.
It has been 724 days since the first documented human case of COVID-19. In 724, Turkic1 peoples hand a major defeat to the Arab Caliphate. This is, in a way, portentious of things to come, because Turkic peoples will come to dominate the Muslim world and supplant Arab rule for centuries. It is interesting to see what political entities rise and fall in history; I see a parallel in how different virus lineages come and go, something we’ll discuss today.
It has also now been one year since the first COVID-19 vaccine efficacy results became available. I will write about this milestone today.
Additionally, I have some influenza virus-related thoughts for you today, and also some pretty interesting reader comments! Also, an important correction relative to the last issue—I misread something, and I want you to know I fixed my error. Letting you know is part of fixing it. If a communications error is made, and nobody hears about the correction, it hasn’t been corrected at all.
Bolded terms are linked to the running newsletter glossary.
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Now, let’s talk COVID.
One year since the first COVID-19 vaccine results
It has now been one year since Pfizer first reported their Phase 3 trial results for their vaccine. I want to take a moment to reflect on this.
Before the pandemic, no one would have considered it possible to conduct clinical trials for a vaccine inside a single year. This would have been thought of as a massive logistical challenge, with patient enrollment being the chief limiting factor.
Instead, multiple vaccines were created in less than one year. Multiple products, all using different strategies, have been demonstrated to be safe and effective in preventing COVID-19. This was one of the greatest triumphs of the health sciences and pharmaceutical industry, working together, in human history. We now know that in the event of a deadly pandemic, we can come together to make this happen. The next influenza virus pandemic is going to be very different from ones that have happened in the past, in light of this.
What’s more, when this became a logistical problem of the manufacturing and distribution of vaccines, we have also seen unprecedented progress. Yes, there is still a great deal of work to be done, but in the last year, about 7.3 billion doses of COVID-19 vaccines have been administered worldwide. Over 52% of the world’s population, or about 4 billion people, have received at least 1 dose of a vaccine against this pandemic disease.
For comparison, banking has existed for centuries, but it took until 2011 for 52% of humanity to have a bank account and thus access to financial services. It took decades for polio vaccination to be rolled out to the world, starting with the invention of the first vaccine against that disease in 1955.
There is a long way to go with COVID-19 vaccination globally, but I think we need to appreciate the amazing strides that have been made in the course of two years.
Influenza B virus Yamagata lineage has all but disappeared, likely because of COVID-19 controls
I’ve been meaning to share this paper, published on the day my daughter was born, for quite some time: https://www.nature.com/articles/s41579-021-00642-4
This article contends that due to COVID-19 pandemic controls, we may have eradicated one lineage of the influenza B virus, named “Yamagata”:
This shows us that COVID-19 measures have had an impact on global influenza, something we were aware of, but is interesting also in that specifically the B/Yamagata lineage looks to have disappeared while the B/Victoria lineage dipped substantially but then recovered.
Influenza viruses that can infect humans are found in 3 general species categories—A, B, and C. Influenza A is the one that we discuss most frequently in humans, and has had the biggest historical burden, particularly because it mutates rapidly enough to cause new seasonal epidemics and is the only species known to cause regular pandemics.
Influenza B viruses mutate more slowly, and influenza C the slowest of all. The influenza B viruses therefore cause some disease burden in humans but tend to have less sweeping annual impacts. They are also less widespread in terms of animal hosts; while influenza A viruses are found in numerous animals, including many mammals and birds, influenza B viruses are known only to infect humans and seals. See this image for a rough diagram of our understanding of these viruses’ ecology:
In light of our knowledge of influenza B ecology, the disappearance of the Yamagata lineage from humans could mean that it has gone extinct during the pandemic. We may not have eradicated SARS-CoV-2, but it’s nice to hear that we might have eradicated another dangerous virus through our disease control measures.
In my experience in the lab, influenza B viruses were always a little more fragile to work with. They had to be grown at lower temperature and required more time to grow. I’m not saying that this has anything to do with what has happened in the wild, but it isn’t a huge surprise that with the more restricted host range and a general reputation for being a bit more of a fragile or lethargic virus, it’s an influenza B lineage that appears hardest-hit by pandemic disease control measures. Influenza B/Yamagata, a virus lineage I have actually grown in the lab with my own hands for experimental work, may well be gone.
On the other hand, just because we don’t know of substantial animal reservoirs doesn’t mean that they don’t exist. It is also possible that the B/Yamagata lineage is lurking in some animal species somewhere that we don’t know about, and will reappear when conditions permit.
International virus surveillance is the only way we’ll find out!
What am I doing to cope with the pandemic? This:
I am behind the times with this—partly because the hospital where our daughter was delivered refused to give me the flu shot when I asked, since a support person is “not a patient”2—but tomorrow, I am going to get my influenza virus vaccination.
You should also get the influenza virus vaccine, if you do not have a medical exemption. Not enough people get influenza virus vaccines, and it kills. Every transmission chain for influenza ending in a fatality traces back to someone who just chose not to get vaccinated. That person may not have suffered much beyond a high fever and feeling crappy for a week, but they allowed the virus to continue moving through society until it killed someone. By getting vaccinated, you take that possibility off your conscience, and you protect yourself from influenza, a disease which, at best, kind of sucks, and at worst kills you.
It’s not too late to get your vaccine. Peak flu season is coming, it’s really never too late to get the vaccine because flu cases continue, and getting the vaccine consistently every year offers you some amount of cumulative protection as well.
You do not want to be going for influenza care in the middle of a pandemic, even if you are vaccinated against COVID-19. Influenza is a hammer on the immune system, and you don’t want to get exposed to SARS-CoV-2 in a medical setting when you also have flu. Coinfection with influenza virus and SARS-CoV-2 is possible, as seen in this article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267808/. However, it is still rare, so we don’t know a lot about the prognosis in such cases. Trust me—you don’t want to be a datapoint in the process of our learning more. Get your flu vaccine.
I have to thank reader Sam for pointing out an error I made in the last issue. A confusing element of the Pfizer press release about PAXLOVID, and my lack of familiarity with HIV drug cocktails, made me misunderstand the components of this product. PAXLOVID is a combination drug, consisting of a new compound called PF-07321332 (doesn’t that just roll off the tongue) plus an older drug called ritonavir. Ritonavir doesn’t particularly do anything to COVID-19 as far as we know; it is included in the drug cocktail to stabilize the PF-07321332 by inhibiting an enzyme called CYP3A4 that would otherwise break down PF-07321332 in the liver. Ritonavir is also used in HIV treatment for this purpose, to stabilize other protease inhibitors.
Sam also shared some thoughts about PAXLOVID’s development process:
I'm very interested in Pfizer's ongoing EPIC-PEP trial, which is looking at the efficacy of Paxlovid for post-exposure prophylaxis. See slide 28 here: https://s21.q4cdn.com/317678438/files/doc_financials/2021/q3/Q3-2021-Earnings-Charts-FINALv2.pdf.
I'm very disappointed that there don't appear to be any plans for pediatric trials currently.
I could envision a future where, essentially, careful people perform home tests multiple times a week, taking a course of antivirals at the first sign of infection to prevent progression to serious disease. Of course, this is a non-starter when antigen tests run $10 a piece.
I find this interesting too. Post-exposure prophylaxis would be an interesting way to use this antiviral. Although vaccination is by far superior, and monoclonal antibodies are more durable in patients where vaccination is suboptimal, there are patients who could use a third-line option—consider Colin Powell, for example, who might have benefited.
On the topic of a pediatric trial, I had the following reply:
PAXLOVID is currently targeting high-risk individuals. The high-risk pediatric population is exceptionally small and probably not large enough to conduct a meaningful trial.
When PAXLOVID conducts trials to expand its use into general patient populations, there will probably be a better case for doing trials in children.
Carl Fink, meanwhile, shared the following question on the potential for molnupiravir to mutate host genomes:
I actually am going to take a rapid antigen test as soon as I finish this comment. No, I'm not sick, but tomorrow I'm going to visit some relatives, and I happen to like them. I don't want to risk bringing a deadly disease with me.
I saw speculation that molnupiravir, despite being meant only to cause mutagenesis in viruses, can do the same to human DNA. For one example:
Or this letter to the BMJ: https://www.bmj.com/content/375/bmj.n2422/rr-5
Doing the search to find that, I was surprised to find out how many publications there are on molnupiravir and its metabolites, so many that there is already at least one systematic review (https://www.researchgate.net/publication/355787582_Molnupiravir_in_COVID-19_A_systematic_review_of_literature)
No matter the situation here, it’s better to get vaccinated and reduce your chance of needing molnupiravir than to not get vaccinated and take your chances with COVID-19. On the specific point of the mutation risk, here is my reply to Carl:
Re: rapid tests, my statement on your plan here is: "This is the way."
On molnupiravir mutagenesis...I have a feeling that the dosage given, over the time period that it is given, makes this a minimal concern if it even matters at all, but that is a supposition. I'll explain my reasoning: The potentially mutagenic metabolite here is being rapidly incorporated into virus RNA, which is being produced in much much greater volumes than host DNA. Meanwhile the metabolite in question has a very short half-life in the human body, around 1-2 hours (see here for PK work done in the clinical trial program: https://pubmed.ncbi.nlm.nih.gov/33649113/ )
With only a short period of administration--and pharmacokinetic as well as pharmacodynamic experiments supporting an optimized dosing approach--I think this is probably not a major risk, at least in adult patients who are not pregnant or trying to become pregnant. Adult cells do not do a lot of DNA replication, so transient exposure to a potentially mutagenic compound is not as worrisome there. Also, humans have more capacity for error-correction in genome replication than coronaviruses do. We're a much more robust system.
In pregnant patients, children, or patients trying to become pregnant I would be cautious about the use of this drug. In those contexts, there is much more active DNA replication taking place than in adults, and while I have no specific evidence showing the drug is mutagenic, I'd still be cautious in the vacuum of data here.
This is all speculative, however. I do think this warrants further investigation. However, in the meantime, if I had symptomatic COVID-19 and this drug is made available for use in my care? I would take it. COVID-19 is the more immediate threat.
You might have some questions or comments! Join the conversation, and what you say will impact what I talk about in the next issue. You can also email me if you have a comment that you don’t want to share with the whole group.
Part of science is identifying and correcting errors. If you find a mistake, please tell me about it.
Though I can’t correct the emailed version after it has been sent, I do update the online post of the newsletter every time a mistake is brought to my attention.
Correction: due to an oversight on my part, I mischaracterized PAXLOVID’s components in the emailed edition of the last issue. As described in the Pandemic Life section today, PAXLOVID is a combination drug, consisting of a new compound called PF-07321332 (doesn’t that just roll off the tongue) plus an older drug called ritonavir. Ritonavir doesn’t particularly do anything to COVID-19 as far as we know; it is included in the drug cocktail to stabilize the PF-07321332 by inhibiting an enzyme called CYP3A4 that would otherwise break down PF-07321332 in the liver. Ritonavir is also used in HIV treatment for this purpose, to stabilize other protease inhibitors.
The online edition of the last issue has been edited to reflect this.
See you all next time. And don’t forget to share the newsletter if you liked it.
This is a very nebulous term that is very general; the specific entity that won this battle was the Turgesh Khaganate, a confederation of different Turkic groups ruled by a khagan.
Everyone around a baby is a potential vector for influenza virus exposure, and influenza is not kind to babies. They should absolutely be able to offer influenza vaccinations to any hospital visitors. I have worked in several hospitals where this was standard practice. “Never miss an opportunity to vaccinate” should be the mantra.