COVID 19 Updates: Mutations And The Endgame
The book of Ecclesiastes in the Bible starts off with a poetic reflection on some of the unchanging aspects of the universe:
4 Generations come and generations go, but the earth remains forever.
5 The sun rises and the sun sets, and hurries back to where it rises.
6 The wind blows to the south and turns to the north;
round and round it goes, ever returning on its course.
7 All streams flow into the sea, yet the sea is never full.
To the place the streams come from, there they return again.
8 All things are wearisome, more than one can say.
The eye never has enough of seeing, nor the ear its fill of hearing.
9 What has been will be again, what has been done will be done again;
there is nothing new under the sun.
10 Is there anything of which one can say, “Look! This is something new”?
It was here already, long ago; it was here before our time.
11 No one remembers the former generations, and even those yet to come
will not be remembered by those who follow them.
Of course, there is a sense where we face new things every day. New technologies, new people, new discoveries…new diseases…the universe has no shortage of the unknown. Even the earth and sun technically will not remain eternal…eventually the sun will grow old and explode in a few billion years, and we think that, at some point, the entire universe will eventually decay into some kind of heat death.
Yet you can also say that the fundamental nature of the universe doesn’t really change. As near as we can tell, the laws of physics and mathematics will always be a constant. Two plus two will always be four. And despite all our technological advances, the fundamental nature of humanity really hasn’t seemed to change. We still need food and water and sleep. We still fight over trivial things, such as toilet paper in the grocery store, as well as over serious things that are a matter of life and death. The risk of plague and disease will always be with us; there have been plenty of plagues throughout our history, and I’m sure we’ll have plenty in the future. We’ll continue to face the same problems that arise from human pride, anger, foolishness, and greed. We’ll all face death one day, no matter how much we pay in insurance premiums or how many health and wellness fads we get drawn into.
Viruses, bacteria, and other infectious agents will always be with us, and they will always be mutating and creating new diseases. As a larger fraction of the world population gets a SARS-CoV-2 vaccine and more parts of our society resume normal activity, I think this a good point to think about viral mutations and the future risks of pandemics we’ll face. With more people concerned about the risk these new SARS-CoV-2 variants pose, it’s important to have a realistic understanding of the long term risks we’ll face, both from this virus as well as others that have the potential to be problematic.
I touched on this in one of my updates last year, but it’s good to understand the differences between diseases that we can effectively eliminate from our population with enough resources (diseases like smallpox, polio, and measles) and diseases that always stay with us (like influenza, HIV, or the common cold coronaviruses). Measles, for example, has effectively been eliminated as a significant public health threat in the developed world ever since mass vaccinations started back in the early 60’s. In that time, measles has not been able to mutate sufficiently to evade the immune protection granted by that vaccination; in 70 years we haven’t needed a new vaccine for measles. If we wanted to, we could actually eliminate measles as a global health threat, but I guess that hasn’t been a particularly high priority for modern society…it’s just not a cool disease to focus on fighting anymore. It’s unfortunate, because measles is still a problem in many countries that don’t have the same healthcare resources as we do here in the US.
HIV, in contrast, is a disease that we really can’t eliminate from the population outside of changing human behavior. The combination of being a virus that infects immune system cells, as well as a virus that mutates rapidly, means our immune system simply cannot fight the virus off. The cells of our immune system are quickly killed off, and the rapid mutation means that a treatment that is working initially to inhibit viral replication won’t be working a month or two later. On top of that, it is a retrovirus, meaning it can hide its genome inside the DNA of an infected cell and stay dormant…thus even if you have successfully eliminated all detectible virus from a person it can still make a comeback. Most of us don’t think of HIV as a major public health threat, simply because we know that the primary risk factor for becoming infected is behavior; if you aren’t engaging in sexual activity with multiple people or reusing needles for injecting drugs, your chances of being infected are basically zero.
Influenza is a unique challenge, particularly because there are a wide range of strains that infect both humans and animals. Not only do you have three types of influenza (A, B, and C) but each of those types also have subtypes.
On top of that, the genome of influenza viruses is broken up into individual segments, much like the human genome is divided up into 23 pairs of chromosomes.
This division, combined with the fact that there are already a wide range of different subtypes infecting multiple organisms, means any animal infected with two different influenza strains at the same time allows the virus to potentially mix and match to create new variations that can escape existing immunity.
You notice that HA and NA parts on the shell of the virus? There are 18 different versions of the H and 11 different versions of the N, which opens up the door for a lot of combinations. As a result, every year the flu shot is…well…a guess of which variations will be most prevalent in the population. The flu shot will actually contain vaccines for 3 or 4 different influenza strains, based on which ones we think we’ll need the most protection from in that year. Each strain is sufficiently different that immunity to one doesn’t necessarily equate to protection from another.
To get an idea of how different they are from each other, the HA protein on the virus is around 560 amino acids long. This is the protein in the flu which binds to N-acetylneuraminic acid on the surface of our cells in order to infect them. Just for kicks, I aligned an H5 protein taken from a flu strain infecting a goose to an H1 protein taken from a 2009 human H1N1 infection:
That’s a 64% match…each of those stars represent amino acids that matched up.
Then, here’s a comparison between that H1N1 case and a 2013 H7N9 infection in Shanghai:
41.3% match there.
I’m just showing these to give you an idea of how different these different flu strains are, and why it’s so problematic that they’re able to mix and match these different variations. It’s why battling influenza is such a complex process.
Now let’s compare those differences to the differences in these SARS-CoV-2 variants. While the HA protein is around 560 amino acids long, the SARS-CoV-2 spike protein is made up of three identical proteins each 1273 amino acids long (fun fact, the Moderna vaccine is called mRNA-1273…scientists are very uncreative when it comes to naming things). This is the protein that targets the ACE2 receptor, and allows the virus to infect cells. Out of those 1273 amino acids, several are changed in each of the different variants we’re keeping an eye on:
B.1.1.7 — Also called the British variant or the 501Y.V1 variant, has 8 mutations in those 1273 amino acids of the spike protein. That’s a 0.63% difference in the protein. Of particular interest is the mutation in the 501st amino acid (hence the name). This one has been in the news a little more lately with the claims that it’s a little more contagious and a little more deadly.
P.1 — Also called the Brazil variant (also called B.1.1.28.1, but that one has just too many numbers in it). That one has 10 mutations in the spike protein, including that 501Y mutation. This one has been in the news a little more with the claims that it caused a second COVID wave in the city of Manaus, of note because some had claimed that the city already has a herd immunity protection effect with 75% of the population already coming down with COVID in the first wave. Thus, the argument is that the P.1 variant was reinfecting people who already had COVID once.
B.1.351 — Also called the South Africa variant. This one has 8 mutations in the spike protein as well, although some of them appear to be problematic due to the location, and seem to slightly reduce the neutralizing effectiveness of antibodies our body generates in response to a normal COVID infection/vaccine.
B.1.427 and B.1.429 — Also called California variants, again only a handful of mutations in the spike protein
B.1.526 — also called the New York variant, also only having a handful of mutations
I could go on and on listing more, there are thousands, but I hope you see the pattern in them: none of them differ by more than 1% from the original virus. Compare that to differences in the various flu strains, which differ by 50% or more. These variants are not drastically different, which is why we call them variants or mutants and not new strains.
And here’s where I want to make a few points, because most of the news reporting on these mutations has been more sensationalism and less on the accuracy side of things. First of all, whenever someone reports that these variants might be more contagious or might be more deadly or might cause reinfections, you should treat it with some skepticism. These claims are not made by actually studying the virus itself; they’re made by looking at overall trends in the population. Often, researchers just assume that if a particular variant becomes more prevalent than others in the population, then it must be more contagious, but that’s not always the case. Populations exist in fairly segmented social bubbles, and as a result one variant could be growing rapidly in one segment while another variant is declining in another. The more relevant question is: Where was the initial exposure that introduced the variant into the population? Was it, say, a giant music festival that resulted in a few thousand infections that then brought them home? And then each of those people infected their families and neighbors? And once the virus finished traveling through that population bubble, it starts declining because that bubble doesn’t interact with others?
This might be referred to as the “Founder Effect” in population genetics. When a new population is established by a very small group, there is sometimes a loss of genetic variation. Maybe there were 100 variations at first, but if only 3 make the jump to the new location, now those three are going to dominate the new area. They aren’t necessarily more contagious or more adapted than the other 97…they just happened to be at the right place at the right time.
Then there’s lethality. Keep in mind, claims of virus lethality are based on patient data, not a specific analysis of the virus. And this is a virus with an estimated infection fatality rate of about 0.3%. If you have 1000 people infected with this, you might expect 3 of them to die, if this was a perfectly representative population. But what happens if it’s 1000 people over the age of 70 in an assisted living home? Then forget 0.3% and start thinking 5% or 10%. What happens if it’s 1000 college students? Half of them probably won’t have any symptoms, and you may not see a single death in the ones that do. Whenever you see claims that the virus is more deadly, you first have to ask: what were the demographics of the population it was discovered in?
There was a decent amount of talk of the California variant being more deadly, for instance. What was left out of the reporting was the fact that this claim was based on less than 10 deaths attributed to the variant.
When you are dealing with numbers this small, the founder effect is very significant and can’t be ignored.
Then there’s the seasonal risk factor aspect. I guess I can’t go an update without mentioning this, but don’t forget that the single greatest risk factor for COVID complications is vitamin D deficiency, which is always more prevalent in the winter months. And when were these variants discovered? During the winter, when we’d expect our immune systems to be weaker. We aren’t just comparing fatality rates between mutations; we’re comparing them over time. We’re comparing the winter fatality rate of, say, the UK variant, to the summer fatality rate of the normal variant. This is a variable we need to consider.
We also need to consider the fact that our hospitals were again put under a greater level of strain during the winter months, and greater strain on hospitals means patient care suffers. You’re more likely to die in a hospital that’s overflowing with COVID patients than a hospital that has 50% of its ICU capacity available and ready for use. Again, that’s a variable we need to take into account when comparing fatality rates over time, because this founder effect can produce very misleading correlations.
Now let’s talk reinfections…starting with Brazil. There was the claim that Manaus already had a herd immunity effect with 75% of the population testing positive for antibodies before their second wave. There is a significant problem with that claim. First of all, they did not have the reported fatalities and hospitalizations to justify such a claim.
The city has a population of about 2 million, and peaked at 100 hospitalizations per day in their first wave in May. Compare that to New York City, population 8.4 million, that peaked with 1500 hospitalizations per day. Also compare their fatality data: NYC peaked around 900 deaths per day, while Manaus peaked at less than 150 excess deaths per day. By any conceivable metric, NYC looks like it was hit worse than Manaus, yet ended up with about 20% of the population testing positive for antibodies. Either Manaus had thousands of deaths that were not reported, or the population is unusually resistant to the disease…or that 75% estimate is completely flawed.
And that’s why we need to understand where that 75% came from. They did not do a random testing of their population…the 75% was based on testing blood donations for antibodies. They just assumed that the population that was donating blood would be a representative sample of the overall city population, but we don’t have to spend too much time thinking about this before we realize this was a flawed assumption. During a pandemic, where many people are told to stay at home, yet it’s safe to go out if you’re already recovered and immune, and by the way we have this convalescent plasma idea where if we get blood from people who have recovered from COVID we can give the antibodies to new patients…are we surprised that patients who recovered from COVID are more likely to donate blood than people who haven’t had the disease? There is no reason to think that 75% of blood donations testing positive for antibodies means that 75% of the general population will also test positive.
On top of that, the actual measured antibody prevalence wasn’t 75%, the highest it was measured in Manaus was in June at 52.5%. They then took that number and bumped it up to 75% based on the assumption that antibody levels wouldn’t last more than a few months and therefore 52.5% antibody prevalence must mean that 75% of the population had had it, and a third of them just lost the antibodies. Now, you’ve probably seen my posts in the past presenting data against the “waning antibody” theory, so I won’t repeat myself, but I remain fairly dismissive of the claim that this is somehow magically the one acute respiratory virus that our immune system cannot make immunity to that lasts more than 3 months.
Now, there is a good experiment that can be done to determine the chance of reinfection, and that brings us to the South Africa variant. The best way is to take antibodies from a recovered patient, mix them with the new virus variant, and then see if the virus is still capable of infecting cells in a petri dish. We call those neutralization assays, testing to see if antibodies neutralize the new virus. And it turns out, with the South African variant, they don’t always do that. Researchers took antibodies from a bunch of different recovered patients who had an earlier COVID infection, and mixed them with the South Africa variant to see if it would be neutralized, and it turns out it was only completely neutralized half the time. This is because each individual immune system is unique; the antibodies my body produces in response to an infection might be different than the ones your body produces. We call this a polyclonal antibody response (as opposed to a monoclonal antibody, meaning all the same).
So there is a chance your unique antibodies might not completely neutralize the South African variant…maybe about a 50–50 shot. Does that matter? Honestly, probably not, because you don’t need complete preexisting neutralization to fight off a virus. Don’t forget, these viruses differ by less than 1%, so just because some of your antibodies won’t work doesn’t mean they all won’t. Your body makes antibodies to a lot of different parts of the virus, and a 1% change is not going to be enough to evade them all.
And in the patient data, that’s exactly what we’re seeing. Confirmed B.1.351 reinfections may give a patient some symptoms, but the only reinfection case I’ve come across that was a significant problem was a patient in France. 58 years old, history of asthma, not much else I saw. This seems to be the exception rather than the rule.
This is an important thing I want to highlight when we’re talking about reinfection data, particularly in the context of whether this virus is going to eventually disappear like small pox or become endemic like the common cold viruses. I don’t care if all an endemic virus does is give me a mild cough and a fever for a few hours. You could be infected with the same virus a dozen times, and each time your body remembers how to fight it off even better the next time. We are exposed to countless viruses and bacteria every day, and our immune system handles them just fine because it’s seen them before. If our immune systems weren’t capable of that, we would have died off as a species a long time ago.
Despite all the hype the media like to throw around about mutations, I have yet to see any convincing data showing that this virus is capable of mutating enough to eliminate the benefit of the vaccines we’re currently using. Even if the vaccine doesn’t give us 100% neutralization protection, it doesn’t matter. I don’t need 100% neutralization; all I need is something that keeps me from getting sick. If we want to put together some new vaccines for a virus that is 1% different, sure, with mRNA vaccines that’s a piece of cake, we can do it in a day (which is why we’ve been putting so much into developing them over the last few decades), but right now that isn’t necessary. In fact, once all of our high risk populations are vaccinated, the risk of hospitals being overwhelmed with COVID cases might be completely eliminated. We don’t need to eliminate the virus to go back to normal, all we need is a combination of vaccinations and treatments that keep everyone out of the hospital.
I hope this highlights the difference between why we need an annual flu shot and why I doubt we’ll need an annual COVID shot. 1% difference between COVID variants is nothing compared to the 50% difference in flu strains, and SARS-CoV-2 does not have the same mix-and-match capacity that influenza viruses have. The SARS-CoV-2 genome is all one piece; there are not individual pieces to swap around. We still would rather limit the number of infections we have of SARS-CoV-2 until we have a decent herd immunity effect, because we’d rather limit the ability of the virus to mutate, but to quote a popular YouTube doctor we should be “alert, not anxious” about this. If I had to put money on it, my guess is this virus is going to be eliminated, rather than become endemic. It just isn’t mutating fast enough yet.
And for those who are still on the fence/a little worried about getting a vaccine, just wanted to give you an update that I just got my first shot Friday. Moderna.
So far I haven’t turned into some crazy monster or grown extra fingers. I felt pretty lousy yesterday overall, but by today I was back to 100%. All the rest of the faculty in my program also work in the hospital, so they were vaccinated back in December and January, and so far none of them have turned into crazy monster things either. I’ll keep you posted if that changes!
And that’s that. There’s a ton more I could talk about here, but I’m already over my page limit and I’m also out of time tonight. I suspect this is going to be my last COVID update…realistically, I don’t see the situations drastically changing over the next few months. A few more vaccines will probably be approved, hopefully at some point the FDA will start to open their eyes to the benefits of ivermectin treatments, but I think we’re really in the home stretch here. Out of the 6 “warp speed” vaccines, 4 have already shown themselves to work and are being used: Moderna, J&J, Oxford, and Novavax (and Novavax seems to be a bit better against that pesky South Africa variant). Merck dropped theirs and switched to focusing on treatments instead, but word on the street is they’re thinking of teaming up with Novavax to help with production of their vaccine. The 6th one, the Sanofi one, is still in the works, and nobody seems to want to talk about it…although I’ve heard the issue with theirs is it doesn’t seem to work as well in older people. On top of that, a lot of other countries have also developed their own vaccines.
If there’s a major breakthrough I feel isn’t getting proper recognition, I’ll try to put an update out about it, but if not, I hope everyone has enjoyed these updates over the last year. I still feel a little embarrassed that my very first update last March was essentially “Guys, stop worrying, this isn’t a big deal, it’s just a silly SARS virus” and then within about two weeks of that first post a lot more data became available that showed it was a big deal…but that’s life. Sometimes we’re wrong, and we have to admit it and adjust. And at the end of the day, life goes on. The sun will rise tomorrow and set again. In 100 years we might have another global pandemic like this one…and maybe for that one people won’t hoard all the toilet paper. New challenges will arise, and we’ll come up with new tools to face them, and maybe half the time those tools will actually make things worse because we really don’t know what we’re doing most of the time. And God remains on His throne throughout it all. In the end, that’s all that really matters.
