COVID Transmissions for 7-26-2021
Understanding what makes Delta different; also, what does it mean when vaccinated people get sick?
Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions, now entering its second year.
It has been 617 days since the first documented human case of COVID-19. In 617, a number of conflicts in the Middle East were setting the stage for the next several centuries. The Byzantine Empire was at war with the Avars to their north and the Persian Empire to their west. These wars were devastating for the Byzantine Empire and the Persian Empire as well. In the meantime, in the Arabian peninsula, Islam was being born. The emergence of Islam would unify a number of peoples in the region, and with the dominant Empires weakened by a recent war, eventually a new political order would emerge, headed by a Muslim Caliphate that ushered in a golden age.
Today in 2021, we talk about an unvaccinated snow leopard, the unusual virological features of the Delta variant, and then I resurrect the “in depth” section to discuss breakthrough disease in vaccinated people.
A housekeeping note: this week I will be attending an intensive work function. It is possible I will not have time to do a Wednesday edition of this newsletter. I will do my very best, but do not be alarmed if you only get COVID Transmissions on Monday and Friday this week.
Bolded terms are linked to the running newsletter glossary.
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Now, let’s talk COVID.
Unvaccinated snow leopard at the San Diego zoo gets infected with SARS-CoV-2
I’m really sharing this story because it starts with “unvaccinated snow leopard.” I knew animals could get SARS-CoV-2 infections, and we’ve talked about it here before. What I didn’t know is that “unvaccinated” is now a meaningful adjective when it comes to animals. There are experimental vaccines for animals that are in emergency use, as detailed in this story about the snow leopard who got infected: https://www.nbcnews.com/news/us-news/unvaccinated-snow-leopard-san-diego-zoo-catches-covid-19-n1274945
I understand the snow leopard to have experienced a cough and runny nose, and I don’t believe the illness was serious.
Sleuthing out the differences in the Delta variant
Note: yes, I’ve given in with regard to using the PANGO name for this variant every time I mention it. I still think the Greek-letter system is a bad one and we’ll eventually run out of letters, but for now, most people know what “Delta” is, so that’s what I’m calling it.
Anyway, on to the story. A recent preprint details an outbreak of the Delta variant in China, with extensive contact tracing and tracking of individual cases. This is a great dataset because it can tell us things about the variant that we don’t know just from the wider epidemiology. Some of those things may help us begin to understand why the Delta variant has risen to global prominence and has out-competed other lineages of SARS-CoV-2.
The article is here: https://www.medrxiv.org/content/10.1101/2021.07.07.21260122v1
This is not peer-reviewed, but it is still interesting content. I am coming to this specifically with the question, “what makes Delta a big deal?” but I will note that the paper looks at some other questions, too—specifically how often certain other mutations emerge during single Delta variant infections is one that I like—but I’ll limit my discussion to what has made Delta stand out among variants.
The top-line answer, as suggested by this paper, is in their finding that Delta variant infections have much higher amounts of virus RNA present, than historical lineages that circulated in 2020. In fact, the authors suggest that the amount of virus RNA—which they mistakenly refer to as “viral load,” a term that means something else—is 1000 times higher at the first positive PCR test with Delta than with historical lineages. That’s a lot higher.
They go even deeper into this, an investigation that is only possible given the excellent epidemic surveillance that they have into this outbreak cluster, and produce the following figure:
This figure is a little tricky, partly because the paper isn’t perfectly written. I need to establish here that China has extremely severe procedures for the isolation of patients with COVID-19. In this particular outbreak, contacts of positive cases were quarantined and tested on a daily basis. Testing was done by a central laboratory at a local Chinese CDC outlet, which I believe provided feedback on whether the subject was “positive” or “negative” according to established criteria. However, these authors also had the ability to measure virus RNA in samples that were collected before the official declaration of positivity. This is, at least, how I understand it. I hope the peer-reviewers of this paper ask for some clarification, since I don’t fully get how a patient could be “negative” and still have virus RNA present, unless some specific rule for what constitutes a positive test is being used, and not fully described in the paper.
Anyway, let’s accept for a minute that patients had detectable virus RNA before they were declared positive. In that situation, we can see that patients infected in this current, Delta-dominated outbreak, had a faster time from infection to their first positive test than patients infected in the pre-Delta 2021 outbreak (here I think we don’t even need the assumption; this appears to be time from exposure to positivity, which is easy to measure with good contact tracing). This implies that the virus is producing more RNA more quickly than in 2021. The presumption is that Delta is responsible for this, and that presumption is confirmed in the next figure panel, where the average “cycle threshold” (Ct) for Delta variant infections vs older-lineages infections is described. We see that the Ct for the Delta variant infections is lower, on average. This means that there was more virus RNA—substantially more—in the Delta variant infections. The lower the Ct value, the more RNA there was in the original sample. So we now have evidence supporting the hypothesis that Delta variant infections turn PCR-positive faster than other lineages because the Delta variant produces more virus RNA—about 1000 times more.
The authors take this a step further. They claim (I don’t see on what basis) that they know a specific threshold PCR value above which a case is typically infectious. I’m willing to believe that such a threshold exists, though I don’t think it’s a stark universal number. Whatever—there is definitely such a threshold. They then show that Delta variant infections typically increase in amount of RNA faster than infections with other lineages, exceeding their “infectiousness” threshold on average sooner than infections with other lineages. So, now, the hypothesis is that Delta variant infections, which have been responsible for faster time-from-exposure-to-positive-test, produce more virus RNA faster than other lineages, and in that way become infectious sooner than other infections with other variants.
This would suggest that the Delta variant may have a longer window of time in which it is able to transmit to other people. It may also suggest that the Delta variant produces more virions that can be transmitted to other people, thus increasing the chances of a successful infection.
However, it does not prove these things. The paper does not involve any recovery of infectious virus. It does not demonstrate that samples from a Delta-infected host are more likely to cause infections or that they cause more cells in tissue culture to become infected. Those are experiments I would want to see to confirm the hypothesis that is set up by this study.
That said, before I saw this paper, I would have said we have guesses, but very little good information, regarding what makes Delta out-compete other lineages for successful transmission opportunities. Now that I have read this paper, I think their data give us a really good hypothesis, that we can go ahead and find a way to test. That’s a big step forward in understanding this variant.
What am I doing to cope with the pandemic? This:
Brunch boat!
Yesterday we had some friends over for brunch. It’s interesting to gradually remember how to spend time with people, after going so long without that. Even though we’ve been having social gatherings for a few months now, I honestly still feel pretty rusty.
Even if I might have been a little socially rusty, you all know I’ve been working hard on cooking throughout the pandemic!
Something I’ve been fixated on for awhile now is a recipe I saw in a video ad, for something called a “brunch boat.” This is, basically, a baguette into which divots have been cut, eggs, poured within, and then the whole thing baked until the eggs are done. I used a recipe that made essentially an omelette mixture with parsley, chives, tomatoes, and mushrooms, and then poured this into a long deep cut made into the baguette.
Put more simply, you turn a baguette into a long bread bowl, put it on a baking sheet,1 then you pour whatever egg concoction you like into that bread bowl, and bake for about a half an hour at 350F. A couple of considerations here: first, this is basically a frittata with more carbs, so I wouldn’t call it health food. Second, I don’t think it would refrigerate and reheat very well, so if I made it again for a smaller group, I’d probably use a bâtard loaf instead of a full-sized baguette.
This was a pretty cool thing, and super easy to make, but I didn’t have the foresight to take a picture. I do plan to do it again, though, and in the meantime I recommend looking up how to make one and trying it out.
So I heard a vaccinated person got COVID-19…
It has been quite a while since I used the “in depth” section header. For those who were never around for one, this is where I go into a topic of interest, at greater length, even if I have no specific news about it.
Today I want to write about breakthrough cases of COVID-19 in vaccinated people. To do that, however, I think it is important that we revisit the distinction between infection and disease.
Infection is the colonization of the host organism by a pathogen, an infectious agent. This is a low bar to cross, and refers to a series of biochemical events that do not necessarily have a noticeable manifestation for the host. In other words, infection doesn’t mean you’re sick. It doesn’t mean you can transmit whatever you’re infected with. It just means the thing has made its way into you. Many other events must occur for infection to turn into disease.
Disease is the manifestation of signs and/or symptoms in the body. This doesn’t just apply to infectious diseases; that is a generalized definition of disease. Strictly speaking, you aren’t “sick” if you don’t feel sick or if there aren’t any signals that can be measured that would indicate that you are sick. In other words, when it comes to disease, if a tree falls in the forest and nobody is around to hear it, it never fell. Please note that this doesn’t preclude a disease manifesting later from events that didn’t yield signs or symptoms when they first occurred. Something may not make you sick the moment it happens, but days, weeks, months, or even years later, the consequences of that event might manifest as disease.
Sort of a fuzzy picture of disease, I know. In the situation of COVID-19, that is the name of the disease—the cluster of symptoms including but not requiring or limited to fever, difficulty breathing, cough, impairment of sense of smell or taste, etc. Disease may progress to a number of outcomes along a spectrum of options, ranging from complete recovery to death with a number of intermediate outcomes along the way. The infection, on the other hand, is the presence of SARS-CoV-2, the virus, in the body. We know the virus doesn’t always cause disease. These are generally called “asymptomatic infections.” Note that this is not called “asymptomatic disease.” It’s not disease. Be wary of news articles that call these “COVID-19 cases.” While they may meet some case definition, they are not disease cases. They are infections with SARS-CoV-2.
Asymptomatic infections are one of the more peculiar things that SARS-CoV-2 does. I cannot think of any respiratory viruses that are well-known which can cause an infection and then be transmitted to others without causing disease. Early in the pandemic, a failure to recognize the possibility of asymptomatic transmission caused many public health authorities to give what we now know is bad advice about protective measures. Thinking that the virus could only be transmitted if symptomatic, as was true for SARS-CoV-1, people were told only to take certain protective measures (like masking and/or isolating) if they knew they were sick. Emerging pathogens often have a phase where errors like this occur, because the pathogen is very new and we do not know a lot about it. The importance of asymptomatic infections in the spread of SARS-CoV-2 was one of these surprises.
That said, we do know of quite a few situations where asymptomatic infection is possible without transmission as well. Many infections with different pathogens can be what is called “abortive,” for a variety of reasons. There are a number of animal viruses that are competent to infect humans but incompetent to make us sick. Sometimes this is because the virus needs some missing factor, present in its animal host, that humans lack. It may replicate for a few cycles and then eventually stop—hence, “abortive” infection. Another option is infection in an immune person. A person who is immune may become infected with a virus, and then proceed not to experience symptoms or transmit that virus due to an effective immune response that controls the infection and eventually eliminates it.
These situations are also not disease.
I’ve gone through this laboriously, because I wanted to emphasize that these situations can all happen in vaccinated people, to varying extents, with SARS-CoV-2 infection. So, when you see information about vaccinated people who “test positive” for “COVID-19,” please question whether they have also shown symptoms of disease, or are merely testing positive for infection. A vaccinated person being exposed to SARS-CoV-2, and even potentially becoming infected with that virus, without getting sick is a very special situation. It is called a “win,” at least in my book. The point of the vaccination is to prevent disease, because disease is what harms or kills people. If the vaccine has created immunity that prevents disease, but not infection, it is still considered protective. These cases of asymptomatic infection are a sign to me of the vaccine doing what we want it to do.
All of that being said, we are definitely also hearing about cases of vaccinated people experiencing disease. However, as I’ve related over the past several weeks, when vaccinated people get sick with COVID-19, they still appear to be experiencing milder illness than unvaccinated people, on average. They are orders of magnitude less likely to become hospitalized or die, compared with unvaccinated people. This is also a success. If a disease is converted from serious or deadly to a less severe average outcome, though use of a vaccine, that is also a win.
However, it is not the biggest of wins. Ideally, we want to prevent transmission of virus between people to prevent the spread of disease. This is especially important because not everyone has a fully protective response to a vaccine—in fact, the existence of vaccinated people who get COVID-19 is evidence of this. We want to protect those people. Stopping the ability of the virus to spread is the best way to do that. So when someone who is vaccinated gets COVID-19, it could mean that the vaccine did not, for them, produce a sufficiently protective response, but it can also mean that they are capable of spreading infection, if not also disease, to others. These are both not ideal things.
These things would be even less ideal if our COVID-19 management strategy was currently optimized towards eradication of the disease. However, we have discussed before that eradication is simply not a realistic goal given what we now know. With so many potential human and animal hosts around the world, it will be very difficult to get rid of COVID-19. The disease—not just the infection—will continue to be with us for a long time.
That isn’t exactly good news, but it isn’t exactly bad, either. Like I mentioned earlier, attenuated disease in a vaccinated person is actually a pretty good outcome. In the situation where a vaccinated person gets a mild case of COVID-19, they have experienced, most likely, a cold. That cold represents an immune response that involves activation of the memory cell populations that they made as a result of their vaccination. Those memory cell populations modify themselves to better target the new infection, control it, and the person gets better. In a world with emerging variants, this actually sounds like pretty good news to me. The variants that we have seen so far are pretty similar to the original virus lineage, so if a vaccinated person gets mildly ill with one, it updates their immunity at the relatively low cost of a minor illness. This means they are more “caught up” with the current status of the circulating virus, and as new variants continue to emerge, might have a better chance of fighting off the descendants of whatever the latest problem lineage happens to be.
There are two key problems with this, however. One, the disease isn’t always mild in these breakthrough cases, and I’m really not sure if “long COVID” or “postacute COVID syndrome,” as the CDC is more fond of calling it, is less frequent in people who have these cases of breakthrough COVID-19. So in some of these breakthrough cases, serious negative impacts—including impairment or death—are possible. They do seem to be meaningfully rarer than in unvaccinated people, however. The second problem is one we already touched on; we don’t know the extent to which spread might be limited when disease happens in a vaccinated person. It might be less likely for SARS-CoV-2 to be communicated from such a person to others. It might be equally likely as from an unvaccinated person. I just don’t know.
Still, I want to look at this practically. Let’s take as accepted that we will not be eradicating COVID-19. Let’s also take as accepted that as time goes on, more people around the world will get vaccinated than are vaccinated right now. This is sort of trivial; though in many countries and localities the pace of vaccination has slowed, there are still new vaccinations occurring every day. So if we take both of these premises as true, then we come to a future where there will still be circulating SARS-CoV-2, and more vaccinated people will get infected with it.
I’m here to tell you that that’s exactly the future you want; you may just not realize it. What I’ve just described is actually the COVID-19 endgame that one wants to see. We know, for example, that vaccinated people are less likely to die of COVID-19—substantially less likely. This is a nice rundown of the fact that unvaccinated people are more likely to die: https://healthfeedback.org/claimreview/unvaccinated-people-are-more-likely-to-die-of-covid-19-because-they-are-more-vulnerable-to-infection-and-severe-disease-tomi-lahren/
If vaccinated people are substantially less likely to die of COVID-19, and there will continue to be increasing numbers of vaccinated people, then even with breakthrough disease cases we will have a result where fewer people die of COVID-19. We will also, incidentally, see reductions in overall cases of COVID-19 relative to pre-vaccine times, because even with breakthrough disease cases that occur infrequently, there are still many people who do not get sick at all, and also many vaccinated people who cannot transmit the virus. They’re out there doing the good work of not spreading the disease, if we happen to be focused on the less-ideal situations in this particular discussion.
So we find ourselves looking at a future where the spread of COVID-19 is restricted by the presence of vaccination and increasing vaccine uptake, but disease is still possible. Even using the most pessimistic numbers I have seen, the risk of serious disease or death is reduced by at least 10 times in a vaccinated person relative to an unvaccinated one. This is a future where COVID-19 is, largely, a nuisance.
I don’t want to pretend that this is a future where COVID-19 can’t kill people. It will continue to kill unvaccinated people, for certain. I think the most important thing we can do right now is encourage those people to become vaccinated, before they either die or cause someone else to die by being part of a sustained transmission chain. It will also probably kill some vaccinated people. These will be rare individuals in whom the vaccine has not induced meaningful immunity, or comorbid conditions have worsened that immunity, or some other combination of biochemical misadventures have compromised the patient’s odds of survival. Each such case will be a tragedy, but these cases will be extremely rare.
The goal in this future is to lower the frequency of these cases to around the frequency of death from common cold coronaviruses. Yes, that happens. People die of colds. They used to do it a lot more frequently, before modern medicine came around, but it still happens. Even when we do prevent those deaths, keep in mind that we haven’t actually prevented anyone from dying. Everyone dies. What medicine hopes to do is add meaningful years to life and help people to go through life being able to achieve their goals with reduced fear of disease stopping them. If we can reduce the odds of COVID-19 death to be comparable to the odds of death from another common cold coronavirus, then we’ve accomplished those goals, on average. Most people will have longer life expectancy than they would without the COVID-19 vaccine. Most people will be able to live without fear that COVID-19 will end their lives early. That will mean we’ve changed COVID-19 from a world-paralyzing scourge to something that requires emergency care in severe cases but can otherwise be ignored by the vast majority of society.
Of course, I would say that people shouldn’t actually ignore it—they should vote for scientists to be funded to study it, they should be interested in the facts about it, and they should continue to read newsletters about it. But we won’t all need to worry about it every day and in quite so many aspects of our basic life functions. That’s another thing that I’d call a “win.”
In the world before any vaccines existed, when new viruses emerged, we would eventually reach this situation anyway. Eventually, as many people as possible would become infected with the new pathogen, those who could get disease would get disease, and those who were likely to die would die. The new pathogen would be passed around the globe and millions would die. The survivors would be immune, and either completely protected or protected enough to experience only mild disease. For COVID-19, I imagine this would have taken up to a decade. With 7-8 billion people living on the planet, and just short of 200 million cases so far in the first 617 days, even with the inevitable acceleration of global spread, I don’t think things would have progressed very quickly. Worse yet, we know that at least 4 million people have died, though the number is probably substantially bigger. If 4 million people die for every 200 million infected, we would be looking at around 50-100 million global deaths. That would have been the cost of reaching some kind of equilibrium with this virus, because the survivors would have had some kind of immunity. Instead, we can get even better immunity using vaccines, and at a much lower human cost.
So, when I hear about these breakthrough cases of COVID-19 in vaccinated people, causing less severe disease and lower likelihood of death, I’m not as worried as you might think. I’m certainly not overjoyed—every disease case is better avoided than tolerated—but compared to the world we were living in before the vaccines, this post-vaccine world is one where we can adjust to something of an equilibrium with this virus. The stories of mild cases in COVID-19 vaccinees, with lower risk of severe disease and death, are to me heralds of that coming future.
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Always,
JS
I did not do this part right, because I lost my baking sheets in my recent move and improvised with tinfoil. I don’t recommend being like me in this regard. Use a baking sheet, and situate your baguette on it before you pour in your eggs.
Interesting (if long-winded) discussion. I agree completely with the distinctions you have made between infection and disease and how those two have been (deliberately?) confounded in the media. For too long, people have accepted PCR positivity as a 'case'. Not only wrong but very misleading.
As for variants, 'delta' or otherwise, their emergence is completely predictable. That's what viruses do, especially RNA viruses with very high mutation rates. The other completely predictable thing is that emergent variants would be more infectious but less virulent. Again, not particularly insightful. Virology 101.
So, I would encourage you to step out of the vaccines only mindset for a moment which leads inevitably to chasing vaiants endlessly and consider an important role for antivirals. Take ivermectin for instance. A Nobel prize-winning drug, cheap, very benign and now with countless clinical studies all pointing towards its effectiveness in suppressing early disease and with potential prophylactic utility. A serious public health policy would take this drug and distribute it widely, to be used in conjunction with vaccines. Telling people to wait until they are seriously ill before seeking medical help, especially when there are reasonable treatments available borders on criminal IMHO.
Your "In Depth" about breakthrough infections reminded me of the 6 nasal spray vaccines now in various stages of testing for COVID-19. One proposed advantage of such a vaccine is that they would be expected to produce high antibody (IgE?) levels in the nasal secretions, and thus act as a barrier to initial infection, rather than allowing the immune system to resist an infection after several replication cycles. What do you think?