COVID Transmissions for 4-27-2021

Vaccines may be better against variants than natural immunity

Apr 27, 2021

Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions.

It has been 526 days since the first documented human case of COVID-19. In 526, an earthquake in Antioch, affecting the entire region of Syria, killed approximately 250,000 people. This may well have been the deadliest earthquake in human history, but there are some other potential candidates since the death toll of this one is not precisely known.

The COVID-19 pandemic, which has killed more than 3 million people, continues to have world-shaking consequences in a more metaphorical sense.

Today we’ll discuss an EU decision to consider allowing vaccinated travelers to visit over the summer, and an exploration of why vaccine-induced immunity may be better than virus-induced immunity—with consequences for how well vaccines work against variants.

As usual, bolded terms are linked to the running newsletter glossary.

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Now, let’s talk COVID.

EU may accept vaccinated travelers from the US by summer 2021

There is a reader comment on this today, but I wanted to let everyone know about another good reason to get vaccinated (as if avoiding death or disability from COVID-19 was not already enough): it opens up a greater world for you to visit.

The European Union President commented recently that the vaccination program in the US will allow US citizens to travel there. This appears to be a consequence of another planned policy shift, where anyone who has received a vaccine that has been approved by the European Medicines Agency will be allowed to travel to the EU. All vaccines authorized in the US qualify by that restriction.

I think that this policy needs more details to be hammered out. If I were an EU leader, I would not necessarily want to admit someone from a country with an extremely high COVID-19 burden, even if they had received a vaccination. The risk that they might be able to carry the virus into my hypothetical country without showing symptoms or without realizing they may have COVID-19 is high enough, even if unlikely, that I don’t think it’s enough just for a traveler to be vaccinated. I think the traveler’s country needs to be vaccinated, too—what I mean by this is that the pandemic needs to be relatively under control in the country of origin. Ideally, the country should have a low case burden and a high vaccine uptake.

You can read more about this EU policy here: https://www.nytimes.com/2021/04/25/world/europe/american-travel-to-europe.html

Vaccines, as currently formulated, likely to remain effective against concerning variants

Another recent New York Times report summarized some recent studies looking at vaccine efficacy against concerning variants. The article focuses on the “New York” variant, B.1.1526, but also includes some information on B.1.351. The upshot is that recent work indicates that vaccines will provide effective protection against these variants. Here’s the article: https://www.nytimes.com/2021/04/22/health/covid-ny-variant-vaccine.html

The article explains things well, but basically, the situation is that vaccine-induced immunity appears to produce a more diverse set of antibodies than virus-induced immunity in the case of SARS-CoV-2, and that diverse immunity means a mutation or two can’t overcome vaccine-induced immunity. This is great news for controlling the pandemic. It also might help us understand the virus a bit better. Let’s delve into that possibility.

I’m going to speculate here, drawing on my experience studying virus-host interactions. Everything here that I’m saying is based on evidence, but I am synthesizing that evidence into a hypothesis that I am not sure has been properly tested.

What I think is happening is that the virus has some capability to disrupt antibody responses, and this capability is based in some protein other than the one used in the vaccines. There is some evidence that natural infection with SARS-CoV-2 can produce low-quality antibodies and otherwise impairs the immune response. You can read more about the impact on antibody-generation here: https://www.virology.ws/2020/10/22/an-explanation-for-the-poor-short-lived-antibodies-produced-during-serious-sars-cov-2-infection/

Many viruses have evolved capabilities to evade immune responses during natural infection, like this proposed immune evasion mechanism seen with SARS-CoV-2. This kind of mechanism is so important to viruses that a lot of the time, vaccine designers focus on finding a way to provide a virus-specific immune stimulus without also providing the immune-evading components of the virus. Sometimes, that is sufficient to produce an immunity-inducing product that cannot cause disease.

The mutations that appear in these variants of interest arose in the context of natural infection, of course. So these are variants that make it easier for the virus to escape the immune response to a natural infection—with all of the virus’s immune evasion tools intact. Like we discussed, one of those tools appears to be the ability to screw up the antibody response.

It would appear that those tools are not present in the vaccines, which only provide the spike protein of SARS-CoV-2. Without the complete virus to disrupt the immune response, a varied antibody response to the vaccine can develop uninhibited. This means that the immune system can accurately and adequately target many different areas on the spike protein. By targeting a variety of sites, this vaccine-induced immune response is less compromised when mutations disrupt antibody recognition of a handful of specific spots on the spike protein.

The set of evidence that we see here—that SARS-CoV-2 infection produces less diverse antibody responses than vaccination and that SARS-CoV-2 infection may inhibit antibody formation and maturation—suggests that there may be some critical immune evasion capability in SARS-CoV-2 that is housed in a protein other than the spike protein. Whatever virus component is potentially responsible for this immune evasion mechanism, I think it will be important to understanding how SARS-CoV-2 works to cause disease in humans.

What am I doing to cope with the pandemic? This:

Synthesizing stir-fry lessons with pasta lessons

If you’ve been watching this space closely, you know that I’ve been interested in pasta-cooking methodology and also in stir-frying.

There happens to be a type of stir-fry that takes both skills: stir-fried noodle dishes!

I think these are pretty hard to make, honestly. Proper stir-frying happens at VERY high temperatures, and freshly-cooked noodles love to stick to very hot things. It takes the right combination of temperature control, management of cooking oil and sauces, and time management to be able to make a good noodle dish happen.

Last night, I built up a chicken stir fry using the techniques I’ve been working on. As I mentioned before, I set up a mise-en-place in advance. I think this is essential when cooking time is so sensitive. I also got my noodles cooked—mostly—in advance. I say mostly because I used the technique of lightly undercooking them in salty water, mentioned recently in this section. I set those aside for when I would need them, and worked them into my dish last. Just an aside about the noodles—for this, I used a package of fresh stir-fry noodles from the only kosher brand available at my local Asian market. After bringing them just shy of cooked, I also set aside about a cup of the cooking liquid, which I also needed for my little experiment in technique-blending.

The stir fry was, relatively simple: garlic, onions, shiitake mushrooms, thinly-sliced chicken, celery, carrots, bok choy, and ginger. I’d marinated the chicken in soy sauce and honey for about an hour. Nothing too fancy.

As usual, I cooked these at very high temperature, adding the ingredients in an order that made sense for their cooking times and the flavors I wanted to develop; they’re listed in that order, from earliest added to the pan to latest, above.

The new trick came at the end. Normally, I try to keep the temperature high when I’m stir-frying, to caramelize things quickly and make sure the cooking is even. However, when adding my noodles, I decided to crash the temperature somewhat by adding the cooking liquid in just before. My thinking was that this would help develop a nice sauce by supplying starch, and this sauce, along with the drop in temperature, would keep the noodles from seriously sticking. The noodles finished while being stir-fried in this sauce, taking on the overall flavor of the dish. But, since I let the temperature gradually climb, I was also able to get some real heat on the noodles so they built up a nice texture. Here’s how that turned out:

Image is a bowl containing a stir-fried noodle dish.

I think this worked out pretty well! I’m going to keep experimenting with this technique.

Our reader comments today all dovetail nicely with today’s headlines; each either directly or indirectly addresses something we touched on in a headline.

Reader Adam asked me about the EU’s plans to open up to travel for vaccinated US persons this summer:

Hey, just wondering what your hot take is on the Schengen area allowing any American who's had both doses to travel for vacation this summer. Reasonable to open up or not very prudent?

I mentioned this a bit earlier, but here are my thoughts on this comment specifically:

I’m glad that you phrased this the way that you did. Not, “is it safe” to open up but is it “reasonable”—a better way to ask the question since safety is a relative matter.
Based on the facts I have in hand now, it is reasonable to open borders to vaccinated people from countries with low COVID-19 burdens. By the summer, I expect the US to have a relatively low COVID-19 burden if vaccination continues at or near its current pace. Unfortunately we have seen some slowing in the daily vaccination rate in the US already, which is troubling, but I understand that we are still on track for a 75% vaccination rate by July.
At that level of vaccination, I expect that we will have the pandemic rather well controlled. If we get there, then I believe it is reasonable to open borders to vaccinated US travelers. They would be unlikely to bring SARS-CoV-2 into whatever target country they are visiting, and also unlikely to get sick in-country and burden the local healthcare system.
But this all relies on a lot of assumptions. It could be that by summer there are new developments that makes this not make sense anymore. We will have to see.

A new reader named Sam asked a comment that I’m going to geek out on a bit:

Hi John,
I just discovered your (great) newsletter while searching for information on a vaccination-related matter on which you'd commented previously. I was wondering if you'd be able to provide an update of sorts, as well as comment on a related matter.
In your 11/18/20 issue, in response to a reader whose husband voiced concerns about mRNA technology, you mentioned that a somewhat less far-fetched concern would be that vaccination could generate an autoimmune response. I've seen these issue raised elsewhere here and there.
Do you view this problem as more, less, or about equally likely to occur as you did in November? Do you believe that we have seen signs of such reactions already, if they were going to occur? On a more theoretical level, are there reasons why we *wouldn't* expect such a reaction to occur, e.g., something distinctive about the vaccine-generated spike vs. the virus-generate spike? How worried should we be?
Similarly, an article appeared recently in the MDPI journal Vaccines (not to be confused the with Elsevier journal Vaccine) suggesting that signaling from the spike protein, via either infection or the vaccine, could lead to pulmonary arterial hypertension (see: https://www.mdpi.com/2076-393X/9/1/36/htm), a frightening prospect. How seriously would you take these concerns? (The article has been gaining some traction on antivax-ish corners of the internet. The authors don't seem like cranks, though I know MDPI's peer review practices have been subject to some criticism.)
Virtually everyone I know is at least partially vaccinated, as am I. Reading these things after the fact has honestly made me start to panic a bit.

I really like these questions, particularly the first one, which connects with something I discussed in the headlines section. This comment gave me a chance to share some of the basic virus-host interactions and vaccinology science that has happened over the last year, and I’m grateful for that opportunity. Here is my response:

Thank you for your kind words about the newsletter, and your insightful questions.
I’m glad you’ve revisited the concern about autoimmunity that I raised before we had approved vaccines. We’ve learned a lot since then, and there’s a lot more to say. At the time, I was basing this possibility on two items. One, that “long COVID” appeared to be an autoimmune condition mediated by exposure to natural infection, and two, that in the past there have been some other vaccines that have induced apparent autoimmune reactions in some patients. I thought it possible that some of the observed long COVID symptoms might be the result of autoimmune reactions induced by antibodies to the spike protein, and if that were the case, there could be some patients who experienced autoimmune reactions to the vaccines as well. My theory here was that the spike protein could contain some sequence that acts as a molecular mimic of something in the human body, and so antibodies against it might cross-react with that human target.
In the time since then, it has become clear that autoimmune reactions are not really happening in response to these vaccines to the degree one would expect in the above case. Another thing that we have learned is that, apparently, vaccination actually seems to alleviate long COVID symptoms in patients who experience them. This latter situation could arise if the vaccines somehow provide a strong and specific immune response that induces the immune system to “prune” back inappropriate responses that developed during natural infection (one of the headlines in tomorrow’s issue with discuss the evidence that natural infection produces worse antibody responses compared with vaccination), but it could also arise if the mechanism behind long COVID turns out to have nothing to do with autoimmunity. There are now immunologists who think that long COVID may actually be the result of persistent virus somewhere in the patient. This would be a complicated explanation, but the vaccine remedying the condition makes it something that has to be considered.
The only apparent autoimmune reaction that I’ve heard about with any COVID-19 vaccine is the vaccine-induced thrombocytopenic thrombosis syndrome that has made negative headlines for the AstraZeneca and J&J vaccines. It appears that in the extremely small population of patients who have this reaction, antibodies are raised against natural clotting factors. This does not appear to have anything to do with the SARS-CoV-2 components of these vaccines, since the mRNA vaccines do not have this problem. It may have to do with the adenovirus vectors that these vaccines use. However, it is exceedingly rare and likely there is something about the few patients in whom this has occurred that made the reaction possible.
Anyway, to turn back to the possibility that long COVID has something to do with autoimmunity. If this is the case, then I suspect that it happens because the full, competent virus disrupts the quality of the antibody response. The vaccines don’t do this, and this is probably because they are lacking in whatever component of the full virus is responsible for this antibody response disruption. I’ll reiterate that it’s not clear whether long COVID actually has an autoimmune mechanism underlying it, but if it does, then I think my hypothesis here reconciles why we don’t see autoimmunity yielding the same effects in response to the vaccines.
Now, to your second question. Wow, that’s a bad paper. I’m actually not sure where to start. I looked into the references (since that is a review), and it is mostly the review authors citing themselves. Those authors are not virologists or vaccinologists and it is apparent that they do not understand the vaccines they are writing about. Their work used the full-length SARS-CoV-2 spike protein without modifications, in a tissue culture setting that models a process that, if it goes on for a long time, might cause disease. Most of the available vaccines use a different construct, and even if the effect they observed in their tissue culture experiments is real, they haven’t demonstrated that it actually happens with the construct used in most vaccines.
That said, I don’t think it’s realistic at all to expect what they have seen in tissue culture to happen in any real way in vaccinated patients. Their experiments were done in cultured lung cells to model pulmonary hypertension. Pulmonary artery hypertension is a condition that can take a long time to develop into symptomatic disease, and what’s more, it takes place in the lungs. None of the vaccines are delivered to vascular cells in the lungs. All of the currently-approved vaccines are delivered to muscle in the arm. They express the spike protein there, and there is no mechanism that can be reasonably expected to deliver the spike protein from muscle cells, far from major arteries and veins, to the lung vasculature. The spike protein does not have a means to exit cells and transport itself such a great distance.
Imagine I am wrong about that, though. The vaccines currently on the market contain a small amount of material that expresses the spike glycoprotein for a short period of time. Imagine that some small fraction of that expressed spike glycoprotein travels, by some mechanism currently unknown to science, to the lungs from the muscles of the arm. There, it causes some cellular protein activation that, if it persists, could eventually lead to pulmonary artery hypertension. Except, it won’t persist—because your body is developing an immune response specifically engineered to destroy the spike glycoprotein. Within a couple of weeks of getting vaccinated, an army of cells and antibodies are patrolling the vaccinated person’s body trying to destroy every single molecule of spike protein that they encounter. Meanwhile, the actual vaccine components degrade eventually. They are not persistent in the body. They are used to make spike protein for a week or two, maybe even less time, and are then digested and destroyed.
So, to summarize: the effect shown in the paper hasn’t been shown in a living system, it hasn’t been shown to happen with any vaccine construct, it hasn’t been shown to be competent to cause disease, and there are several reasons to be skeptical that there is any mechanism by which the observed experimental effect could be seen in an actual living system, particularly not for long enough to cause disease. With all of those points separating these results from the likely reality, I don’t take these concerns seriously at all.
What’s more, if the proposed spike protein-mediated risk for PAH is even possible, it’s clear that the risk posed by virus infection, which expresses large quantities of the spike protein right inside the lungs, would without a doubt be higher than any risk that the vaccine could possibly pose. Since the vaccine doesn’t express spike protein in the lungs and actively helps you prevent the expression of spike protein in the lungs, it seems that even if this effect is real, the vaccine is actually your best method to prevent this only-possibly-real effect.
I’m honestly stunned that a journal targeted to vaccinologists would even run such a paper. But, we should know by now—peer review is not even close to a perfect system. It has its uses, but it also has its share of failures.

You might have some questions or comments! Send them in. As several folks have figured out, you can also email me if you have a comment that you don’t want to share with the whole group.

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