COVID Transmissions for 4-16-2021
Are variants escaping vaccine protection? I think not.
Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions.
It has been 515 days since the first documented human case of COVID-19. In 515, the Byzantine Empire managed to turn around a losing streak against the rebelling general Vitalian and finally defeat him.
The news recently might have you thinking that variants are trying to overthrow our vaccine success. Today I have a couple of stories about the Pfizer vaccine and the potential ability of variants to escape the protection it creates.
A weekend is coming! I hope you get the chance to enjoy it. Time off is precious.
As usual, bolded terms are linked to the running newsletter glossary.
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Now, let’s talk COVID.
Israeli study: what variants are “breaking through” vaccination?
A study was recently reported that looked at what sorts of SARS-CoV-2 variants are involved when people who have been vaccinated do get sick with COVID-19. I’ve been meaning to cover this study all week, but there have been some major events that have bumped it from the docket each day. A lot of bad news stories have wildly misinterpreted the results of this study, so I think it’s important that it be clarified here.
The study can be found here: https://www.medrxiv.org/content/10.1101/2021.04.06.21254882v1
What happened in this study is that the researchers compared a group of vaccinated people (specifically who received the Pfizer vaccine) who got COVID-19 with unvaccinated people who got COVID-19. They compared the genomes of the virus variants responsible for the infections in both groups, and found that there were some differences.
Vaccinated people *who got sick with COVID-19* were more likely to be infected with newer variants like B.1.1.7 and particularly like B.1.351. This doesn’t mean what a lot of people think it means, though.
First, the real-world data used here are from Israel, where wider real-world data has demonstrated that the efficacy of the Pfizer vaccine is comparable to what was seen in the clinical trial of this vaccine. So, we need to make sure this fact is placed at the top of any story about this—the effectiveness of this vaccine in the wild, even in the presence of variants, looks to be the same as the efficacy seen in the clinical trial setting. In other words, the vaccine is not compromised.
So with that having been said, there were cases of COVID-19 rarely in people vaccinated in the clinical trials, and there are also rare cases of COVID-19 in vaccinated people in the “real-world”1 setting. The study we are talking about here was not able to answer the question, “Are variants overcoming vaccine-induced immunity?” Because the rate of vaccine success is what the clinical trials predicted, the answer to this question looks like no.
Instead, the study pre-selected patients who still got COVID-19. This is a very small group of patients, and I bet that those patients were still somewhat susceptible to any variant of SARS-CoV-2. It just looks like they may be a little more susceptible to the B.1.1.7 and B.1.351 variants, based on the data reported in this study.
The real research question is this: “We know that sometimes, the vaccine doesn’t protect every individual fully. In these not-fully-protected individuals, what variants are most likely to be the cause of disease?”
The answer is that the new variants are more likely to cause disease in that type of patient, and probably because they have some mutations that impact how the immune response can recognize them. But that doesn’t mean these variants have “defeated” the vaccine. My feeling is that these patients could have gotten sick from SARS-CoV-2 infection with a variety of lineages, but they happen to be most permissive to these particular variants.
So, that’s the story there. This isn’t a sign that the vaccines are losing efficacy—we have data saying otherwise—but it’s a story that helps us understand which variants are most able to benefit from incomplete vaccine-induced immunity. That could be informative about how the variants work, much more so than it says anything about the vaccines, in my opinion.
Pfizer CEO suggests booster doses may be needed annually
A story broke yesterday where Pfizer CEO Albert Bourla said that we may need booster doses annually: https://www.cnbc.com/2021/04/15/pfizer-ceo-says-third-covid-vaccine-dose-likely-needed-within-12-months.html
I think this is total speculation and he’s totally out on a limb here. We have no data that suggest this one way or another. He said this is “likely” and I absolutely do not see any evidence to support the likelihood of this at all.
My feeling is that because of vaccine-induced protection, it is possible that COVID-19 will become a cold-like illness and exposure to virus variants will supplement vaccine-induced immunity to where we may not need any vaccination updates at all, even if the virus mutates substantially over a period of years.
Yes, it’s also possible that the virus mutates faster than that (so far, I don’t think it has shown signs of doing this), and if it does, then it’s possible that what Bourla is saying is true. But I don’t see any data saying that’s “likely,” and I don’t understand why he would say it is likely.
Or at least, I don’t understand it until I remember that he is the CEO of a publicly traded company and part of his job description is making statements that suggest Pfizer could make a lot of money in the future, because that will increase the PFE stock price and thus improve shareholder value. If this forecast is taken seriously, then it helps his investors, so I think he has a real incentive to talk up this possible future.
I wouldn’t make too much of his statement here, though.
Cool herd immunity simulation
NPR ran a cool article that has a built-in simulation of herd immunity. Check it out, I think it really illustrates the concept well: https://www.npr.org/sections/health-shots/2021/02/18/967462483/how-herd-immunity-works-and-what-stands-in-its-way
What am I doing to cope with the pandemic? This:
Walking in the rain
Today, we really needed to get out of the apartment, but it was raining pretty hard. So we put on our raincoats, walked around for awhile, and got some hot chocolate while we were at it. It’s good to just get outside, even when it’s raining.
Time to catch up on my comment backlog!
Carl Fink made the point that a drop in thrombocytes isn’t too uncommon with clotting disorders:
Hi, John,
As a platelet donor, I selectively notice stuff about thromobocytopenia (and thrombocytes in general). It isn't that uncommon for clotting syndromes to be associated with thrombocytopenia, in at least some cases because suddenly forming a lot of clots removes many platelets from circulation (literally). Note also that COVID-19 seems to be associated with thromobocytopenia in some cases, e. g. https://pubmed.ncbi.nlm.nih.gov/32178975/
You wrote, "All have been between the ages of 18 and 48. Even early in 2020, before many treatment modalities were available, patients in this age range were seen to have a case-fatality rate from COVID-19 that is substantially less than 1%, ranging from about 0.2% in the youngest bracket in this range to 0.4% in the oldest bracket. These risks will be lower now." Contrariwise, the variants like B.1.1.7 seem to be more dangerous for younger patients than the originally-detected strain.
As a critical thinking person, it's interesting watching myself think about this matter. I find myself looking for ways to explain away the J&J/AZ clotting phenomenon, because I really, really want it to not be real. It takes real mental effort to acknowledge one's own bias and force oneself to follow the evidence.
Carl’s not wrong here, the platelet population can be diminished by clotting. However I think the thrombocytopenia in the J&J patients with CVST was a little more extreme than this effect usually produces, I’m pretty sure. Meanwhile, I share similar feelings as Carl with regard to seeing a vaccine safety issue. Here’s my reply:
It's true that there can be a drop in platelet counts during major clotting events, but it's not usually so extreme as what was seen in these patients. Specifically, it's not usually so extreme as to make heparin contraindicated for fear of worsening the thrombocytopenia.
That's a good point about B.1.1.7, and I have also heard that it is having bigger impacts on younger populations. I'm just not entirely certain if that's a change in mortality risk or if it's a change in absolute numbers of deaths due to an increase in overall infections with that lineage vs ancestral ones. The epidemiology of B.1.1.7 is full of conflicting information, with some studies saying it has no impact on case fatality rate and others saying it has quite large impacts on CFR. Without a clear scientific consensus I am not sure what to say.
I have to echo your feelings about this clotting situation. I also want it to be some random thing that is not vaccine associated. However, the more I learn about it the more it looks like it could be caused by these vaccines--although I must emphasize that it is still very rare and most people who have received them should not be concerned about this. It's hard to want to be a good vaccine advocate and also talk about a vaccine safety issue. It feels like undermining the cause of vaccination, but the fact is, we do have to follow the evidence because that is what makes vaccines so great--they are evidence-supported tools and they are only approved because there is evidence that their benefits far outweigh their risks. When we are faced with the possibility of a safety issue, taking is seriously and being cautious is vital because it establishes the credibility of the evidence-based approach that forms the foundation for vaccine development and deployment. Or at least, that's the hypothesis I'm operating on.
Reader Rreedd also had a comment about the J&J vaccine situation:
Hi John,
Do these two vaccines (J&J and AstraZeneca) have tPA as an adjuvant?
I could see a scenario in which an over-activated fibrinolytic system could steadily consume platelets leaving a patient thrombocytopenic.
I’m also wondering if recent (possibly asymptomatic) infection with SARS-Cov-2 might be at play? I’m not very familiar with the vascular effects of this virus but I could also see how compromised vessel walls could also consume platelets and simultaneously activate the body’s coagulation system.
I have to explain some terms here. Adjuvants we have discussed before. tPA is an acronym for something called tissue plasminogen activator, a protein that is involved in clotting. It is used in the treatment of certain types of stroke. A segment of the tPA protein has also been explored for use in the enhancement of DNA-based vaccines, but it is not a functional part of the protein. It is something called a signal peptide, which just tells the cell where to send the protein while it is making it. Full-length tPA is not used as a vaccine adjuvant. The tPA signal peptide was a component of an early candidate for the J&J vaccine, but ultimate the inclusion of tPA signal peptide didn’t work, so the lead candidate that was explored did not use it and the final vaccine does not contain sequence for it. See here for more information on that: https://www.nature.com/articles/s41541-020-00243-x
All that having been said, here is my reply:
No, neither the J&J or AZ vaccines contain any adjuvants. Viral vector vaccines usually do not contain adjuvants because of how closely the vector-borne approach is thought to mimic natural infection and thus stimulate an immune response.
I've wondered also about whether there were SARS-CoV-2 infections in these patients that went undetected. SARS-CoV-2 definitely increases clotting risk, it is well-established as an issue that occurs in COVID-19. I hope we learn more about these cases soon.
I hope this helps clear things up to the extent possible.
I owe Rreedd a reply on another comment, but it is going to be an involved reply because they asked a lot of questions about virus origins. I had actually typed up a long reply to this reader when my browser decided to refresh the page and I lost my words. A sad time, for sure, and when my period of mourning for my lost reply is completed, I will write a new reply and share it here.
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See you all next time.
Always,
JS
Things that happen outside of clinical trials are called “real-world” in pharma. Clinical trials also happen in the real world, clearly, but they are full of such strict protocols and close patient monitoring that the results are considered to be somewhat artificial. The “real world” setting is used to describe the more relaxed, less intensely scrutinized setting of typical clinical practice.
John,
I appreciate your responses! And apologies for the errors, grammatical and otherwise!
Re: Israeli study: in order to conclude that this study is *not* evidence that efficacy is reduced against variants, it seems like you have to assume that every single one of the infected people in the study would have gotten infected by *some strain* anyways on the same timeline in the absence of vaccination.
Which is a pretty wild assumption - as far as I can tell, the straightforward model for infection is "every day, for each strain, you flip a weighted coin, and if it comes up heads, you get a COVID-19 case from that strain", and vaccination affects the coin weight (differently for each strain, since the distribution of strains among vaccinated cases differs from the distribution among unvaccinated cases). So it would be quite weird if vaccination had literally zero effect on the number of recorded cases. And yet this zero effect is mathematically required in order to keep the overall efficacy the same.
The fact that the observed overall efficacy matches what was seen in the clinical trials does point towards "they would have gotten infected anyways", but it's still pretty hard to explain that with a reasonable model of the mechanics of transmission/infection.