Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions.
It has been 535 days since the first documented human case of COVID-19. In 535, Emperor Justinian I began a campaign to reconquer Italy for the Roman Empire.
As we vaccinate the world, I’m thinking about visiting places instead of conquering them.
Today, we’ll talk about a key policy change that may help get the world vaccinated. We’ll also look at a study of vaccine-induced immunity in patients taking immunosuppressive treatments, and then there’s an interesting comment exchange on the paper that I shared yesterday.
As usual, bolded terms are linked to the running newsletter glossary.
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Now, let’s talk COVID.
Biden administration is exploring relaxing patent protections for COVID-19 vaccines
Very little is known at the time I am writing this, but what is known is available in this New York Times article: https://www.nytimes.com/live/2021/05/05/world/covid-vaccine-coronavirus-cases/covid-vaccine-patent-biden
As longtime readers will know, in the past I have advocated that the US government should just buy the patents for the COVID-19 vaccines produced domestically and then void them. This solution appears to be similar, though a little less free market-friendly.
I anticipate that this will apply largely to vaccines that the US directly funded, and I also anticipate that there will be restrictions on the countries where the patents are waived. Most likely the waiver will apply to countries where the cost of manufacture for the patent owners would never be recouped by the prices that the local market is able to sustain.
Keep in mind that the vaccine makers whose patents are likely to be suspended during this crisis have still made large amounts of money off of the developed countries deploying these vaccines and the research investment given to them by the US government.1 I do not expect this special emergency to have a substantial chilling effect on future pharmaceutical development based on this. Everyone has won here on some level, and the markets that I expect to be excepted from patent protections are not ones where I believe manufacturers were expecting to turn any profits at all.
We’ll learn more in the days to come but I think the bottom line is we need every stop pulled out in order to get the world vaccinated. The situation in India has made it clear that this pandemic can and will destabilize the world if we cannot get it under control globally. Also, it is the right thing to do to save lives.
Vaccine immune response in patients with immune compromise
Another in the series of papers that readers and friends have sent to me is the following, which examines how immunosuppressive treatments impact the immune response to COVID-19 vaccines: https://www.medrxiv.org/content/10.1101/2021.04.05.21254656v2
This paper is a study in humans, so we are not talking about a modeling situation. The small number of patients is probably a limitation, but with 133 patients with chronic inflammatory disease is still pretty sizable.
These patients were receiving a variety of different therapies that suppress the immune system, but the study separated them by treatment. This is where we start to run into an issue, because the numbers of patients get very small. We’ll come back to that.
The researchers here looked at the immune responses, as measured by neutralizing antibody titers, in these patients when given COVID-19 vaccines. I’ll note here that also there doesn’t appear to have been one specific vaccine administered. Patients’ responses were assessed two weeks after completing vaccination with whatever option they received. Because the study was conducted in a US setting, this probably means the overwhelming majority received either the Moderna or Pfizer vaccines.
Here are the results for antibody titers in control patients vs patients with chronic inflammatory disease:
Here, it looks like patients with CID undergoing treatment have a deficit in immune responses to COVID-19 vaccines, but I have to provide some caution here. These graphs are all in log scale, and the difference is actually less than one order of magnitude. Each step there is another power of 10. There is a reason for this. These sorts of experiments use something called a serial dilution. In serial dilution experiments, a sample is diluted by a fixed amount in series. In this case, the dilution series is a 10x dilution. Two dilution steps is a 100x dilution, and so forth. What the experimenters do is perform this dilution on their patient sample until it no longer has optimal virus-neutralizing activity. The dilution step where this happens tells you how concentrated the original sample was with antibodies against COVID-19.
A similar system was used to make a scale for how spicy hot peppers are. The units are called Scoville units, and they represent how much sugar water is required to dilute a hot pepper until its spice can no longer be tasted. If the pepper is very spicy, it takes a lot of sugar water to do that. If the pepper is less spicy, it takes less sugar water. This is the same kind of thing. The antibody is diluted until its effects on the virus cannot be detected anymore.
Here, the control patients required a 10,000x dilution before neutralizing activity was compromised. This means that the antibody concentration in their samples is around 10,000 times more concentrated than it needs to be in order to have an effect on the virus. In the patients with CID, the titer fell, but by a factor less than 10. That means that even in the patients with immunocompromise, although the immune response is weaker, the antibody concentration was still at least 1000 times what it needed to be in order to have an effect on the virus. These vaccines produce a pretty strong immune response, don’t they?
However, these are just the data in aggregate. There were certain drugs that seemed to attenuate antibody responses to a greater degree. Specifically, glucocorticoids and B cell depleting therapies (BCDTs), seemed to impair antibody levels by substantial amounts. Both of these drug classes on their own appeared to have effects that reduced antibody titers by more than 10x. However, I think this needs to come with a lot of caveats.
For one thing, I think given that these titers were still around 1000x as concentrated as they “needed” to be, this is a pretty potent response. It’s possible that the overall vaccine efficacy could be compromised here, but I don’t think these results alone indicate that there is substantial added risk of disease in vaccinated patients being treated with CID compared with patients without such diseases.
Another issue is that these two treatment classes happened to be among the least frequently used in the entire CID sample, with only 10-14 patients receiving them. The distribution of values for each of them was quite scattered, which introduces error into the sample and makes these subgroup results less reliable.
On the whole I think that this indicates not that vaccines are less effective in patients being treated with these drugs as a group but rather that some individual patients may have substantially compromised vaccine responses. Based on that, I wouldn’t say that patients on these medications, or patients with CID at all, should assume they will not have an effective response to COVID-19 vaccines. Instead, I would say that I think it is worth their checking with their doctor to develop a plan for the best way to confirm the quality of their immune responses after vaccination. There are currently marketed tests that will allow a doctor to measure a patient’s antibody response to vaccination, and so it may be worthwhile for patients being treated with CID to explore using such tools where available. And I won’t pretend that immunosuppressive treatments don’t have an impact at all—it is important for patients on immunosuppressive treatments to be watchful for disease symptoms and work to protect themselves from it. Even if optimally vaccinated, I think that such patients might do well to take extra precautions compared with people who are fully immunocompetent.
Even having said this, it still doesn’t look to me like the impact is very extreme. It probably warrants further exploration, but with highly effective vaccines that prevent a large proportion of even the mildest disease cases, I think it is likely that patients with CID who are being treated with these drugs will still generally have meaningful protection from COVID-19 as a result of vaccination.
Better studies will tell us more, though.
What am I doing to cope with the pandemic? This:
Streaming a Wedding from Israel
Today I watched a family wedding in Israel. It was kind of an amazing thing to see, because basically nobody was masked and it looked totally normal. This was possible because in Israel, COVID-19 has been reduced to negligible levels by widespread vaccine uptake. Watching this wedding today—mazal tov to those readers who attended—was like seeing a vision of the future that I hope to see in the US. People safely interacting and having a celebration, because vaccination has made it possible. This can happen around the world! We just need to bring vaccines to the people, and get them to accept vaccination. We can all contribute to this—by getting vaccinated, and by telling everyone we know to do the same.
Carl Fink had a comment on the paper I shared yesterday, linking to a blogger who was also talking about the potential for vaccine spike to cause vascular problems:
Steve Novella disagrees with you about the mRNA vaccines, specifically the Pfizer vaccine. He says it does in fact contain a complete and functional spike protein. (He doesn't say "functional," but I think he implies it.) https://sciencebasedmedicine.org/spike-proteins-covid-19-and-vaccines/?utm_source=rss&utm_medium=rss&utm_campaign=spike-proteins-covid-19-and-vaccines
My reply is based on my opinion, though there are matters of fact that cause me to hold my opinion. My statements about vaccine contents are matters of fact. My statements about what this means are at some level a judgment call (I’ll explain this in full after my comment reply). Here’s my reply:
Thanks for the opportunity to talk about some of the engineering that went into these vaccines.
Dr. Novella is technically correct that a full-length spike protein is used in the Pfizer vaccine, but he clearly (at least to me) thinks that the protein is still functional, and he is very wrong about that. I chose "fully functional" on purpose (and not just as a Star Trek: TNG reference), because while it is full-length, it is non-functional. Here's why:
The mRNA vaccines all use a prefusion-stabilized construct. The Pfizer vaccine does use a full-length spike, but it is locked into its prefusion conformation by the introduction of 2 key proline amino acids to prevent the conformational change that allows the spike protein to function. This modification is described in detail here: https://cen.acs.org/pharmaceuticals/vaccines/tiny-tweak-behind-COVID-19/98/i38
The prefusion-stabilized spike protein is functionally incompetent and this is very important. While it is possible that the functions observed in the pseudovirus paper that I shared are preserved in the construct, this is highly unlikely. The conformational change is necessary for the fusion of virus particles to cells, and the spike protein is pretty useless without it. See more on the cell entry mechanisms here: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009225
I just don't really see how a prefusion-stabilized S protein could have these kinds of impacts on a cell or its levels of ACE2. Since the paper didn't study the prefusion-stabilized construct, I am definitely making a call here based on a gut feeling, but I feel pretty confident about it. Still, I'd be curious what a coronavirus entry expert would say about this.
Anyway another dimension to all of this that I didn't mention--and should have yesterday--is that none of the vaccines contain the machinery needed for SARS-CoV-2 budding. None of the vaccines express the virus membrane (M) or envelope (E) proteins, which are both important in the budding process. So, none* of the vaccines can produce even replication-incompetent virus particles that could somehow migrate to the lung. The only mechanism by which any of the prefusion-stabilized spike could even get to the lungs would be if input vaccine material was carried there, something that I really don't believe happens. And even then, it isn't a functional spike protein.
I should also note that the AstraZeneca vaccine DOES use a competent spike protein that is full-length. I still think that, injected intramuscularly, it would not get to the lungs, and it remains that no lung pathology has been observed in vaccinees. If Dr. Novella had leveled his points at that vaccine, though, rather than the Pfizer vaccine, I would think he had a better point.
*Except the weird, apparently replication-competent mutant of Sputnik V, but I'm not really considering that to be a vaccine--it certainly isn't the Sputnik V product as-designed.
I do want to emphasize that it is still possible that the prefusion-stabilized S protein could have some of these effects in tissue culture, in the hamster model, or if delivered directly into the lungs. I can’t know for sure that it has lost this capacity, because I haven’t seen an experiment where the stabilized construct is compared with the natural S protein. I would like to see that experiment to know for sure, because I think it could have implications for the development of intranasal, inhaled COVID-19 vaccines. Still, and this is sort of obvious, I think I’m probably right that the perfusion stabilization breaks the S protein such that it can’t have the observed vascular damage effect.
Anyway, one thing I’m quite certain of is that none of the injected vaccines have this effect. No such effects were seen in clinical trials, and no such effect has been seen in the hundreds of millions of vaccine doses administered around the globe. So I feel pretty confident there. And, due credit to Dr. Novella, he also makes the same point that no such effect has been observed in clinical study or use of any COVID-19 vaccine.
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.
Join the conversation, and what you say will impact what I talk about in the next issue.
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See you all next time.
Always,
JS
A couple of exceptions apply here. AstraZeneca and J&J have committed to selling their vaccine at cost (meaning they won’t really be losing anything to generic competition), but have accepted large amounts of research support funds. Pfizer has not accepted any funding but has sold their vaccine at a rate that turns a profit. Moderna, the least established company, has both accepted public funds and charged a profitable rate for their vaccine.