Thanks for your continuous work on this news letter! It is very informative.
I am European, more specifically Dane located in London. The big story over the last two weeks on mainland Europe has been AZ and the risk for blood clots. Here is a small article from BBC about it: https://www.bbc.co.uk/news/world-europe-56440139 It has not been covered much in the UK news compared to the Danish news. I am wondering if these press stories might have influenced AZ release of preliminary data?
There is still no more blood clots in the people that got AZ compared to the once that did not. The main concern is that the blood clots in question have an unusual combination of symptoms (blood clots, haemorrhages and low platelet counts). If this is related to the AZ vaccine it is very rare and I would still take the AZ jab if I was offered. For me the benefit outweighs the possible risk.
Thank you for your comment, Sara! And for your kind words :)
I like the way you have looked at this issue and think it is worth holding up as an example--it is likely meaningful that the risk of blood clot in the general population is similar to the risk in those who received the AZ vaccine, but you have not simply accepted that at face value. You also consider that the etiology of blood clots observed in patients who also received the AZ vaccine is unusual, which is a matter requiring further investigation but not necessarily a vaccine-related safety signal. This is the kind of medical safety analysis that regulatory agencies do all the time.
I am reassured that, if I were to receive the AZ vaccine, my risk of blood clot appears to be same as if I had not gotten the vaccine. Perhaps the blood clot that I could get would be a little different were I to get that particular vaccine, but it seems to me the actual risk of such a medical event for the average patient remains the same.
I am certain we will learn more in the days to come, but essentially, I agree with your take on this.
"AstraZeneca is an extremely well-established pharmaceutical company that really ought to know better." Not to mention, you know, their partners at the University of Oxford. I'm not in your field, but I hear their rep is pretty impressive.
I actually get my own first dose on Friday. (I've been fanatically isolating for the past week, because the last thing I want to do is the ending of a war movie, where someone gets killed two days before peace is declared.) I also delayed a while despite a comorbidity because I'm lucky enough to be able to work from home.
Something I read last week, I believe in Nature, that surprised me: the AZ half-dosing mess was also a timing mess. The people who initially got a half-dose of the vaccine also had a longer wait between doses than was specified by the protocol, and at least some researchers think that this longer wait was responsible for the improved effectiveness. Yet another protocol breach, but an interesting effect if it's real--there have also been reports that other vaccines continue to have strengthening effects for several weeks after the arbitrary cutoff point set by study protocols.
You're the expert, but to me that implies that booster shots, should they be required, will be quite effective.
Yes, I've seen some reports indicating that the viral vector-based vaccines seem to get more effective over time (to a point). It also seems that waiting to boost these vaccines for a little longer may be helpful. I wonder if, perhaps, this is an effect of letting the immune response to the vector attenuate somewhat. I'm not really sure and am actively looking for more research to be done on this topic.
I think you're kind of missing the point on RaDVaC.
RaDVaC was put together by people with the appropriate expertise applying reasonable design criteria, and it uses a delivery mechanism that is (as far as I know) incredibly difficult to render unsafe. So I'd ballpark a 10% chance that it does work, and a 1% or less chance that using it could hurt you.
A 10%-chance effective (but almost certainly safe) vaccine is pretty crummy, but you can't evaluate that in a vacuum - you have to compare it to what the regulated pharma pipeline has produced, which is, for me, a 34-year-old healthy male in the United States, no vaccine whatsoever so far. And there's not a lot of reason to believe that the existing system would move any faster for a variant that evaded existing vaccines. Given that situation, I think "take your chances with RaDVaC (assuming they updated it to address emerging strains)" is far from a stupid move.
You correctly point out that RaDVaC isn't produced according to modern pharmaceutical standards, but I think this is not an especially compelling objection. The impossible-to-homebrew part (peptide synthesis) is handled by firms with the specialized equipment to do it, and there's no strong reason to think that they'd fail to do their job. And I think you overstate the extent to which careful production controls are strictly necessary, even for products that are complex mixes of large organic molecules: as far as I know, smallpox vaccination ~100 years ago involved individual pharmacists just kinda getting vaccinia preparations from a catalog and mixing them up in the kitchen, so to speak. I doubt that this would pass modern regulatory scrutiny, and yet it worked well enough.
At a high level, I think the level of care our civilization has taken around COVID-19 vaccines is striking the wrong cost-benefit tradeoff in the face of a disease that's killing thousands of people every day.
To be clear: here's the decision I think is appropriate for me: if RaDVaC cost <$20, I would take it and then continue to take lots of precautions. I'm not very confident in RaDVaC's effectiveness, but it's better than nothing.
I haven't taken RaDVaC because I think it would take at least $1,000 of time and money.
I've chosen to reply here because I believe this is the completed version of your thought. I think you're wrong, to be very clear. I think you are missing quite a few key points of understanding on the difference between products created for human use versus products created for research use, which is really vitally important to understand the issues with RaDVaC and other DIY operations compared with regulated manufacturers with real oversight. I'll discuss that in detail, but I want to begin with this:
"I am not very confident in RaDVaC's effectiveness, but it's better than nothing."
Prove it. What makes it better than nothing? What is the safety profile of RaDVaC that supports this claim? How many people will have fatal allergic reactions if this preparation is administered to them? How many people will have debilitating neurological reactions? What is the dollar value of the healthcare resources that will be diverted, per dose administered, to dealing with less severe adverse reactions to this product?
Answering these questions is why we do clinical trials. We do not have the answers to these questions for these DIY vaccines, and untested medications create unreasonable systemic burdens, so you cannot explain this away by saying it is a "personal choice." It is not a personal choice if you end up filling a hospital bed.
Physicians and other healthcare professionals have a crystal-clear perspective on the need to maintain standards, because every intervention that is not safe has the potential to turn them from a healer into an assassin. There is a reason that an evidence-based approach to medicine has evolved over the years, and it is because we wish to be certain beyond reasonable doubt that the risk-benefit profile of a given medication is favorable in the prevention or treatment of the indicated condition.
When "citizen-scientists" circumvent the scientific process through projects like this, they not only harm the cause of evidence based medicine, though. They also harm the cause of science. We've developed science in order to answer questions in a way that gives us reliable answers. We have left in the past the days of trying to do things off a guess and hoping for the best. RaDVac represents a return to the latter out of desperation, and it is a definitive step backwards.
You bring up a claim that vaccinia preparations were made generally by individual pharmacists 100 years ago--though I'm aware the article you shared indicates that this isn't actually true. Even so, let's travel back to an even more recent world where smallpox vaccination was routine. Vaccinia causes serious adverse reactions. It can spread from the site of vaccination throughout the body, and to other people, potentially causing fatal infections. See here for a summary: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1069029
However, we are aware that it works and that the risk of death from smallpox is substantially higher than the risk of death from the vaccine. This is, again, something that we learned through careful study, development, and improvement of the vaccine and the vaccination process. By the 1960s, there were still fatal events involving the smallpox vaccine, although they had become exceedingly rare. Before the 20th century, however, we did not have the medical surveillance quality to really monitor these events. The standardization of manufacturing has also coincided with improvements in our ability to detect safety events in the field use of medical products--a field known as pharmacovigilance.
I'm saying this to point out that we don't really know how many people bad smallpox vaccines killed before there were standards in place for their manufacture. It's not an example we can actually have a fully informed conversation about. We can't support the claim that it "worked well enough." It took almost 200 years to eradicate smallpox, and for most of that time, we don't have any information on whether or not common vaccine preparations did more harm than good, because we didn't have robust clinical trials or the technology to run them. In the end we beat smallpox, but I don't feel confident saying we beat it with an optimal strategy and no unnecessary deaths.
However, there are some things I do feel confident making statements about. We do know that vaccine manufacture can go quite wrong. The Cutter Incident, a famous disaster involving polio vaccine manufacturing, resulted in 5 fatalities and even more cases of disease. That was an error made by improper inactivation of polio virus at Cutter Labs, and was a key moment in the history of GxP development. A lot of the standards that are observed today originated with things like the Cutter Incident, because the fact is, when mistakes are made, people can die. Another more recent example has to do with the contamination of the rotavirus vaccine Rotarix with porcine circoviruses. Sure, these are ultimately considered harmless, but there are many non-harmless pathogens that can find their way into bioreactors. If a massive pharmaceutical company with legions of quality control specialists missed virus contamination, do you think a rogue operator with no process control would somehow do better? If you wish to make a bet on this, remember what you're gambling with--it's not just the lives of the people receiving the vaccine, it's also the reputation of vaccination as a concept.
When people die or have other adverse outcomes, there are serious and impactful harms on the overall cause of vaccination. Antivaccination campaigners are, I assure you, delighted to see people play fast and loose with safety in the medical community. It provides them with ammunition to claim that the industry cares only about profits and that "natural" treatments are safer.
Public confidence in vaccines matters a lot. For vaccines to be really effective, they need to be adopted at a scale where they have population-level impacts. We're seeing this now in Israel with COVID-19 vaccines, as the overall rates of disease and even test positivity are plummeting as more and more of the country is vaccinated. This is made possible by a public that trusts the science behind vaccination--because that science is available. I can't condone any kind of maverick project that could potentially put an unsafe treatment into a human being, kill them, and thus undermine another 100 or 1,000 people's confidence in vaccination. The only thing that I can condone is evidence-based approaches that show us that a product works.
Now, you can object that COVID-19 is killing thousands of people every day, and we have to do something. And you're right, but the thing you're suggestion isn't it. What we had to do was isolate, wear masks, and develop national test-and-trace strategies. Most countries did this, and the ones that did not have suffered worse for their recklessness. Trying to solve that recklessness with more reckless and risky approaches doesn't make sense to me.
I'm glad we didn't trade the problem of COVID-19 for the problem of open-air medical experimentation on desperate people with interventions that were about as likely to do harm than good. Yes, it meant we had to wait longer for a safe and effective vaccine, but the fact that some countries let the pandemic run amok during that waiting time is not the fault of the vaccination development program. That part was run responsibly and was a huge success. In the US at least, it's everything else that failed.
Thanks for your continuous work on this news letter! It is very informative.
I am European, more specifically Dane located in London. The big story over the last two weeks on mainland Europe has been AZ and the risk for blood clots. Here is a small article from BBC about it: https://www.bbc.co.uk/news/world-europe-56440139 It has not been covered much in the UK news compared to the Danish news. I am wondering if these press stories might have influenced AZ release of preliminary data?
There is still no more blood clots in the people that got AZ compared to the once that did not. The main concern is that the blood clots in question have an unusual combination of symptoms (blood clots, haemorrhages and low platelet counts). If this is related to the AZ vaccine it is very rare and I would still take the AZ jab if I was offered. For me the benefit outweighs the possible risk.
Keep up the good work :D
Thank you for your comment, Sara! And for your kind words :)
I like the way you have looked at this issue and think it is worth holding up as an example--it is likely meaningful that the risk of blood clot in the general population is similar to the risk in those who received the AZ vaccine, but you have not simply accepted that at face value. You also consider that the etiology of blood clots observed in patients who also received the AZ vaccine is unusual, which is a matter requiring further investigation but not necessarily a vaccine-related safety signal. This is the kind of medical safety analysis that regulatory agencies do all the time.
I am reassured that, if I were to receive the AZ vaccine, my risk of blood clot appears to be same as if I had not gotten the vaccine. Perhaps the blood clot that I could get would be a little different were I to get that particular vaccine, but it seems to me the actual risk of such a medical event for the average patient remains the same.
I am certain we will learn more in the days to come, but essentially, I agree with your take on this.
"AstraZeneca is an extremely well-established pharmaceutical company that really ought to know better." Not to mention, you know, their partners at the University of Oxford. I'm not in your field, but I hear their rep is pretty impressive.
I actually get my own first dose on Friday. (I've been fanatically isolating for the past week, because the last thing I want to do is the ending of a war movie, where someone gets killed two days before peace is declared.) I also delayed a while despite a comorbidity because I'm lucky enough to be able to work from home.
Something I read last week, I believe in Nature, that surprised me: the AZ half-dosing mess was also a timing mess. The people who initially got a half-dose of the vaccine also had a longer wait between doses than was specified by the protocol, and at least some researchers think that this longer wait was responsible for the improved effectiveness. Yet another protocol breach, but an interesting effect if it's real--there have also been reports that other vaccines continue to have strengthening effects for several weeks after the arbitrary cutoff point set by study protocols.
You're the expert, but to me that implies that booster shots, should they be required, will be quite effective.
Yes, I've seen some reports indicating that the viral vector-based vaccines seem to get more effective over time (to a point). It also seems that waiting to boost these vaccines for a little longer may be helpful. I wonder if, perhaps, this is an effect of letting the immune response to the vector attenuate somewhat. I'm not really sure and am actively looking for more research to be done on this topic.
I think you're kind of missing the point on RaDVaC.
RaDVaC was put together by people with the appropriate expertise applying reasonable design criteria, and it uses a delivery mechanism that is (as far as I know) incredibly difficult to render unsafe. So I'd ballpark a 10% chance that it does work, and a 1% or less chance that using it could hurt you.
A 10%-chance effective (but almost certainly safe) vaccine is pretty crummy, but you can't evaluate that in a vacuum - you have to compare it to what the regulated pharma pipeline has produced, which is, for me, a 34-year-old healthy male in the United States, no vaccine whatsoever so far. And there's not a lot of reason to believe that the existing system would move any faster for a variant that evaded existing vaccines. Given that situation, I think "take your chances with RaDVaC (assuming they updated it to address emerging strains)" is far from a stupid move.
You correctly point out that RaDVaC isn't produced according to modern pharmaceutical standards, but I think this is not an especially compelling objection. The impossible-to-homebrew part (peptide synthesis) is handled by firms with the specialized equipment to do it, and there's no strong reason to think that they'd fail to do their job. And I think you overstate the extent to which careful production controls are strictly necessary, even for products that are complex mixes of large organic molecules: as far as I know, smallpox vaccination ~100 years ago involved individual pharmacists just kinda getting vaccinia preparations from a catalog and mixing them up in the kitchen, so to speak. I doubt that this would pass modern regulatory scrutiny, and yet it worked well enough.
At a high level, I think the level of care our civilization has taken around COVID-19 vaccines is striking the wrong cost-benefit tradeoff in the face of a disease that's killing thousands of people every day.
I realized that I didn't have as clear a picture of early smallpox vaccine production as I thought. I found this pretty informative: https://www.sciencedirect.com/science/article/pii/S0264410X2030668X
This is a great article. I'm about to post another reply starkly disagreeing with you, but I am grateful that you shared this, thank you.
To be clear: here's the decision I think is appropriate for me: if RaDVaC cost <$20, I would take it and then continue to take lots of precautions. I'm not very confident in RaDVaC's effectiveness, but it's better than nothing.
I haven't taken RaDVaC because I think it would take at least $1,000 of time and money.
I've chosen to reply here because I believe this is the completed version of your thought. I think you're wrong, to be very clear. I think you are missing quite a few key points of understanding on the difference between products created for human use versus products created for research use, which is really vitally important to understand the issues with RaDVaC and other DIY operations compared with regulated manufacturers with real oversight. I'll discuss that in detail, but I want to begin with this:
"I am not very confident in RaDVaC's effectiveness, but it's better than nothing."
Prove it. What makes it better than nothing? What is the safety profile of RaDVaC that supports this claim? How many people will have fatal allergic reactions if this preparation is administered to them? How many people will have debilitating neurological reactions? What is the dollar value of the healthcare resources that will be diverted, per dose administered, to dealing with less severe adverse reactions to this product?
Answering these questions is why we do clinical trials. We do not have the answers to these questions for these DIY vaccines, and untested medications create unreasonable systemic burdens, so you cannot explain this away by saying it is a "personal choice." It is not a personal choice if you end up filling a hospital bed.
Physicians and other healthcare professionals have a crystal-clear perspective on the need to maintain standards, because every intervention that is not safe has the potential to turn them from a healer into an assassin. There is a reason that an evidence-based approach to medicine has evolved over the years, and it is because we wish to be certain beyond reasonable doubt that the risk-benefit profile of a given medication is favorable in the prevention or treatment of the indicated condition.
When "citizen-scientists" circumvent the scientific process through projects like this, they not only harm the cause of evidence based medicine, though. They also harm the cause of science. We've developed science in order to answer questions in a way that gives us reliable answers. We have left in the past the days of trying to do things off a guess and hoping for the best. RaDVac represents a return to the latter out of desperation, and it is a definitive step backwards.
You bring up a claim that vaccinia preparations were made generally by individual pharmacists 100 years ago--though I'm aware the article you shared indicates that this isn't actually true. Even so, let's travel back to an even more recent world where smallpox vaccination was routine. Vaccinia causes serious adverse reactions. It can spread from the site of vaccination throughout the body, and to other people, potentially causing fatal infections. See here for a summary: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1069029
However, we are aware that it works and that the risk of death from smallpox is substantially higher than the risk of death from the vaccine. This is, again, something that we learned through careful study, development, and improvement of the vaccine and the vaccination process. By the 1960s, there were still fatal events involving the smallpox vaccine, although they had become exceedingly rare. Before the 20th century, however, we did not have the medical surveillance quality to really monitor these events. The standardization of manufacturing has also coincided with improvements in our ability to detect safety events in the field use of medical products--a field known as pharmacovigilance.
I'm saying this to point out that we don't really know how many people bad smallpox vaccines killed before there were standards in place for their manufacture. It's not an example we can actually have a fully informed conversation about. We can't support the claim that it "worked well enough." It took almost 200 years to eradicate smallpox, and for most of that time, we don't have any information on whether or not common vaccine preparations did more harm than good, because we didn't have robust clinical trials or the technology to run them. In the end we beat smallpox, but I don't feel confident saying we beat it with an optimal strategy and no unnecessary deaths.
However, there are some things I do feel confident making statements about. We do know that vaccine manufacture can go quite wrong. The Cutter Incident, a famous disaster involving polio vaccine manufacturing, resulted in 5 fatalities and even more cases of disease. That was an error made by improper inactivation of polio virus at Cutter Labs, and was a key moment in the history of GxP development. A lot of the standards that are observed today originated with things like the Cutter Incident, because the fact is, when mistakes are made, people can die. Another more recent example has to do with the contamination of the rotavirus vaccine Rotarix with porcine circoviruses. Sure, these are ultimately considered harmless, but there are many non-harmless pathogens that can find their way into bioreactors. If a massive pharmaceutical company with legions of quality control specialists missed virus contamination, do you think a rogue operator with no process control would somehow do better? If you wish to make a bet on this, remember what you're gambling with--it's not just the lives of the people receiving the vaccine, it's also the reputation of vaccination as a concept.
When people die or have other adverse outcomes, there are serious and impactful harms on the overall cause of vaccination. Antivaccination campaigners are, I assure you, delighted to see people play fast and loose with safety in the medical community. It provides them with ammunition to claim that the industry cares only about profits and that "natural" treatments are safer.
Public confidence in vaccines matters a lot. For vaccines to be really effective, they need to be adopted at a scale where they have population-level impacts. We're seeing this now in Israel with COVID-19 vaccines, as the overall rates of disease and even test positivity are plummeting as more and more of the country is vaccinated. This is made possible by a public that trusts the science behind vaccination--because that science is available. I can't condone any kind of maverick project that could potentially put an unsafe treatment into a human being, kill them, and thus undermine another 100 or 1,000 people's confidence in vaccination. The only thing that I can condone is evidence-based approaches that show us that a product works.
Now, you can object that COVID-19 is killing thousands of people every day, and we have to do something. And you're right, but the thing you're suggestion isn't it. What we had to do was isolate, wear masks, and develop national test-and-trace strategies. Most countries did this, and the ones that did not have suffered worse for their recklessness. Trying to solve that recklessness with more reckless and risky approaches doesn't make sense to me.
I'm glad we didn't trade the problem of COVID-19 for the problem of open-air medical experimentation on desperate people with interventions that were about as likely to do harm than good. Yes, it meant we had to wait longer for a safe and effective vaccine, but the fact that some countries let the pandemic run amok during that waiting time is not the fault of the vaccination development program. That part was run responsibly and was a huge success. In the US at least, it's everything else that failed.