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.
Ignoring the condescension inherent in your criticism here--this is an explanatory newsletter for lay audiences, of course it's going to go into great detail on simple concepts--I have one question only:
You made claims of "countless clinical studies" pointing towards various medical effects of a specific drug. What clinical studies? Please provide citations that I can review. Thanks.
Some good, some not as good. But taken together, the evidence is very strong that ivermectin is effective.
The history of drug development has countless examples of drugs developed for one indication that turn out to be effective for other indications. This is not unusual. What is unusual with covid is how genuine attempts by doctors to treat their patients with reasonable therapeutics have been attacked, censored, sanctioned. I have no explanation for this but I will point out one thing. Emergency use authorization can only be used if there are no effective treatments. If it turns out that effective treatments were suppressed so that vaccines could be authorized under EUA, then yes that would be criminal.
I am going to attack the sources you have linked, and your (clearly false) claim of a conspiracy to suppress ivermectin, just fair warning. None of the sources are reliable or reasonable. The claims of suppression here are just a bad argument, based on false premises that make it appear that you doth protest too much about having ivermectin studies criticized. That said, please do stay with this comment because I think ivermectin deserves fair hearing as an investigational product for COVID-19. We'll get there. But we're not going to get there from these kinds of sources or wild accusations, and we'll begin with that.
The Association of American Physicians and Surgeons is a right-wing political organization that engages in disinformation, including but not limited to HIV/AIDS denialism. It is not a reputable source of medical guidance.
The "study" you link is not a study. It is a review paper. It cites several actual studies, most of which are not clinical trials but rather bias-rife observational studies. One of the only randomized controlled trials included is the now-discredited fraudulent Elgazzar study, a preprint which was withdrawn by a preprint server for its massive and obvious evidence of fraud, including but not limited to obvious copy-paste data duplication in underlying data, plagiarism of substantial amounts of the study content, and findings which actually contradict each other within the same study. The other clinical trials included are pitifully small or do not contain actual reliable control groups. This review paper is from a group that has explicitly said they are opposed to conducting trials of COVID-19 therapeutics. I don't know why they feel this way, but they seem to be against evidence-based medicine. I support evidence-based medicine, and there is good reason to do so. It has brought us unprecedentedly effective medical technologies. Alternatives to evidence-based medicine brought us nonsense like homeopathy. Here's more on their positioning: https://www.medpagetoday.com/infectiousdisease/covid19/90552
The final website that you cite does seem to make an effort to include anything and everything about ivermectin possible, but it has a clear editorial agenda and the meta-analysis that it conducts is fundamentally flawed as well. It is not assessing publication bias in any way, it mixes very different types of trials and does not properly have prespecified inclusion and exclusion criteria, and more. Something that the pharmaceutical industry is regularly dinged for is only publishing positive studies; this leaves out the negative studies, which can really undermine meta-analysis. You need both to have a full picture, and academics rarely publish negative results. That site lists 30 "randomized controlled trials" (not all are controlled; some have a "no treatment" control, which is not an appropriate control). These trials use wildly different dosing, and most use extremely small patient populations. Others simply use very small ones. The largest contained 500 patients. For reference, the study that established dexamethasone as a therapeutic for COVID-19 had over 6000 patients. 500 is not enough. However, in that 500-patient study, by far the largest of this set, ivermectin was seen to increase risk of death from COVID-19 by 33%. Also in this set, not all studies are blinded and not all use active or placebo controls. It is exceptionally poor research practice to compare trials with such different designs to each other using meta-analysis. The first rule of meta-analysis is "garbage in, garbage out." That rule has been fulfilled here. The studies that this person cites justify a Phase 3 trial of ivermectin for COVID-19. They don't justify its widespread use. As you'll see later, I want the trial, not the speculative use of an unproven product.
So, none of these sources satisfy the claim that ivermectin should be approved or even given an EUA.
Finally, the claims that you end your comment with are simply false. There are evidence-based drugs for COVID-19 that are in use. Emergency Use Authorizations are not limited to a circumstance where no drugs are available. They are limited to circumstances where the need for additional options is dire, such as a global pandemic, and the normal years-long bureaucratic process of FDA approval is not possible. For example, if Ivermectin were ever to show a genuine effect in a real Phase 3 RCT for use in COVID-19, it would almost certainly receive an EUA, not an approval. The premise here of some kind of conspiracy to keep ivermectin down is built on a misinterpretation of what allows an EUA to be applied.
The only thing that is needed for an EUA to be used is a letter authorizing the use of an EUA, from the Secretary of HHS. With the letter in place, EUAs are allowed. That's all. There is such a letter in place. Ivermectin is no threat to any vaccine EUA.
Anyway, let's put aside these inaccurate conspiratorial accusations, and just talk about ivermectin for a minute.
I will acknowledge that there are some small clinical trials showing some potential benefits for ivermectin. The attempt to use meta-analysis to pool these results into a larger body of evidence is probably not a bad idea, but it is no substitute for a real trial with thousands of patients. Instead, this meta-analysis is good justification for a larger, genuine trial to be run. I believe such a trial should be conducted, because I find the evidence compelling justification to do a study, even if I do not find it compelling evidence to give every person in the world ivermectin. Really, two trials should be run--not just for the therapeutic effect supposed here for ivermectin, but also for the potential prophylactic effect. For some reason, the people who most vociferously support ivermectin for COVID-19 have also been vociferously opposed to conducting such trials. If the drug works so well, why not do the trials and prove it? It's a win-win. You get to treat thousands of patients in a clinical trial, so if it works, it's a good thing for those patients. And you get evidence, which if it works, is a good thing for the agenda of promoting ivermectin.
Ivermectin has certain attractive advantages as a potential therapeutic product. For one, it's cheap, and we know the size of the safe dose in humans already. Incidentally, people have been taking doses far beyond that size, which is not wise. However, we do know how it can be administered safely and it is easy to manufacture as well as widely available. So, if it can be established that it works, great--but again, that needs to be established according to real and reliable standards of medical evidence.
As a prophylactic, ivermectin is fatally flawed, however. Any drug would be. Prophylactic drugs require daily or weekly dosing. Vaccines require, at most, one to two doses a year. Giving everyone on Earth a drug every day or every week is just not practical by comparison to giving them a vaccine every six months at most. Still, I actually do support a phase 3 trial to study ivermectin as a COVID-19 prophylactic.
It might seem strange that I'm OK with doing that trial even though I strongly support vaccines. Well, I am quite aware that there are people in whom vaccines aren't enough, such as those with compromised immune systems. I think it would be valuable to be able to offer these people additional options for prevention of COVID-19. In the context of this small population, a drug option would be valuable. Is that drug option ivermectin? Well, do the trial.
Right now, by the way, it is perfectly possible for a physician to prescribe ivermectin in the US for a patient with COVID-19. It is also possible for them to prescribe it for prevention of COVID-19. This is off-label prescribing, and it comes with certain risks--particularly if the drug causes harm to the patient. However, if a physician believes that this is the correct course of action, and their patient consents, there is nothing stopping them.
The better approach would be to make it available through a randomized controlled trial, and then test its effects. Again, I don't see why this isn't being supported by the people championing ivermectin. I won't speculate as to why, either, but it really is a shame.
Anyway, I'm going to be frank: I'm OK with investigating ivermectin in a real phase 3 trial, but I'm not OK with histrionics, propaganda, conspiracy accusations, scientific fraud, or bad research methods. You get one freebie posting that kind of thing here, and only one warning. This newsletter is my domain, and further content of this type will result in your being banned from posting here. Complaining about my setting this boundary will also result in a ban. A ban may also be issued for completely arbitrary reasons; this is my house and you are a guest here.
To return to a more positive tone, and summarize: When we started this, your claim was that there were "countless" clinical studies of ivermectin in COVID-19. According to your own source that counted them, there are 30. Of those 30, none are adequately sized or powered. The evidence they present is not meaningless; it justifies a phase 3 trial. Do that trial, then let's talk about it. Until the data from such a trial are available, I will consider this topic closed. I genuinely look forward to discussing it again when reliable double-blind, randomized, controlled, phase 3 trial data are available.
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?
I know you appreciate the details, so I'll note that IgA is the name of the mucosal antibody you're looking for.
We've talked about the nasal spray vaccines before, and I agree that the theory that they will induce better mucosal immunity is a good one. Had you asked me a year ago, I would have said "Well, this is a respiratory virus, and nucleic acid vaccines have been a joke for decades, so I think we're going to need a wide variety of technologies and I hope we get some intranasal vaccines soon."
Except the RNA vaccines have been so fantastically successful that I think all bets are off on what I thought. We don't fully understand yet how or why they work so well against this virus. We know they produce large amounts of IgG antibodies that are neutralizing, but why are blood antibodies so effective against a respiratory virus?? There is likely more to this story than antibodies. We also know that T-cell responses are induced with these mRNA viruses as well. What we don't know is the contribution of these various responses to the immunity that is induced, or how exactly the immune effect is brought about.
Similarly, we don't know why chimeric vaccine options, or even the subunit vaccine options, induce protective immunity. We're still relatively in the dark as to the overall mechanisms of immunity and correlates of protection.
So will an intranasal vaccine induce meaningful immunity against SARS-CoV-2? Your guess is as good as mine. But I'd like to find out through some kind of clinical studies.
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.
Ignoring the condescension inherent in your criticism here--this is an explanatory newsletter for lay audiences, of course it's going to go into great detail on simple concepts--I have one question only:
You made claims of "countless clinical studies" pointing towards various medical effects of a specific drug. What clinical studies? Please provide citations that I can review. Thanks.
No condescension intended. Sorry if it came off that way.
A good place to start re antiviral treatment would be the website of the American association of Physicians And Surgeons:
https://aapsonline.org/
You will find detailed protocols for treating Covid patients at all phases of the disease.
A recent peer reviewed study detailing clinical evidence in favour of ivermectin is here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088823/
You can also find a repository of studies here:
https://c19ivermectin.com/
Some good, some not as good. But taken together, the evidence is very strong that ivermectin is effective.
The history of drug development has countless examples of drugs developed for one indication that turn out to be effective for other indications. This is not unusual. What is unusual with covid is how genuine attempts by doctors to treat their patients with reasonable therapeutics have been attacked, censored, sanctioned. I have no explanation for this but I will point out one thing. Emergency use authorization can only be used if there are no effective treatments. If it turns out that effective treatments were suppressed so that vaccines could be authorized under EUA, then yes that would be criminal.
I am going to attack the sources you have linked, and your (clearly false) claim of a conspiracy to suppress ivermectin, just fair warning. None of the sources are reliable or reasonable. The claims of suppression here are just a bad argument, based on false premises that make it appear that you doth protest too much about having ivermectin studies criticized. That said, please do stay with this comment because I think ivermectin deserves fair hearing as an investigational product for COVID-19. We'll get there. But we're not going to get there from these kinds of sources or wild accusations, and we'll begin with that.
The Association of American Physicians and Surgeons is a right-wing political organization that engages in disinformation, including but not limited to HIV/AIDS denialism. It is not a reputable source of medical guidance.
The "study" you link is not a study. It is a review paper. It cites several actual studies, most of which are not clinical trials but rather bias-rife observational studies. One of the only randomized controlled trials included is the now-discredited fraudulent Elgazzar study, a preprint which was withdrawn by a preprint server for its massive and obvious evidence of fraud, including but not limited to obvious copy-paste data duplication in underlying data, plagiarism of substantial amounts of the study content, and findings which actually contradict each other within the same study. The other clinical trials included are pitifully small or do not contain actual reliable control groups. This review paper is from a group that has explicitly said they are opposed to conducting trials of COVID-19 therapeutics. I don't know why they feel this way, but they seem to be against evidence-based medicine. I support evidence-based medicine, and there is good reason to do so. It has brought us unprecedentedly effective medical technologies. Alternatives to evidence-based medicine brought us nonsense like homeopathy. Here's more on their positioning: https://www.medpagetoday.com/infectiousdisease/covid19/90552
The final website that you cite does seem to make an effort to include anything and everything about ivermectin possible, but it has a clear editorial agenda and the meta-analysis that it conducts is fundamentally flawed as well. It is not assessing publication bias in any way, it mixes very different types of trials and does not properly have prespecified inclusion and exclusion criteria, and more. Something that the pharmaceutical industry is regularly dinged for is only publishing positive studies; this leaves out the negative studies, which can really undermine meta-analysis. You need both to have a full picture, and academics rarely publish negative results. That site lists 30 "randomized controlled trials" (not all are controlled; some have a "no treatment" control, which is not an appropriate control). These trials use wildly different dosing, and most use extremely small patient populations. Others simply use very small ones. The largest contained 500 patients. For reference, the study that established dexamethasone as a therapeutic for COVID-19 had over 6000 patients. 500 is not enough. However, in that 500-patient study, by far the largest of this set, ivermectin was seen to increase risk of death from COVID-19 by 33%. Also in this set, not all studies are blinded and not all use active or placebo controls. It is exceptionally poor research practice to compare trials with such different designs to each other using meta-analysis. The first rule of meta-analysis is "garbage in, garbage out." That rule has been fulfilled here. The studies that this person cites justify a Phase 3 trial of ivermectin for COVID-19. They don't justify its widespread use. As you'll see later, I want the trial, not the speculative use of an unproven product.
So, none of these sources satisfy the claim that ivermectin should be approved or even given an EUA.
Finally, the claims that you end your comment with are simply false. There are evidence-based drugs for COVID-19 that are in use. Emergency Use Authorizations are not limited to a circumstance where no drugs are available. They are limited to circumstances where the need for additional options is dire, such as a global pandemic, and the normal years-long bureaucratic process of FDA approval is not possible. For example, if Ivermectin were ever to show a genuine effect in a real Phase 3 RCT for use in COVID-19, it would almost certainly receive an EUA, not an approval. The premise here of some kind of conspiracy to keep ivermectin down is built on a misinterpretation of what allows an EUA to be applied.
The only thing that is needed for an EUA to be used is a letter authorizing the use of an EUA, from the Secretary of HHS. With the letter in place, EUAs are allowed. That's all. There is such a letter in place. Ivermectin is no threat to any vaccine EUA.
Anyway, let's put aside these inaccurate conspiratorial accusations, and just talk about ivermectin for a minute.
I will acknowledge that there are some small clinical trials showing some potential benefits for ivermectin. The attempt to use meta-analysis to pool these results into a larger body of evidence is probably not a bad idea, but it is no substitute for a real trial with thousands of patients. Instead, this meta-analysis is good justification for a larger, genuine trial to be run. I believe such a trial should be conducted, because I find the evidence compelling justification to do a study, even if I do not find it compelling evidence to give every person in the world ivermectin. Really, two trials should be run--not just for the therapeutic effect supposed here for ivermectin, but also for the potential prophylactic effect. For some reason, the people who most vociferously support ivermectin for COVID-19 have also been vociferously opposed to conducting such trials. If the drug works so well, why not do the trials and prove it? It's a win-win. You get to treat thousands of patients in a clinical trial, so if it works, it's a good thing for those patients. And you get evidence, which if it works, is a good thing for the agenda of promoting ivermectin.
Ivermectin has certain attractive advantages as a potential therapeutic product. For one, it's cheap, and we know the size of the safe dose in humans already. Incidentally, people have been taking doses far beyond that size, which is not wise. However, we do know how it can be administered safely and it is easy to manufacture as well as widely available. So, if it can be established that it works, great--but again, that needs to be established according to real and reliable standards of medical evidence.
As a prophylactic, ivermectin is fatally flawed, however. Any drug would be. Prophylactic drugs require daily or weekly dosing. Vaccines require, at most, one to two doses a year. Giving everyone on Earth a drug every day or every week is just not practical by comparison to giving them a vaccine every six months at most. Still, I actually do support a phase 3 trial to study ivermectin as a COVID-19 prophylactic.
It might seem strange that I'm OK with doing that trial even though I strongly support vaccines. Well, I am quite aware that there are people in whom vaccines aren't enough, such as those with compromised immune systems. I think it would be valuable to be able to offer these people additional options for prevention of COVID-19. In the context of this small population, a drug option would be valuable. Is that drug option ivermectin? Well, do the trial.
Right now, by the way, it is perfectly possible for a physician to prescribe ivermectin in the US for a patient with COVID-19. It is also possible for them to prescribe it for prevention of COVID-19. This is off-label prescribing, and it comes with certain risks--particularly if the drug causes harm to the patient. However, if a physician believes that this is the correct course of action, and their patient consents, there is nothing stopping them.
The better approach would be to make it available through a randomized controlled trial, and then test its effects. Again, I don't see why this isn't being supported by the people championing ivermectin. I won't speculate as to why, either, but it really is a shame.
Anyway, I'm going to be frank: I'm OK with investigating ivermectin in a real phase 3 trial, but I'm not OK with histrionics, propaganda, conspiracy accusations, scientific fraud, or bad research methods. You get one freebie posting that kind of thing here, and only one warning. This newsletter is my domain, and further content of this type will result in your being banned from posting here. Complaining about my setting this boundary will also result in a ban. A ban may also be issued for completely arbitrary reasons; this is my house and you are a guest here.
To return to a more positive tone, and summarize: When we started this, your claim was that there were "countless" clinical studies of ivermectin in COVID-19. According to your own source that counted them, there are 30. Of those 30, none are adequately sized or powered. The evidence they present is not meaningless; it justifies a phase 3 trial. Do that trial, then let's talk about it. Until the data from such a trial are available, I will consider this topic closed. I genuinely look forward to discussing it again when reliable double-blind, randomized, controlled, phase 3 trial data are available.
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?
I know you appreciate the details, so I'll note that IgA is the name of the mucosal antibody you're looking for.
We've talked about the nasal spray vaccines before, and I agree that the theory that they will induce better mucosal immunity is a good one. Had you asked me a year ago, I would have said "Well, this is a respiratory virus, and nucleic acid vaccines have been a joke for decades, so I think we're going to need a wide variety of technologies and I hope we get some intranasal vaccines soon."
Except the RNA vaccines have been so fantastically successful that I think all bets are off on what I thought. We don't fully understand yet how or why they work so well against this virus. We know they produce large amounts of IgG antibodies that are neutralizing, but why are blood antibodies so effective against a respiratory virus?? There is likely more to this story than antibodies. We also know that T-cell responses are induced with these mRNA viruses as well. What we don't know is the contribution of these various responses to the immunity that is induced, or how exactly the immune effect is brought about.
Similarly, we don't know why chimeric vaccine options, or even the subunit vaccine options, induce protective immunity. We're still relatively in the dark as to the overall mechanisms of immunity and correlates of protection.
So will an intranasal vaccine induce meaningful immunity against SARS-CoV-2? Your guess is as good as mine. But I'd like to find out through some kind of clinical studies.
Like the U. of Iowa experiments I had mailed you a couple of hours ago, for example? :-)
Yeah, I was guessing about the type of antibody involved.
Yes, something like those :) I hope we'll get some nice data out of those human trials they've begun.
Cuba is now claiming their homegrown vaccine is 100% effective against severe disease: https://www.pri.org/stories/2021-07-19/cuba-s-promise-homegrown-covid-19-vaccine