"without the virus to disrupt the immune response" - it's probably a stupid question, but what about people who got covid between the vaccine doses. Would the infection right after the first dose of the vaccine disrupt the immune response to the first vaccine dose?
This is a good question. I have no idea what the answer to this is!
I can speculate, though: it really would depend on when this SARS-CoV-2 infection takes place. If it happens a couple of weeks after the first dose, it might trigger a memory response, which might limit the infection very well. It’s hard to say, because the two-dose vaccines weren’t generally also studied in single-dose format.
If the SARS-CoV-2 infection happened earlier on, before the immune response to the first vaccine dose could have fully matured, I think it could well impact the quality of the immune response to that first dose.
This would be interesting to study somehow! In an animal model, or after the fact, in patient cases.
However, I do feel confident saying that this outcome would not be a big problem in the long run. There is at this point good evidence that getting past COVID-19 followed by even one vaccine dose produces meaningful protective immunity. So that having been said, in this hypothetical situation, the second vaccine dose would be able to strengthen the immune response if it is in any way disrupted. By the time the second dose has been completed and the two-week waiting period expires, such a patient might actually be quite well-protected, having received two doses of vaccine as well as having had experience with the actual virus.
Thanks for your thoughtful response to my inquiries. A couple follow-ups:
1. Is there a plausible mechanism by which COVID vaccines could cause an autoimmune response further down the road, rather than fairly soon after vaccination?
2. If your hypothesis is correct, and long COVID is caused at least in part by a less-than-ideal immune response, would we then expect breakthrough cases to be less likely to develop into long COVID? (I've seen very little on the topic of breakthroughs and long COVID, but here's what Akiko Iwasaki had to say on the topic: https://dearpandemic.org/will-vaccines-prevent-long-covid/).
1) No. The vaccines express S protein in the body transiently and then stop. Reactions to them will mostly start within 2 weeks of their administration, though I would believe it possible for reactions to emerge within 6 weeks. When regulators and experts reviewed these vaccines for approval, one item that was considered was whether it was possible for a delayed reaction to a vaccine to emerge. A comprehensive review of vaccine trials was performed to understand this. The finding, according to Dr. Paul Offit, noted vaccine expert, was that they were unable to find any instance in which a vaccine adverse reaction emerged more than 6 weeks after vaccination. That is not to say that all adverse reactions resolve within 6 weeks—some are longer term—but there was no reaction they could identify that emerged for the first time after 6 weeks had passed. This makes sense, because by about 6 weeks after administration, the complete immune response to the vaccine has probably run its course.
At this time we have plenty of people who have had 6 weeks and more of follow up after vaccination, and no such reactions have been detected, so if something like that were to happen, it would be an unprecedented historic first (and I would also struggle to explain how it could possibly happen).
2) I’m actually not sure what my hypothesis about long COVID is anymore. I’ve read the cited thread by Dr. Iwasaki and it made me even less certain of what I think. I try to speak of possible mechanisms for long COVID because it’s very possible that many different things are going on and combining to cause this syndrome.
That said, if long COVID is encouraged in part by virus-mediated disruption of the immune system, then I think that it could be possible for a vaccinated person to be more protected from long COVID *even if* they still get COVID-19, because the vaccination might have primed such people to have a more coherent memory response. We know already that these vaccines reduce the odds of severe disease more than they reduce the odds of disease at all, which is suggestive of a continuum of quality of immune responses to vaccination. It would not surprise me if there were a step along that continuum where cases of long COVID are prevented but acute disease is not.
I would not, however, *expect* this to be the case, because I don’t have a specific hypothesis about the causes of long COVID that would predict this to be the case. I have only a number of different competing, not even mutually exclusive possible contributing factors to the development of long COVID. I may not have made that clear enough in my last response to you, and thanks for the opportunity to clear that up.
Thank for clarifying. "Expect" was too strong, but I think you got what I meant to ask. Basically, I was wondering if it was scientifically plausible that vaccines could help prevent long COVID, independent of blocking infection and transmission. Obviously, there's no evidence way at this point (though I hope someone is looking into it).
So, your answer to Sam's question reminded me of one I had. If it's the adenovirus vector that turns out to cause the rare thrombocytopenic thromboses, would that not imply that wild-form adenoviruses might be responsible for normal incidence of that very rare syndrome? Would that perhaps lead to a vaccine search for adenoviral disease prevention?
Like everything Phase 1, I'll believe it's real when I see efficacy data. Super early days. We'll still need these antivirals, though, by the time this gets to Phase 3. So far we've had vaccines available for 6ish months and only about 500 million people worldwide are fully vaccinated. I hope we'll be speeding things up, but even if we double that rate, it'll be quite some time before the global need for COVID-19 antivirals has ended.
I think you're raising a question that is going to be a hot focus of virus engineering research for another decade, now. There's clearly something going on with these viral vector COVID-19 vaccines that leads to very rare clotting outcomes. But what? And is it the combination of the vector and spike, or just the vector alone? There's some evidence that preexists that shows a platelet-activating effect for certain adenoviruses; it's thought that the amount in the vaccine is too low for this to be impactful, but maybe there is a very small group of people in which that's not true. That's all speculative! I just don't know.
If we think about other applications of adenoviruses, I think for most gene therapies, the patient population is so small that I doubt this would ever have been detected as an issue without these vaccines coming onto the scene. There are a lot of unknowns here, and thankfully, these events are extremely rare.
But, given the unknowns, all I can say is that it seems to be an open question requiring attention from basic scientists to understand. It would be good if we could engineer applied adenovirus tools to prevent these reactions, rare though they are.
"without the virus to disrupt the immune response" - it's probably a stupid question, but what about people who got covid between the vaccine doses. Would the infection right after the first dose of the vaccine disrupt the immune response to the first vaccine dose?
This is a good question. I have no idea what the answer to this is!
I can speculate, though: it really would depend on when this SARS-CoV-2 infection takes place. If it happens a couple of weeks after the first dose, it might trigger a memory response, which might limit the infection very well. It’s hard to say, because the two-dose vaccines weren’t generally also studied in single-dose format.
If the SARS-CoV-2 infection happened earlier on, before the immune response to the first vaccine dose could have fully matured, I think it could well impact the quality of the immune response to that first dose.
This would be interesting to study somehow! In an animal model, or after the fact, in patient cases.
However, I do feel confident saying that this outcome would not be a big problem in the long run. There is at this point good evidence that getting past COVID-19 followed by even one vaccine dose produces meaningful protective immunity. So that having been said, in this hypothetical situation, the second vaccine dose would be able to strengthen the immune response if it is in any way disrupted. By the time the second dose has been completed and the two-week waiting period expires, such a patient might actually be quite well-protected, having received two doses of vaccine as well as having had experience with the actual virus.
Thank you for the explanation.
Thanks for your thoughtful response to my inquiries. A couple follow-ups:
1. Is there a plausible mechanism by which COVID vaccines could cause an autoimmune response further down the road, rather than fairly soon after vaccination?
2. If your hypothesis is correct, and long COVID is caused at least in part by a less-than-ideal immune response, would we then expect breakthrough cases to be less likely to develop into long COVID? (I've seen very little on the topic of breakthroughs and long COVID, but here's what Akiko Iwasaki had to say on the topic: https://dearpandemic.org/will-vaccines-prevent-long-covid/).
1) No. The vaccines express S protein in the body transiently and then stop. Reactions to them will mostly start within 2 weeks of their administration, though I would believe it possible for reactions to emerge within 6 weeks. When regulators and experts reviewed these vaccines for approval, one item that was considered was whether it was possible for a delayed reaction to a vaccine to emerge. A comprehensive review of vaccine trials was performed to understand this. The finding, according to Dr. Paul Offit, noted vaccine expert, was that they were unable to find any instance in which a vaccine adverse reaction emerged more than 6 weeks after vaccination. That is not to say that all adverse reactions resolve within 6 weeks—some are longer term—but there was no reaction they could identify that emerged for the first time after 6 weeks had passed. This makes sense, because by about 6 weeks after administration, the complete immune response to the vaccine has probably run its course.
At this time we have plenty of people who have had 6 weeks and more of follow up after vaccination, and no such reactions have been detected, so if something like that were to happen, it would be an unprecedented historic first (and I would also struggle to explain how it could possibly happen).
2) I’m actually not sure what my hypothesis about long COVID is anymore. I’ve read the cited thread by Dr. Iwasaki and it made me even less certain of what I think. I try to speak of possible mechanisms for long COVID because it’s very possible that many different things are going on and combining to cause this syndrome.
That said, if long COVID is encouraged in part by virus-mediated disruption of the immune system, then I think that it could be possible for a vaccinated person to be more protected from long COVID *even if* they still get COVID-19, because the vaccination might have primed such people to have a more coherent memory response. We know already that these vaccines reduce the odds of severe disease more than they reduce the odds of disease at all, which is suggestive of a continuum of quality of immune responses to vaccination. It would not surprise me if there were a step along that continuum where cases of long COVID are prevented but acute disease is not.
I would not, however, *expect* this to be the case, because I don’t have a specific hypothesis about the causes of long COVID that would predict this to be the case. I have only a number of different competing, not even mutually exclusive possible contributing factors to the development of long COVID. I may not have made that clear enough in my last response to you, and thanks for the opportunity to clear that up.
Thank for clarifying. "Expect" was too strong, but I think you got what I meant to ask. Basically, I was wondering if it was scientifically plausible that vaccines could help prevent long COVID, independent of blocking infection and transmission. Obviously, there's no evidence way at this point (though I hope someone is looking into it).
*either way
OK, this will get meta.
So, your answer to Sam's question reminded me of one I had. If it's the adenovirus vector that turns out to cause the rare thrombocytopenic thromboses, would that not imply that wild-form adenoviruses might be responsible for normal incidence of that very rare syndrome? Would that perhaps lead to a vaccine search for adenoviral disease prevention?
How about the use of adenovirus vectors for (actual) gene therapies, as Steve Novella wrote about here: https://sciencebasedmedicine.org/viral-vectors-for-gene-therapy/ ?
Hey! "Pfizer CEO Says Antiviral Pill To Treat Covid Could Be Ready By End Of The Year"
https://www.forbes.com/sites/tommybeer/2021/04/27/pfizer-ceo-says-antiviral-pill-to-treat-covid-could-be-ready-by-end-of-the-year/?sh=377670462a0d
Like everything Phase 1, I'll believe it's real when I see efficacy data. Super early days. We'll still need these antivirals, though, by the time this gets to Phase 3. So far we've had vaccines available for 6ish months and only about 500 million people worldwide are fully vaccinated. I hope we'll be speeding things up, but even if we double that rate, it'll be quite some time before the global need for COVID-19 antivirals has ended.
I think you're raising a question that is going to be a hot focus of virus engineering research for another decade, now. There's clearly something going on with these viral vector COVID-19 vaccines that leads to very rare clotting outcomes. But what? And is it the combination of the vector and spike, or just the vector alone? There's some evidence that preexists that shows a platelet-activating effect for certain adenoviruses; it's thought that the amount in the vaccine is too low for this to be impactful, but maybe there is a very small group of people in which that's not true. That's all speculative! I just don't know.
If we think about other applications of adenoviruses, I think for most gene therapies, the patient population is so small that I doubt this would ever have been detected as an issue without these vaccines coming onto the scene. There are a lot of unknowns here, and thankfully, these events are extremely rare.
But, given the unknowns, all I can say is that it seems to be an open question requiring attention from basic scientists to understand. It would be good if we could engineer applied adenovirus tools to prevent these reactions, rare though they are.