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From the Nature article: "Peak antibody levels were 3.5 times higher in those who waited 12 weeks for their booster shot than were those in people who waited o

From the Nature article: "Peak antibody levels were 3.5 times higher in those who waited 12 weeks for their booster shot than were those in people who waited only 3 weeks. Peak T-cell response was lower in those with the extended interval. But this did not cause antibody levels to decline more quickly over the nine weeks after the booster shot." I care less about short-term peak antibody response than longer-term T-cell response or longest-term immunizing antibody response. On the latter two points, this study was not encouraging or outright silent. Nor was there any indication of how well these folks fared after they returned to the wild. This info doesn't seem sufficient to draw meaningful conclusions about longer term protection.

hprotagonist 5y ago
in particular, a linear change in antibody levels, which trigger an exponential response, doesn't really mean very much!
wutbrodo 5y ago
Some more info from the uni that performed the study[1]: > In relation to the cellular (or T cell) immune response, which plays an important role in supporting and maintaining antibody production, the team found that within the three-week interval group, 60% had a confirmed cellular response at two to three weeks following the second vaccine - although this fell to only 15% eight to nine weeks later. > The proportion of participants showing a cellular response in the 12-week-interval group was only eight per cent at five to six weeks after the first vaccine, but this rose to 31% two to three weeks after the second vaccine. Research is required to further explore these variations in responses. You're correct that the evidence isn't dispositive yet, but it's an encouraging signal. Antibody response in the short-term is positive and in the medium-term cellular response possibly converges. More importantly, the implications for the first doses first strategy are positive. Those who know how to reason under uncertainty saw the UK's strategy as a calculated gamble based on a model that extended the point information provided by the vaccine efficacy RCT; critics were generally incoherent but their claim was that it was likely to cause large _negative_ effects on efficacy, worth paying the cost of vaccinating far fewer people. On top of the priors that led to the decision, we now have signal from the way the winter surge played out in the UK, and the increased antibody response alone provides further weak signal that the delay was worth it - and conversely, that the US's approach cost lives). The evidence still isn't dispositive, but crucially, there's no such strong basis for believing the alternative either: that extending doses _reduces_ efficacy and that vaccine availability should be limited in the name of adhering rigidly to the RCT-studied timeline. The status quo bias of medical culture killed a lot of people during this pandemic by continuing their habit of pretending that certainty exists where none does and refusing to engage in critical thinking about uncertainty. Refusing to explicitly extrapolate a model from few high-quality samples really just means "implicitly extrapolating a crappy model through bias and guesswork". This may be adaptive in the normal medical context, where the status quo is generally fine, but is an incredibly poor fit for a fast-moving pandemic that was killing thousands a day in the US alone. [1] https://www.birmingham.ac.uk/news/latest/2021/05/covid-pfizer-vaccination-interval-antibody-response.aspx https://www.birmingham.ac.uk/news/latest/2021/05/covid-pfize...
- arcticfox 5y ago
  I completely agree with everything you said. That said, the most effective defense I've seen for the seemingly incoherently cautious status quo approach is that the medical community doesn't operate on the span of one pandemic, but is rather in a perpetual struggle. So even if the short-term expected value of an excessively cautious approach is negative, resulting in more deaths and a longer pandemic, it might be outweighed by reducing the chance of damaging public faith in medicine long-term by an erroneous more aggressive move. I still don't agree, but that very long-term view is the only defense I see for the approach given what we knew at the time.
  - wutbrodo 5y ago
    Thank you for bringing that up. That makes a lot of sense, and public health absolutely does need to consider mass psychology and their credibility. The theory that they're overindexing on protecting that credibility doesn't really comport with their behavior the rest of pandemic, however. Leaving aside all of the blood on the hands of mindless bureaucracy (like effectively banning testing for Covid in the early pandemic when it was most crucial), there has been decision after decision that prioritized status quo bias and RCT-worship even when the long game suggests it would damage their credibility (the fervent anti-mask recommendations in the early pandemic is a great example, as is the bizarre insistence on recommending precautions against fomites over aerosols until extremely late). More importantly, "public health is misleading you at the cost of your health/life because they're playing the long game" doesn't actually preserve much credibility. It certainly casts public health figures in a more positive light, but I'm not really thinking in terms of blaming individuals over institutions/cultures anyway. It doesn't really matter _why_ public health advice is wrong in obvious and significant ways. What matters is the ultimate conclusion: if you have basic scientific literacy and an IQ over 105, form your own broad understanding of the science. This isn't a call to jettison epistemic humility: you're not going to be able to understand things anywhere close to as well as an individual epidemiologist can. But the point is that listening to the science as filtered through public health advice _is even worse_, in the same way that getting nutrition advice from the USDA will.
    - 5y ago
throwawayboise 5y ago
And how much antibody response is enough? Is more always better? Or is it diminishing returns? IIRC one of the tricky things in the development of mRNA vaccines was being careful to not overstimulate the immune systems, triggering autoimmune types of reactions. It seems plausible to me that there is a "safe" level of immune response, and either too much or too little could be less desirable (maybe for different reasons).
- arcticfox 5y ago
  I'd also be curious to hear about an expert weigh in on "original antigenic sin" in this context. (My lay understanding: your immune system gets partially locked onto its first response to an antigen, and may fail to respond as well as it could to future variants). If you power up the response to massive levels, does it also augment the downsides of that "original antigenic sin"?
- elif 5y ago
  This is exactly what they are finding. https://www.medrxiv.org/content/10.1101/2021.05.03.21256520v1 https://www.medrxiv.org/content/10.1101/2021.05.03.21256520v... The Pfizer vaccine is shown here to elicit increased cytokine immune response to many types of non-covid agitants like mold and bacteria. The danger there would be cytokine storm in the extreme or cytokine-induced inflammation in mild cases.
  - muttled 5y ago
    Might be chance (it is spring) but my allergies were rocked after the shots. I wonder if revving up your immune system also revs up allergies since they're just an immune over-response?
    - QuercusMax 5y ago
      Fascinating - that was my experience as well. But I can't say whether it's just been an especially bad allergy season in general.
    - myself248 5y ago
joshgel 5y ago
Lots of people in the medical/scientific community expected this result. The best explanation I have heard is that the vaccine companies planned these sub-optimal trials with 2-3 weeks between shots, because it meant getting the vaccines to market much more quickly. Instead of having vaccines available in December, they might not have been available until February. So far, the evidence is pretty compelling that the vaccines have continued efficacy 6-7 months post-administration. It's obviously impossible to know much beyond a couple months however.
- esyir 5y ago
  Mind you, there's a delicate balancing game here though. Slower vaccines, even if more optimal, come with their own costs.
jfengel 5y ago
Does this suggest anything about side effects? Is it likely to make them better, worse, or none at all? I'm aware that there's not enough information to say yet, but it's something I'd like to see them look out for. The side effects are absolutely not a good enough reason to avoid getting vaccinated, both for your own sake and as a participant in herd immunity, but I've personally witnessed enough unpleasantness to know that there will be people who avoid it just to avoid the side effects. Being able to provide good advice to help the rational but fearful may help get us over the threshold, despite the large numbers of irrationally fearful. We'll need every single one to get there.
- brewdad 5y ago
  Anecdotally, in my home, my wife had chills and general ickyness from about 12-36 hours post 2nd dose. Myself and my teenager had no side effects at all. Even the soreness at the injection site was less after shot #2 than it was for the first. Don't let fear of side effects drive you away from getting the necessary booster. As of today, Fauci says I can ditch the mask. I'll still be keeping one in my pocket just in case though.
- kiawe_fire 5y ago
  I really wish more were being done to openly address the more extreme cases of side effects, so we could try to find other contributing factors and perhaps mitigation strategies. The number of poor reactions is very small, but pretending like they don’t exist or failing to address ways to overcome them only further fuels the fear in those hesitant to get vaccinated, and furthers the divisiveness in an issue we should all be working together on. Which makes sense if you’re a politician or Dr. Fauci, but doesn’t make sense if you just care about the health and safety of everyone and want to get this damn pandemic over with already. Forcing or shaming the hold outs to get vaccinated won’t do this, but giving honest confidence in the vaccine to people will.
Abishek_Muthian 5y ago
> This info doesn't seem sufficient to draw meaningful conclusions about longer term protection. Is it because the study period is just that i.e. 12 weeks? Even the studies on natural immunity from COVID suggests at least 6 - 8 months antibody persistence because the study period were just that[1][2]. Note that policies are being made now to defer the jab for those who got infected by COVID, based on these studies. We'll likely see studies confirming long term protection from vaccines & natural immunity after disease in coming months. Btw, How much is long term? [1]https://www.nih.gov/news-events/nih-research-matters/lasting-immunity-found-after-recovery-covid-19 https://www.nih.gov/news-events/nih-research-matters/lasting... [2]https://www.nejm.org/doi/full/10.1056/NEJMoa2034545?s=09 https://www.nejm.org/doi/full/10.1056/NEJMoa2034545?s=09 [3]https://twitter.com/PTI_News/status/1392715110821494789 https://twitter.com/PTI_News/status/1392715110821494789
northerdome 5y ago
And 12 weeks is a long time. I honestly would rather get an immunity boost after 3 weeks than wait the 12 for a second. A lot can happen in twelve weeks.

hprotagonist 5y ago

in particular, a linear change in antibody levels, which trigger an exponential response, doesn't really mean very much!

wutbrodo 5y ago

Some more info from the uni that performed the study[1]: > In relation to the cellular (or T cell) immune response, which plays an important role in supporting and maintaining antibody production, the team found that within the three-week interval group, 60% had a confirmed cellular response at two to three weeks following the second vaccine - although this fell to only 15% eight to nine weeks later. > The proportion of participants showing a cellular response in the 12-week-interval group was only eight per cent at five to six weeks after the first vaccine, but this rose to 31% two to three weeks after the second vaccine. Research is required to further explore these variations in responses. You're correct that the evidence isn't dispositive yet, but it's an encouraging signal. Antibody response in the short-term is positive and in the medium-term cellular response possibly converges. More importantly, the implications for the first doses first strategy are positive. Those who know how to reason under uncertainty saw the UK's strategy as a calculated gamble based on a model that extended the point information provided by the vaccine efficacy RCT; critics were generally incoherent but their claim was that it was likely to cause large _negative_ effects on efficacy, worth paying the cost of vaccinating far fewer people. On top of the priors that led to the decision, we now have signal from the way the winter surge played out in the UK, and the increased antibody response alone provides further weak signal that the delay was worth it - and conversely, that the US's approach cost lives). The evidence still isn't dispositive, but crucially, there's no such strong basis for believing the alternative either: that extending doses _reduces_ efficacy and that vaccine availability should be limited in the name of adhering rigidly to the RCT-studied timeline. The status quo bias of medical culture killed a lot of people during this pandemic by continuing their habit of pretending that certainty exists where none does and refusing to engage in critical thinking about uncertainty. Refusing to explicitly extrapolate a model from few high-quality samples really just means "implicitly extrapolating a crappy model through bias and guesswork". This may be adaptive in the normal medical context, where the status quo is generally fine, but is an incredibly poor fit for a fast-moving pandemic that was killing thousands a day in the US alone. [1] https://www.birmingham.ac.uk/news/latest/2021/05/covid-pfizer-vaccination-interval-antibody-response.aspx https://www.birmingham.ac.uk/news/latest/2021/05/covid-pfize...

arcticfox 5y ago
I completely agree with everything you said. That said, the most effective defense I've seen for the seemingly incoherently cautious status quo approach is that the medical community doesn't operate on the span of one pandemic, but is rather in a perpetual struggle. So even if the short-term expected value of an excessively cautious approach is negative, resulting in more deaths and a longer pandemic, it might be outweighed by reducing the chance of damaging public faith in medicine long-term by an erroneous more aggressive move. I still don't agree, but that very long-term view is the only defense I see for the approach given what we knew at the time.
- wutbrodo 5y ago
  Thank you for bringing that up. That makes a lot of sense, and public health absolutely does need to consider mass psychology and their credibility. The theory that they're overindexing on protecting that credibility doesn't really comport with their behavior the rest of pandemic, however. Leaving aside all of the blood on the hands of mindless bureaucracy (like effectively banning testing for Covid in the early pandemic when it was most crucial), there has been decision after decision that prioritized status quo bias and RCT-worship even when the long game suggests it would damage their credibility (the fervent anti-mask recommendations in the early pandemic is a great example, as is the bizarre insistence on recommending precautions against fomites over aerosols until extremely late). More importantly, "public health is misleading you at the cost of your health/life because they're playing the long game" doesn't actually preserve much credibility. It certainly casts public health figures in a more positive light, but I'm not really thinking in terms of blaming individuals over institutions/cultures anyway. It doesn't really matter _why_ public health advice is wrong in obvious and significant ways. What matters is the ultimate conclusion: if you have basic scientific literacy and an IQ over 105, form your own broad understanding of the science. This isn't a call to jettison epistemic humility: you're not going to be able to understand things anywhere close to as well as an individual epidemiologist can. But the point is that listening to the science as filtered through public health advice _is even worse_, in the same way that getting nutrition advice from the USDA will.
  - 5y ago

throwawayboise 5y ago

And how much antibody response is enough? Is more always better? Or is it diminishing returns? IIRC one of the tricky things in the development of mRNA vaccines was being careful to not overstimulate the immune systems, triggering autoimmune types of reactions. It seems plausible to me that there is a "safe" level of immune response, and either too much or too little could be less desirable (maybe for different reasons).

arcticfox 5y ago
I'd also be curious to hear about an expert weigh in on "original antigenic sin" in this context. (My lay understanding: your immune system gets partially locked onto its first response to an antigen, and may fail to respond as well as it could to future variants). If you power up the response to massive levels, does it also augment the downsides of that "original antigenic sin"?
elif 5y ago
This is exactly what they are finding. https://www.medrxiv.org/content/10.1101/2021.05.03.21256520v1 https://www.medrxiv.org/content/10.1101/2021.05.03.21256520v... The Pfizer vaccine is shown here to elicit increased cytokine immune response to many types of non-covid agitants like mold and bacteria. The danger there would be cytokine storm in the extreme or cytokine-induced inflammation in mild cases.
- muttled 5y ago
  Might be chance (it is spring) but my allergies were rocked after the shots. I wonder if revving up your immune system also revs up allergies since they're just an immune over-response?
  - QuercusMax 5y ago
    Fascinating - that was my experience as well. But I can't say whether it's just been an especially bad allergy season in general.
  - myself248 5y ago

joshgel 5y ago

Lots of people in the medical/scientific community expected this result. The best explanation I have heard is that the vaccine companies planned these sub-optimal trials with 2-3 weeks between shots, because it meant getting the vaccines to market much more quickly. Instead of having vaccines available in December, they might not have been available until February. So far, the evidence is pretty compelling that the vaccines have continued efficacy 6-7 months post-administration. It's obviously impossible to know much beyond a couple months however.

esyir 5y ago
Mind you, there's a delicate balancing game here though. Slower vaccines, even if more optimal, come with their own costs.

jfengel 5y ago

Does this suggest anything about side effects? Is it likely to make them better, worse, or none at all? I'm aware that there's not enough information to say yet, but it's something I'd like to see them look out for. The side effects are absolutely not a good enough reason to avoid getting vaccinated, both for your own sake and as a participant in herd immunity, but I've personally witnessed enough unpleasantness to know that there will be people who avoid it just to avoid the side effects. Being able to provide good advice to help the rational but fearful may help get us over the threshold, despite the large numbers of irrationally fearful. We'll need every single one to get there.

brewdad 5y ago
Anecdotally, in my home, my wife had chills and general ickyness from about 12-36 hours post 2nd dose. Myself and my teenager had no side effects at all. Even the soreness at the injection site was less after shot #2 than it was for the first. Don't let fear of side effects drive you away from getting the necessary booster. As of today, Fauci says I can ditch the mask. I'll still be keeping one in my pocket just in case though.
kiawe_fire 5y ago
I really wish more were being done to openly address the more extreme cases of side effects, so we could try to find other contributing factors and perhaps mitigation strategies. The number of poor reactions is very small, but pretending like they don’t exist or failing to address ways to overcome them only further fuels the fear in those hesitant to get vaccinated, and furthers the divisiveness in an issue we should all be working together on. Which makes sense if you’re a politician or Dr. Fauci, but doesn’t make sense if you just care about the health and safety of everyone and want to get this damn pandemic over with already. Forcing or shaming the hold outs to get vaccinated won’t do this, but giving honest confidence in the vaccine to people will.

Abishek_Muthian 5y ago

> This info doesn't seem sufficient to draw meaningful conclusions about longer term protection. Is it because the study period is just that i.e. 12 weeks? Even the studies on natural immunity from COVID suggests at least 6 - 8 months antibody persistence because the study period were just that[1][2]. Note that policies are being made now to defer the jab for those who got infected by COVID, based on these studies. We'll likely see studies confirming long term protection from vaccines & natural immunity after disease in coming months. Btw, How much is long term? [1]https://www.nih.gov/news-events/nih-research-matters/lasting-immunity-found-after-recovery-covid-19 https://www.nih.gov/news-events/nih-research-matters/lasting... [2]https://www.nejm.org/doi/full/10.1056/NEJMoa2034545?s=09 https://www.nejm.org/doi/full/10.1056/NEJMoa2034545?s=09 [3]https://twitter.com/PTI_News/status/1392715110821494789 https://twitter.com/PTI_News/status/1392715110821494789

northerdome 5y ago

And 12 weeks is a long time. I honestly would rather get an immunity boost after 3 weeks than wait the 12 for a second. A lot can happen in twelve weeks.