On your “WHY”, you seem to be presenting reasons why other people not believing your model shouldn’t count as strong evidence against it. Which is all fair. But I’m still curious for positive evidence to believe your model in the first place. Maybe this would be obvious if I knew more biology, but as it is, I don’t know why I should place higher credence in your model than any other model (e.g. the one at the bottom of this comment, if that counts).
...Then that bimodal response could directly and cleanly justify claiming “antibody response was 3.5-fold higher” in some very fuzzy and general way (because 28% x 3.5 = 98%)
As far as I can tell, “antibody response was 3.5-fold higher” just means that, on average, people in the extended dosing schedule had 3.5x more antibodies. I can’t tell whether you interpret it in some other way, or if you think this is a misleading way to describe things, or if you’re making some other point...?
The graph you included as a supporting claim was, I think, just the B panel from the totality of Figure 2 which is nice in many ways.
Yup!
The data in Panel A therefore seems consistent to me that “eventually” there is some roughly normal and acceptable level of “vaccinated at all, in an essentially bimodal way” that two doses reaches faster than typical?
Ok now I’m confused.
Do you think that all people on these graphs have reached a “normal and acceptable level of ‘vaccinated at all, in an essentially bimodal way’ ”?
If so, do you not think that there’s any important immunity difference between a single-vaccinated person around 1-10 on the graph, or a doubly-vaccinated person around 1000-10000?
Or if you think that only some of the people on this graph are immune, where do you think the line between immune and not-immune should be drawn on these graphs? (The distribution seems to be fairly continuous everywhere, to me, so it seems arbitrary to draw the line anywhere.)
Or if you think the important immunity difference isn’t captured by antibody-levels, what is it about?
And re “that two doses reaches faster than typical”; are you implying that the single-dosed people’s antibody response would’ve kept increasing beyond the 5-6 week mark and eventually gotten as high as the doubly-vaccinated people? That seems unlikely to me. (Other than maybe the few people where their antibodies did increase, but I’m happy to ignore them until I understand the most normal response curve better.)
My hunch is that extended Bleed3 would show a decline from the extended Bleed2 measurement…
Agreed.
The thing I’m asking for is: what’s the best second epicycle to add? What is the mechanism? If someone is already seroconverted, what would you measure to detect “that their mechanistic biological state is not ALREADY in the configuration that you’d be hoping to cause to improve via the administration of a third dose”?
Here’s one suggestion:
1. The more antibodies you have, the less probability of getting sick, the less probability of getting severe disease, etc.
2. More vaccines increases the number of antibodies you have.
3. Therefore you want to have more vaccines.
I would’ve thought (1) to be fairly uncontroversial? And the linked study seems to provide good evidence for (2) when going from 1 to 2 doses, increasing antibodies by roughly a factor of 100. And of course adding more vaccines will eventually stop adding more antibodies. But right now I don’t have any reason to believe in a big difference between going from 1->2 vaccines vs going from 2->3 vaccines (other than 2 vaccines being the general standard). So I wouldn’t be surprised if taking a 3rd vaccine could increase your antibodies by another order of magnitude.
Maybe you think this doesn’t provide enough of a “mechanism”? Biology being complicated, I’m very happy to take empirical data for what it is, and make extrapolations even if I don’t know what the mechanism is. Personally, I also don’t feel like I have any more mechanism for “vaccine have a fixed probability of causing antibodies if you don’t already have them, otherwise they don’t do much” than “vaccine typically increases antibodies by a lot regardless of whether you have them or not”. So when the evidence clearly indicates the latter, I will definitely believe it.
And yeah, also, if someone has the option, I agree that it seems probably better to get a different vaccine than the same vaccine again!
I sort of tapped out because “very long posts with an explosion of quotes” is a smell for me, but I wanted to continue because other indicators suggest “teaching and/or learning in good faith” <3
Finally posting now because of a big update from elsewhere...
On your “WHY”, you seem to be presenting reasons why other people not believing your model shouldn’t count as strong evidence against it. Which is all fair. But I’m still curious for positive evidence to believe your model in the first place.
For me, evidence happens at the point of measurement. Then often measurements are summarized in language by people who don’t think clearly, or worry about standard misinterpretations of simple measurements… so careful reading is sometimes required just to acquire evidence able to distinguish between models.
So for me, the default is to need to think about mechanistic timecourse evidence through the screen of “how it was confusingly explained to me” by people who often aren’t worried about mechanistic timecourse dynamics.
I kinda don’t care if people don’t believe my model, I just want my models to get better over time… and I’m happy to explain them to people, and I like teaching… but if people don’t believe me, then it is their tragedy that they believe false things, not my tragedy. (Conversely, people teaching me things is awesome!)
But to make my models better I don’t just import other people’s posterior believes about how a mechanistic system works, but rather see if my own model can “round trip” through my best guess of the raw data that they observed in a specific situation. If people have bad reasoning, then their posteriors are even less safe to import than otherwise...
FWIW, just tonight I got around to reading this cousin comment by Connor and it swiftly tipped me over almost entirely. Three doses… might work? Sure.
I already thought there were empirical reasons to think it, so for me I think the key words in Connor’s post started somewhere around:
And not only does it increase count, secondary responses vastly increase antibody affinity and produce different antibody types, e.g. the primary response is more IgM whereas secondary response produces more IgG and IgA (the latter aiding especially in mucosal immunity). [Citations for this can be found on pgs 413-414 of the Janeway immunobiology book, and I can maybe link pictures.]
The filter I have I think, is that I want to hear about mechanisms when it comes to biological theories.
I’m not saying button mashing doesn’t work. That plus “copy the winner” is how most actual technical innovation occurs and scales in practice most of the time. Its fine <3
But… a HUGE filter that avoids adding broken bits to my general reasoning capacities is whether someone can offer keywords that connects their proposed mechanism to ALL THE OTHER MECHANISMS in physics and chemistry and evolution and all of it.
I have paragraphs and paragraphs of text from my first attempt at a response, trying to explain “I don’t know and neither do you (but politely and at length)”.
They are deleted from this response. Maybe “two people debugging epistemics in the face of ignorance” is useful somehow for something, but I’m not attached to it. I could PM it maybe if you care?
Practical upshot: empirically more doses has worked, and now I have heard some “new magic mechanism words” from Connor, who seems to me to clearly knows his shit backwards and forwards and also seems to be in tentative favor of a third dose :-)
Maybe interesting: my main argument AGAINST a third dose is part of why I thought it might be smart to give single doses as fast as possible several months ago. Now that like… “mechanisms are mechanically different (giving more than just lots of IgM)” I feel like I learned enough to even notice errors in past thinking?
But also… weirdly(?) this same body of empirical results says that the second reaction works BETTER after … <missing mechanism that somehow is time dependent> has had 12 weeks to <do something> instead of just 3 weeks?
On your “WHY”, you seem to be presenting reasons why other people not believing your model shouldn’t count as strong evidence against it. Which is all fair. But I’m still curious for positive evidence to believe your model in the first place. Maybe this would be obvious if I knew more biology, but as it is, I don’t know why I should place higher credence in your model than any other model (e.g. the one at the bottom of this comment, if that counts).
As far as I can tell, “antibody response was 3.5-fold higher” just means that, on average, people in the extended dosing schedule had 3.5x more antibodies. I can’t tell whether you interpret it in some other way, or if you think this is a misleading way to describe things, or if you’re making some other point...?
Yup!
Ok now I’m confused.
Do you think that all people on these graphs have reached a “normal and acceptable level of ‘vaccinated at all, in an essentially bimodal way’ ”?
If so, do you not think that there’s any important immunity difference between a single-vaccinated person around 1-10 on the graph, or a doubly-vaccinated person around 1000-10000?
Or if you think that only some of the people on this graph are immune, where do you think the line between immune and not-immune should be drawn on these graphs? (The distribution seems to be fairly continuous everywhere, to me, so it seems arbitrary to draw the line anywhere.)
Or if you think the important immunity difference isn’t captured by antibody-levels, what is it about?
And re “that two doses reaches faster than typical”; are you implying that the single-dosed people’s antibody response would’ve kept increasing beyond the 5-6 week mark and eventually gotten as high as the doubly-vaccinated people? That seems unlikely to me. (Other than maybe the few people where their antibodies did increase, but I’m happy to ignore them until I understand the most normal response curve better.)
Agreed.
Here’s one suggestion:
1. The more antibodies you have, the less probability of getting sick, the less probability of getting severe disease, etc.
2. More vaccines increases the number of antibodies you have.
3. Therefore you want to have more vaccines.
I would’ve thought (1) to be fairly uncontroversial? And the linked study seems to provide good evidence for (2) when going from 1 to 2 doses, increasing antibodies by roughly a factor of 100. And of course adding more vaccines will eventually stop adding more antibodies. But right now I don’t have any reason to believe in a big difference between going from 1->2 vaccines vs going from 2->3 vaccines (other than 2 vaccines being the general standard). So I wouldn’t be surprised if taking a 3rd vaccine could increase your antibodies by another order of magnitude.
Maybe you think this doesn’t provide enough of a “mechanism”? Biology being complicated, I’m very happy to take empirical data for what it is, and make extrapolations even if I don’t know what the mechanism is. Personally, I also don’t feel like I have any more mechanism for “vaccine have a fixed probability of causing antibodies if you don’t already have them, otherwise they don’t do much” than “vaccine typically increases antibodies by a lot regardless of whether you have them or not”. So when the evidence clearly indicates the latter, I will definitely believe it.
And yeah, also, if someone has the option, I agree that it seems probably better to get a different vaccine than the same vaccine again!
I sort of tapped out because “very long posts with an explosion of quotes” is a smell for me, but I wanted to continue because other indicators suggest “teaching and/or learning in good faith” <3
Finally posting now because of a big update from elsewhere...
For me, evidence happens at the point of measurement. Then often measurements are summarized in language by people who don’t think clearly, or worry about standard misinterpretations of simple measurements… so careful reading is sometimes required just to acquire evidence able to distinguish between models.
So for me, the default is to need to think about mechanistic timecourse evidence through the screen of “how it was confusingly explained to me” by people who often aren’t worried about mechanistic timecourse dynamics.
I kinda don’t care if people don’t believe my model, I just want my models to get better over time… and I’m happy to explain them to people, and I like teaching… but if people don’t believe me, then it is their tragedy that they believe false things, not my tragedy. (Conversely, people teaching me things is awesome!)
But to make my models better I don’t just import other people’s posterior believes about how a mechanistic system works, but rather see if my own model can “round trip” through my best guess of the raw data that they observed in a specific situation. If people have bad reasoning, then their posteriors are even less safe to import than otherwise...
FWIW, just tonight I got around to reading this cousin comment by Connor and it swiftly tipped me over almost entirely. Three doses… might work? Sure.
I already thought there were empirical reasons to think it, so for me I think the key words in Connor’s post started somewhere around:
The filter I have I think, is that I want to hear about mechanisms when it comes to biological theories.
I’m not saying button mashing doesn’t work. That plus “copy the winner” is how most actual technical innovation occurs and scales in practice most of the time. Its fine <3
But… a HUGE filter that avoids adding broken bits to my general reasoning capacities is whether someone can offer keywords that connects their proposed mechanism to ALL THE OTHER MECHANISMS in physics and chemistry and evolution and all of it.
Gimme a word like “IgA” and I can find my way to new and helpful parts of the truth mine! I can round trip it through general science, and so on.
I have paragraphs and paragraphs of text from my first attempt at a response, trying to explain “I don’t know and neither do you (but politely and at length)”.
They are deleted from this response. Maybe “two people debugging epistemics in the face of ignorance” is useful somehow for something, but I’m not attached to it. I could PM it maybe if you care?
Practical upshot: empirically more doses has worked, and now I have heard some “new magic mechanism words” from Connor, who seems to me to clearly knows his shit backwards and forwards and also seems to be in tentative favor of a third dose :-)
Maybe interesting: my main argument AGAINST a third dose is part of why I thought it might be smart to give single doses as fast as possible several months ago. Now that like… “mechanisms are mechanically different (giving more than just lots of IgM)” I feel like I learned enough to even notice errors in past thinking?
But also… weirdly(?) this same body of empirical results says that the second reaction works BETTER after … <missing mechanism that somehow is time dependent> has had 12 weeks to <do something> instead of just 3 weeks?
F-ing immunology, man. Its crazy.