One more piece I was a little surprised you didn't mention, but which makes a lot of sense to me about variants and dosage: both Pfizer and Moderna are only barely less effective at full immunization* but both have been mentioned to have a much smaller (1/4?) neutralizing antibody response to certain VOC then they do to Covid Classic. Just they already had such a huge immune response that it was still enough. So if Curevac wasn't starting with anywhere near as huge and immune response then I could see it mattering a lot more that the VOCs were pretty much everything it was dealing with.
(Another bit that informs my query here is that some of the initial data from Hopkins' research with transplant patients seem to be that Moderna, with three times the genetic material, was somewhat more likely to produce spike antibodies than Pfizer. (They've just published something about a third dose, mix and match, seeming helpful for these immune compromised patients but I have not looked at it and that's attention anyway))
Am I off base on this, or would embracing the power of And (less mRNA -> less good at variants b/c less NA) be the rest of the story?
* Or after one dose for everybody but Delta so far, but Delta was at around 30ish percent for one dose of Pfizer or AZ; haven't seen the data for Moderna
The reason I didn't mention this is that CureVac had good neutralization titers, as I recall similar to those of the other mRNA vaccines, in its Phase 2 results and earlier. so it seemed like it was on par with these other vaccines. I would like to see CureVac's full Phase 3 data--hopefully there will be some additional information about the immune response--but for the time being it seemed more prudent to compare vaccine efficacy endpoints to each other, because these represent the practical effects. It is a more apples-to-apples comparison.
I've covered the reduction in neutralizing titers for specific variants here before, and communicated the same thing--that there is an apparent reduction in neutralization for certain variants, but the antibody titers are already so high with 2 doses of the approved mRNA vaccines that the reduction doesn't seem to take things down below the apparent protective threshold.
The big quirk to all of this is that we *still* don't know entirely enough about the immune response to COVID-19 to understand if antibodies actually represent the whole picture. While we are working under the assumption that antibodies are a correlate of protection, and using them for immunobridging studies (studies where an immunological correlate of protection is used as the endpoint rather than disease protection) in children, the correlation with protection may not be 100% solid. Given that CureVac showed good antibody titers in early phases but then failed in phase 3, I'm really wondering about that. I would very much like to see data from CureVac on durability of response and also neutralization titers in their phase 3 subjects for this reason, but they left that out of the press release. Which is kind of odd, since it would have potentially bolstered their "but the variants!!" argument.
My impression was that most of the VRBPAC members recognized at least some need to vaccinate young children, but expressed concerns about whether the safety and efficacy data will be enough to permit authorization later this year. It seems to me, though, that increasing the follow-up time wouldn't be particularly helpful (Paul Offit said the same in the meeting); and increasing the size of the trial to the point where it could detect rare safety signals would take an untenably long time.
An interesting question hung over the meeting, which is whether we should consider just direct costs vs. benefits to individual patients, or also factor in the benefits to the wider society. I favor the latter position, but I also don't think you need to do so in order to support vaccination of kids under 12. It may not have been clear a year ago that the short- medium- and potential long-term effects of the virus are a very significant danger to people in every age group, but it absolutely is now.
I would agree that the argument for vaccinating children looks favorable either way you slice it, but I do want to see more clinical data before saying it definitively IS favorable.
I'm pretty embarrassed by my off-the-cuff reaction to the missing numerator from Indonesia.
One thing I didn't notice in the article: CureVac's vaccine uses unmodified mRNA. Moderna and Pfizer make vaccines that contain nucleoside-modified mRNA. This might be in some way responsible for the apparent difference in effect. At least, I'd like to hear your opinion.
I wouldn't be embarrassed. The article was written in such a way as to encourage hasty reactions. For whatever it is worth.
Good point about the absence of pseudouridine substitution in the CureVac option. That could also be relevant, though I can't entirely figure out how or why that would have impacted efficacy and yet still allowed for induction of an antibody response, to be quite honest.
One more piece I was a little surprised you didn't mention, but which makes a lot of sense to me about variants and dosage: both Pfizer and Moderna are only barely less effective at full immunization* but both have been mentioned to have a much smaller (1/4?) neutralizing antibody response to certain VOC then they do to Covid Classic. Just they already had such a huge immune response that it was still enough. So if Curevac wasn't starting with anywhere near as huge and immune response then I could see it mattering a lot more that the VOCs were pretty much everything it was dealing with.
(Another bit that informs my query here is that some of the initial data from Hopkins' research with transplant patients seem to be that Moderna, with three times the genetic material, was somewhat more likely to produce spike antibodies than Pfizer. (They've just published something about a third dose, mix and match, seeming helpful for these immune compromised patients but I have not looked at it and that's attention anyway))
Am I off base on this, or would embracing the power of And (less mRNA -> less good at variants b/c less NA) be the rest of the story?
https://yourlocalepidemiologist.substack.com/p/vaccine-table-update-june-4-2021 is where I'm getting the 1/4.
* Or after one dose for everybody but Delta so far, but Delta was at around 30ish percent for one dose of Pfizer or AZ; haven't seen the data for Moderna
The reason I didn't mention this is that CureVac had good neutralization titers, as I recall similar to those of the other mRNA vaccines, in its Phase 2 results and earlier. so it seemed like it was on par with these other vaccines. I would like to see CureVac's full Phase 3 data--hopefully there will be some additional information about the immune response--but for the time being it seemed more prudent to compare vaccine efficacy endpoints to each other, because these represent the practical effects. It is a more apples-to-apples comparison.
I've covered the reduction in neutralizing titers for specific variants here before, and communicated the same thing--that there is an apparent reduction in neutralization for certain variants, but the antibody titers are already so high with 2 doses of the approved mRNA vaccines that the reduction doesn't seem to take things down below the apparent protective threshold.
The big quirk to all of this is that we *still* don't know entirely enough about the immune response to COVID-19 to understand if antibodies actually represent the whole picture. While we are working under the assumption that antibodies are a correlate of protection, and using them for immunobridging studies (studies where an immunological correlate of protection is used as the endpoint rather than disease protection) in children, the correlation with protection may not be 100% solid. Given that CureVac showed good antibody titers in early phases but then failed in phase 3, I'm really wondering about that. I would very much like to see data from CureVac on durability of response and also neutralization titers in their phase 3 subjects for this reason, but they left that out of the press release. Which is kind of odd, since it would have potentially bolstered their "but the variants!!" argument.
My impression was that most of the VRBPAC members recognized at least some need to vaccinate young children, but expressed concerns about whether the safety and efficacy data will be enough to permit authorization later this year. It seems to me, though, that increasing the follow-up time wouldn't be particularly helpful (Paul Offit said the same in the meeting); and increasing the size of the trial to the point where it could detect rare safety signals would take an untenably long time.
An interesting question hung over the meeting, which is whether we should consider just direct costs vs. benefits to individual patients, or also factor in the benefits to the wider society. I favor the latter position, but I also don't think you need to do so in order to support vaccination of kids under 12. It may not have been clear a year ago that the short- medium- and potential long-term effects of the virus are a very significant danger to people in every age group, but it absolutely is now.
I would agree that the argument for vaccinating children looks favorable either way you slice it, but I do want to see more clinical data before saying it definitively IS favorable.
I'm pretty embarrassed by my off-the-cuff reaction to the missing numerator from Indonesia.
One thing I didn't notice in the article: CureVac's vaccine uses unmodified mRNA. Moderna and Pfizer make vaccines that contain nucleoside-modified mRNA. This might be in some way responsible for the apparent difference in effect. At least, I'd like to hear your opinion.
I wouldn't be embarrassed. The article was written in such a way as to encourage hasty reactions. For whatever it is worth.
Good point about the absence of pseudouridine substitution in the CureVac option. That could also be relevant, though I can't entirely figure out how or why that would have impacted efficacy and yet still allowed for induction of an antibody response, to be quite honest.