Yeah, I don’t think it’s implausible. When I said I don’t “understand” why it would impact things considering that the CureVac vaccine showed an immune response in earlier trials, that doesn’t mean I think it can’t be a factor. It just means that I can’t square the two facts with each other. But at the same time, I can’t square most of the facts in this disappointment with each other. There are obviously some things that we don’t know about immune response to COVID-19. Additionally, we should consider that changes to lockdown conditions and other behavioral factors might also have impacted the CureVac trial.
When it comes specifically to the substitution of pseudouridine in the other vaccines vs the normal uridine in the CureVac option, what’s really confusing is that pseudouridine is supposed to reduce immune responses, not increase them. But for some reason, CureVac doesn’t seem to have done the job, even without this modulating substitution. I can speculate as to how that may be related. Perhaps CureVac has a kinetic problem—low RNA dose combined with too-strong activation of an innate immune response. One thing that innate immune responses can do is activate host cells’ RNAse L, which rapidly degrades every RNA in the cell. Maybe a low dose of RNA combined with a strong activator of innate responses degrades the CureVac RNA too quickly for it to be effective.
But if that’s true, where did the antibodies seen in earlier trials come from? Very confusing. The article you linked does note that those levels were lower than what we see with the other mRNA vaccines, but still around as high as seen with natural SARS-CoV-2 infection. In that same section, they suppose as I did before that dose was a big factor here. But it really is too early to know. I hope we get more detailed information soon.
Perhaps what Biden was trying to say is that Delta likely causes more severe disease in general, and so may inflict more severe disease on young people in absolute terms, even if they're still, ceteris paribus, relatively more protected from it than older people.
Very possible! Even if it causes equally severe disease, though, its enhanced contagiousness might make it even more dangerous on its own, at a population level. That will increase its likelihood of getting to those young people who are most vulnerable. I’m not sure which it is, but I can see a number of scenarios where it could be pretty dangerous.
Nature has an article on the CureVac disappointment.
https://www.nature.com/articles/d41586-021-01661-0?utm_source=Nature+Briefing&utm_campaign=a2a2c7317d-briefing-dy-20210621&utm_medium=email&utm_term=0_c9dfd39373-a2a2c7317d-45428970
There are vaccinologists who agree with me that the unsubstituted uridine of the CureVac mRNA is a plausible reason, but it isn't the only one.
Yeah, I don’t think it’s implausible. When I said I don’t “understand” why it would impact things considering that the CureVac vaccine showed an immune response in earlier trials, that doesn’t mean I think it can’t be a factor. It just means that I can’t square the two facts with each other. But at the same time, I can’t square most of the facts in this disappointment with each other. There are obviously some things that we don’t know about immune response to COVID-19. Additionally, we should consider that changes to lockdown conditions and other behavioral factors might also have impacted the CureVac trial.
When it comes specifically to the substitution of pseudouridine in the other vaccines vs the normal uridine in the CureVac option, what’s really confusing is that pseudouridine is supposed to reduce immune responses, not increase them. But for some reason, CureVac doesn’t seem to have done the job, even without this modulating substitution. I can speculate as to how that may be related. Perhaps CureVac has a kinetic problem—low RNA dose combined with too-strong activation of an innate immune response. One thing that innate immune responses can do is activate host cells’ RNAse L, which rapidly degrades every RNA in the cell. Maybe a low dose of RNA combined with a strong activator of innate responses degrades the CureVac RNA too quickly for it to be effective.
But if that’s true, where did the antibodies seen in earlier trials come from? Very confusing. The article you linked does note that those levels were lower than what we see with the other mRNA vaccines, but still around as high as seen with natural SARS-CoV-2 infection. In that same section, they suppose as I did before that dose was a big factor here. But it really is too early to know. I hope we get more detailed information soon.
Perhaps what Biden was trying to say is that Delta likely causes more severe disease in general, and so may inflict more severe disease on young people in absolute terms, even if they're still, ceteris paribus, relatively more protected from it than older people.
Very possible! Even if it causes equally severe disease, though, its enhanced contagiousness might make it even more dangerous on its own, at a population level. That will increase its likelihood of getting to those young people who are most vulnerable. I’m not sure which it is, but I can see a number of scenarios where it could be pretty dangerous.