https://www.science.org/content/blog-post/mrna-vaccines-what-s-adjuvant
I believe that mRNA vaccines are a real advance in the field, but there’s no doubt that we’re in the early days of their use. And given the complexities of the immune system, it’s not surprising that we haven’t worked out all the details - if you really want to get down to it, we don’t have all the details on any therapy involving the immune system at all. Which doesn’t mean that we shouldn’t use them! Let’s get even more real, and say that the same statement applies to small molecule drugs as well, whether they have an immune component or not. We can see the outcomes, we can measure risk/reward and safety/efficacy, and make informed decisions about when to use them and for what.
I’m beating on this point so hard, as I’m sure people will have realized, because of the violent hostility of the current US federal health authorities towards vaccination, which is generally given an extremely annoying won’t-someone-think-of-the-children spin about how gosh, we haven’t worked out all the details yet so why are we running cruel experiments on helpless pediatric patients, etc. This is how you can easily weaponize the “precautionary principle” into making sure that you take no actions at all because you can’t understand their full consequences down to the last detail (so you can’t be sure that nothing bad is happening and if you can’t be sure than how can you in good conscience and so on).
This new paper, for example, has more details about how mRNA formulations induce such useful immune responses. It’s already been noted that the lipid nanoparticles involves in packing the mRNA payloads have some inherent adjuvant activity, which is convenient. Non-native mRNA certainly has such activity, too, but in the vaccines the use of modified nucleosides turns down a lot of the innate immune system activity that would otherwise kick in. Almost all conventional vaccines have some sort of adjuvant to stimulate the immune system and make the antibody-eliciting effects more prominent (indeed, some of them would be almost useless without it at the dosages administered). I’ve written about adjuvants before, but there’s obviously a lot more to say about them because again, there’s a lot that we haven’t uncovered about their modes of action.
The LNP and mRNA components are both playing key roles in these vaccine effects, and I’m going to reproduce the graphical abstract of the paper to give you some idea of what’s going on. Well, perhaps. One thing it’s sure to do is make you glad that you’re not an immunologist, because I assure you that this is a very simplified picture as well. What you’re seeing are effects on dendritic cells (the “DC”) in the middle, and it turns out that both components of the vaccine are acting on these but through different pathways. To add to the fun, both involve CD4-bearing T cells and the associated T-follicular helper (Tfh) cells, but again through different pathways.
This research group has evidence that the nucleoside-modified mRNA used in the vaccines does not completely make them invisible to the innate immune system’s pattern-recognition-receptors that are always watching for foreign mRNA. Those are also why the mRNA constructs used in the vaccines need to be well purified to remove double-stranded species, which will really trip those receptors for you if present. It turns out that the purified, nucleoside-modified mRNAs do set off a Type I interferon response that had not been worked out before, and the authors propose that there must be a less-characterized pattern recognition receptor or perhaps a yet-undescribed mechanism of action for existing ones that causes this. They haven’t found either one yet, but their evidence strongly suggests that something like one of these has to be out there.
But the responses to both the lipid nanoparticles and the mRNA species are important here, and when things go correctly they actually reinforce each other. There are other experiments in the paper that show that the LNP response is a local one, almost entirely occurring in the nearly draining lymph node to the vaccine injection site, instead of a system-wide effect. It doesn’t even look as if you have to inject them at the same time or in any physically coupled formulation (as we do) - the effect works either way. But since we need the LNPs to protect the mRNA and to get good uptake into cells, it’s certainly good that they’re such mechanistic partners. This could well help to explain the failures of many other plausible mRNA delivery systems that were tried in the earlier years of such research.
The hope is that as we study these systems more closely we can work out how to hit this balance by design rather than by trying years of things that don’t work as well (or at all!) We’ve got a ways to go before we get to that point, but learning all the tiny switches and dials of the vaccine immune response is going to be a very worthwhile endeavor.
https://www.science.org/content/blog-post/mrna-vaccines-what-s-adjuvant
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