3 ms·

Thing is, the "not healthy" group is bigger than most people think. Anaphylaxis is a very controllable situation, whereas severe COVID is not. Non of the reacti

Thing is, the "not healthy" group is bigger than most people think. Anaphylaxis is a very controllable situation, whereas severe COVID is not. Non of the reacting subjects hasn't had a history of anaphylaxis AFAIK. Nothing in the mRNA vaccines was chosen to enhance immune response, nothing is an adjuvant as with other vaccines. On the contrary, the polymers and co are there to protect the mRNA from immune system clearance (and are used in other non-vaccine medications too). It's worth noting, an allergic reaction is mediated by a completely different branch of the immune system. Non of the "adjuvants" aren't to be found in common household items, food and cosmetics, which is probably why the allergic people reacted in the first place. Very few, very allergic people, seem to react to these. If so, you treat them with an antihistamine and similar.

mlyle 6y ago
> Nothing in the mRNA vaccines was chosen to enhance immune response, nothing is an adjuvant as with other vaccines. This isn't -exactly- true. There's no traditional adjuvant added, but... the fact that the formulation caused adjuvant-like effects was seen as a feature, not a bug. Added care to minimize immune response has been used in the development of mRNA drug platforms > Non of the "adjuvants" aren't to be found in common household items, food and cosmetics You can find PEG in lots of things, but PEGylated large molecules aren't exactly common items around the home.
- monopoledance 6y ago
  > but... the fact that the formulation caused adjuvant-like effects was seen as a feature, not a bug. > Added care to minimize immune response has been used in the development of mRNA drug platforms I don't get it. Either they want the immune response or not. Do you have a link to source your claim, they favored "adjuvant-like effects"?
  - mlyle 6y ago
    > I don't get it. Either they want the immune response or not. When mRNA is used in typical drug platforms-- you don't want the immune response. mRNA vaccine platforms-- you do want the vaccine response. So, e.g. Moderna has an "N1GL" formulation intended, in part, to tamp down reactogenicity that it is using for its drugs in development, and "V1GL" formulation intended for vaccines where they don't care so much. N1GL both more completely envelops the mRNA and consists of components that themselves are less "adjuvant". (And N1GL is probably not quite good enough, yet...) edit: Now it seems there's N2GL where they claim causes much less reactogenicity/toxicity on repeated administration and produces less anti-PEG IgM e.g. https://zerista.s3.amazonaws.com/item_files/f228/attachments/413374/original/83_2803.pdf https://zerista.s3.amazonaws.com/item_files/f228/attachments... slides 19-20
    - monopoledance 6y ago
      But the mRNA vaccine isn't what the immune system is responding to directly, but the spike protein produced by the cells, which got infused with the mRNA. Anything that makes the immune system attack the vaccine, prevents the delivery of the mRNA. Sorry, I don't think your reasoning is sound and very based.
      - mlyle 6y ago
        I don't know how my reasoning could be more "based", but here--- listen to some pharmaceutical and vaccine experts and see what you think. Here's what Derek Lowe had to say: https://blogs.sciencemag.org/pipeline/archives/2021/01/21/mrna-vaccines-what-happens https://blogs.sciencemag.org/pipeline/archives/2021/01/21/mr... So to get a good RNA vaccine, you frankly have to make it work like a particularly stealthy virus, and not trip every single alarm before your payload gets a chance to enter the cells. But as mentioned, some activation of the innate system is needed to get the adjuvant boost. A lot of that work has to be done empirically, which is why we’ve seen so many RNA and DNA formulation ideas over the years. None of these have been stupid ideas (far from it) but some of them work better than others, and the current lipid nanoparticle ones are the current state of the art – the LNPs themselves activate the innate immune system, but in a way that doesn’t seem to trigger too much of a self-defeating cytokine response. It’s a useful enough effect that they’re being proposed as adjuvant additions to other, more traditional vaccines for that effect alone. Me: Both the LNPs and the mRNA itself stimulate the immune system. Basically the vast majority of work in mRNA drugs for the last decade has been to try to reduce that-- and associated toxicity and unpredictable clearance. Meanwhile, the (right amount of) immunogenicity has been accepted as a feature in vaccine candidates. And in a series of journal articles e.g. in Frontiers in Immunology: https://www.frontiersin.org/articles/10.3389/fimmu.2018.02224/full https://www.frontiersin.org/articles/10.3389/fimmu.2018.0222... "This was observed in the case of administration of empty PEGylated liposomes, which were able to elicit IgM response in an in-vivo model. (27, 28). Besides their potential to deliver various immune stimulators to the specific sites as well as into the deep tissues where vaccine molecules alone may not able to reach, these NPs have also been exploited as adjuvants to augment immunogenicity of vaccine candidates." Nature / npj Vaccines: https://www.nature.com/articles/s41541-020-0159-8 https://www.nature.com/articles/s41541-020-0159-8 "Thus, multi-antigen candidates necessitate a significant amount of LNP for a given dose. LNPs are known to have inherent adjuvant properties." Nature / npj vaccines: https://www.nature.com/articles/nrd.2017.243 https://www.nature.com/articles/nrd.2017.243 "Exogenous mRNA is inherently immunostimulatory, as it is recognized by a variety of cell surface, endosomal and cytosolic innate immune receptors (Fig. 1) (reviewed in Ref. 35). Depending on the therapeutic application, this feature of mRNA could be beneficial or detrimental. It is potentially advantageous for vaccination because in some cases it may provide adjuvant activity to drive dendritic cell (DC) maturation and thus elicit robust T and B cell immune responses. ... The immunostimulatory properties of mRNA can conversely be increased by the inclusion of an adjuvant to increase the potency of some mRNA vaccine formats. These include traditional adjuvants as well as novel approaches that take advantage of the intrinsic immunogenicity of mRNA"

mlyle 6y ago

> Nothing in the mRNA vaccines was chosen to enhance immune response, nothing is an adjuvant as with other vaccines. This isn't -exactly- true. There's no traditional adjuvant added, but... the fact that the formulation caused adjuvant-like effects was seen as a feature, not a bug. Added care to minimize immune response has been used in the development of mRNA drug platforms > Non of the "adjuvants" aren't to be found in common household items, food and cosmetics You can find PEG in lots of things, but PEGylated large molecules aren't exactly common items around the home.

monopoledance 6y ago
> but... the fact that the formulation caused adjuvant-like effects was seen as a feature, not a bug. > Added care to minimize immune response has been used in the development of mRNA drug platforms I don't get it. Either they want the immune response or not. Do you have a link to source your claim, they favored "adjuvant-like effects"?
- mlyle 6y ago
  > I don't get it. Either they want the immune response or not. When mRNA is used in typical drug platforms-- you don't want the immune response. mRNA vaccine platforms-- you do want the vaccine response. So, e.g. Moderna has an "N1GL" formulation intended, in part, to tamp down reactogenicity that it is using for its drugs in development, and "V1GL" formulation intended for vaccines where they don't care so much. N1GL both more completely envelops the mRNA and consists of components that themselves are less "adjuvant". (And N1GL is probably not quite good enough, yet...) edit: Now it seems there's N2GL where they claim causes much less reactogenicity/toxicity on repeated administration and produces less anti-PEG IgM e.g. https://zerista.s3.amazonaws.com/item_files/f228/attachments/413374/original/83_2803.pdf https://zerista.s3.amazonaws.com/item_files/f228/attachments... slides 19-20
  - monopoledance 6y ago
    But the mRNA vaccine isn't what the immune system is responding to directly, but the spike protein produced by the cells, which got infused with the mRNA. Anything that makes the immune system attack the vaccine, prevents the delivery of the mRNA. Sorry, I don't think your reasoning is sound and very based.
    - mlyle 6y ago
      I don't know how my reasoning could be more "based", but here--- listen to some pharmaceutical and vaccine experts and see what you think. Here's what Derek Lowe had to say: https://blogs.sciencemag.org/pipeline/archives/2021/01/21/mrna-vaccines-what-happens https://blogs.sciencemag.org/pipeline/archives/2021/01/21/mr... So to get a good RNA vaccine, you frankly have to make it work like a particularly stealthy virus, and not trip every single alarm before your payload gets a chance to enter the cells. But as mentioned, some activation of the innate system is needed to get the adjuvant boost. A lot of that work has to be done empirically, which is why we’ve seen so many RNA and DNA formulation ideas over the years. None of these have been stupid ideas (far from it) but some of them work better than others, and the current lipid nanoparticle ones are the current state of the art – the LNPs themselves activate the innate immune system, but in a way that doesn’t seem to trigger too much of a self-defeating cytokine response. It’s a useful enough effect that they’re being proposed as adjuvant additions to other, more traditional vaccines for that effect alone. Me: Both the LNPs and the mRNA itself stimulate the immune system. Basically the vast majority of work in mRNA drugs for the last decade has been to try to reduce that-- and associated toxicity and unpredictable clearance. Meanwhile, the (right amount of) immunogenicity has been accepted as a feature in vaccine candidates. And in a series of journal articles e.g. in Frontiers in Immunology: https://www.frontiersin.org/articles/10.3389/fimmu.2018.02224/full https://www.frontiersin.org/articles/10.3389/fimmu.2018.0222... "This was observed in the case of administration of empty PEGylated liposomes, which were able to elicit IgM response in an in-vivo model. (27, 28). Besides their potential to deliver various immune stimulators to the specific sites as well as into the deep tissues where vaccine molecules alone may not able to reach, these NPs have also been exploited as adjuvants to augment immunogenicity of vaccine candidates." Nature / npj Vaccines: https://www.nature.com/articles/s41541-020-0159-8 https://www.nature.com/articles/s41541-020-0159-8 "Thus, multi-antigen candidates necessitate a significant amount of LNP for a given dose. LNPs are known to have inherent adjuvant properties." Nature / npj vaccines: https://www.nature.com/articles/nrd.2017.243 https://www.nature.com/articles/nrd.2017.243 "Exogenous mRNA is inherently immunostimulatory, as it is recognized by a variety of cell surface, endosomal and cytosolic innate immune receptors (Fig. 1) (reviewed in Ref. 35). Depending on the therapeutic application, this feature of mRNA could be beneficial or detrimental. It is potentially advantageous for vaccination because in some cases it may provide adjuvant activity to drive dendritic cell (DC) maturation and thus elicit robust T and B cell immune responses. ... The immunostimulatory properties of mRNA can conversely be increased by the inclusion of an adjuvant to increase the potency of some mRNA vaccine formats. These include traditional adjuvants as well as novel approaches that take advantage of the intrinsic immunogenicity of mRNA"