Also, there were smaller sub-trials done with just one shot, and those showed significantly weaker immunization, although telling exactly how much weaker is hard due to little data available and thus very large margins of error.
We know that both the Moderna and Pfizer vaccines look about 80% effective from 10 days after dose 1 up to dose 2. We really should be doing a trial on delaying dose 2 a bit: it might very well make the dose 2 side effects smaller, increase efficacy, and stretch vaccine supplies.
Even for younger adults, chances of dying if infected with Covid are much higher than that.
The vaccines have a higher side effect rate than we're used to, but they're orders of magnitude safer than the risk we have from being exposed to COVID, infected, and then having a bad outcome.
Some of this relates to the rush to market and the desire for very high efficacy even if we were somewhat surprised/incorrect on required neutralization titers. When COVID-19 is rarer, we likely will need safer vaccines against it, though. This may just be a question of turning down dosage a bit.
As others have pointed out, the risk/benefit calculation here is extreme: a few bad reactions per million vs. a disease that has already killed more than 1000 people per million population in the US.
For a healthy young adult, chances of dying from Covid are in the same ballpark.
So it is sort of the same ballpark for the very youngest adults, but a factor of 3 isn't nothing. It's higher for people in their 20s already. We can be talking about different things though, as it isn't 100% likely a given person will be infected.
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.
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.
> 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"?
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... slides 19-20
Here's what Derek Lowe had to say: 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.2018.0222... "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 "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 "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"
https://www.ft.com/content/de00fe75-9ba1-4be7-8cf1-6e9fa55f0...
Additionally the advice to delay the second dose is now also part of the WHO recommendations.
The immune system doesn't like non-human RNA. Certain sequences, or even abundance of certain amino acids out of balance with human codes can set it off. Special RNA coding may be used in place of traditional adjuvants but much of it is proprietary at this point
Traditionally, mRNA vaccines were not very effective. There's definitely some magic "trade secret" sauce in these vaccines.
The sequence is actually public, but as far as I know no one has figured out what optimizations worked in the end aside from the uracil-depletion + 1-methylpseudouridine trick to avoid an immune response to what looks like viral RNA. https://mednet-communities.net/inn/db/media/docs/11889.doc