"What’s interesting is the last paragraph, which suggests that no adaptive immune response occurred to target luciferase, although it does appear that an adaptive immune response was formed against the modRNA, and it appears that it depends on the type of LNP used."
You may have already spotted it, but 4.5.9 suggests the T Cell / ELISpot response was elicited with the luciferase peptides. A quick review of the research suggests that ELISpot with luciferase peptides is typically used for testing gene vector platforms that are intended to NOT induce an adaptive immune response - https://www.nature.com/articles/3300951 - so, just like here, it may be a common thing that antibody screening usually misses luciferase sensitization and that is why ELISpot is preferred. (Just guessing since I can't find any specific mention of antibodies in conjunction with luciferase gene platform trials.)
So, it probably didn't add a ton of value to the distribution study. A separate immunogenicity study would still be wanted.
There's a non-redacted summary of R-20-0072 and more good stuff in the Australia nonclinical overview that was released last week-ish (including more "spike in the nucleus?" stains) https://www.tga.gov.au/sites/default/files/foi-2389-06.pdf
Thanks for pointing that out Brian! I will admit it was a fairly preliminary viewing, and trying to piece together the bits that weren't redacted was a bit frustrating. Hopefully other papers provide additional information as the sensitization to luciferase would not be applicable to spike proteins, of which we know should elicit a response. The only assumption made here is if something may have attributed to hinder a response?
Thanks for the additional post. It seems that the Australian government wanted their own study as well? But as for that pg 40 that would indicate that references to LNP8 may refer to the GMP pairing? That would actually make the paper a lot easier to assess even with the redactions as then any reference to Acuitas may just refer to the proprietary blend.
It's the same study - it's just the Australians were sent a summary drafted by Pfizer instead of the BioNTech paper. But since the Australians didn't maul said summary with redactions, it ends up revealing the missing information for the other two formulations, and the graphs. LNP8 and 5 also have different encapsulation and size values.
LNP12 is the non-Acuitas formulation, which is the one that the other two have 20X the luciferase expression vs. So it would seem that the lower T Cell response is simply an outcome of lower payload delivery/expression.
The lack of transparency in data submitted to federal agencies happens at the EPA also. For pesticide approvals, only the active ingredient in the pesticide has to be declared. The active ingredient can be as little as 1% of the whole formula.
There is an urban myth that the government tests everything and nothing unsafe would ever be released on to the market. We all need to dispel that myth. Talk to family and friends and explain why they can't trust any product. Buyer beware!
It is rather weird that the FDA is arguing that they are so busy that they couldn't release all of these documents, since that would at least mean that the FDA is probably always too busy to deal with all of the requests they get and therefore a lot of things may be missed or slipped.
I think it's definitely true that the FDA has outsourced a lot of these things to the pharmaceutical companies and they just hope that they are being trustful. It really is such a strange spot to be in right now, and I think everyone should try viewing everything with a good degree of skepticism.
Thanks so much for digging into the data! I just read naked emperor too, and I'm excited for the scientist substackers to work together on this data. I have to say it's really fun and so educating to watch you all collaborate. 👍🏼💕
I love your white pill conclusion, that while it's unethical that so much is redacted and cannot really be peer reviewed, hopefully it will get out that this is the way the FDA review process works. You concluded that your brief experience interacting with the FDA means that is the normal way they operate. I imagine that is true, even with your brief anecdotal experience, because it showed what type of person they want on board; someone who is okay skirting the scientific and strict review process.
I should have elaborated, but the job would have essentially meant that I look at these types of papers for "weird things". What weird things? I don't know, considering many times a large portion of the paper is gone. But yes this seems to be the standard practice that you just block a ton of stuff and pass it onto the FDA for review as if it doesn't look suspicious at all.
I hope a lot of people see the end and really understand that this is the norm not the exception and to really question a lot of the bureaucratic processes that have been going on.
And yes, I don't want to spend my entire time on these especially if it means really trying to filter through a lot of the information. I did a very preliminary glance of this paper and considering there are tons more I hope it just means that there will be plenty of people to find some things, even if it doesn't turn out fruitful.
I read the article on AOC in the New Yorker and she said Congress is a shitshow. "Honestly, it is a shit show. It’s scandalizing, every single day. What is surprising to me is how it never stops being scandalizing. Some folks perhaps get used to it, or desensitized to the many different things that may be broken, but there is so much reliance on this idea that there are adults in the room, and, in some respect, there are. But sometimes to be in a room with some of the most powerful people in the country and see the ways that they make decisions—sometimes they’re just susceptible to groupthink, susceptible to self-delusion."
I bet this is true throughout the government, a few adults, and a lot of childish adults running things.
"What’s interesting is the last paragraph, which suggests that no adaptive immune response occurred to target luciferase, although it does appear that an adaptive immune response was formed against the modRNA, and it appears that it depends on the type of LNP used."
You may have already spotted it, but 4.5.9 suggests the T Cell / ELISpot response was elicited with the luciferase peptides. A quick review of the research suggests that ELISpot with luciferase peptides is typically used for testing gene vector platforms that are intended to NOT induce an adaptive immune response - https://www.nature.com/articles/3300951 - so, just like here, it may be a common thing that antibody screening usually misses luciferase sensitization and that is why ELISpot is preferred. (Just guessing since I can't find any specific mention of antibodies in conjunction with luciferase gene platform trials.)
So, it probably didn't add a ton of value to the distribution study. A separate immunogenicity study would still be wanted.
There's a non-redacted summary of R-20-0072 and more good stuff in the Australia nonclinical overview that was released last week-ish (including more "spike in the nucleus?" stains) https://www.tga.gov.au/sites/default/files/foi-2389-06.pdf
Lists the redacted products on p 40
mRNA Luciferase LNP12 - DODMA:Chol: DOPE:PEGcerC16 (40:48:10:2); RNA-EH190611-01c, FSU- 1#029, 79% encapsulation, 0.9053 mg/ ml encapsulated RNA, diameter 84 .nm. polydispersity 0.202, storage temperature +4°C.
mRNA Luciferase LNP5 - Acuitas proprietary; RNA-EHl90611-0lc, batch FM-1055-D, 79% encapsulation, 0.924 mg/ ml encapsulated RNA, diameter 108 nm. polydispersity 0.091, storage temperature -80°C.
Thanks for pointing that out Brian! I will admit it was a fairly preliminary viewing, and trying to piece together the bits that weren't redacted was a bit frustrating. Hopefully other papers provide additional information as the sensitization to luciferase would not be applicable to spike proteins, of which we know should elicit a response. The only assumption made here is if something may have attributed to hinder a response?
Thanks for the additional post. It seems that the Australian government wanted their own study as well? But as for that pg 40 that would indicate that references to LNP8 may refer to the GMP pairing? That would actually make the paper a lot easier to assess even with the redactions as then any reference to Acuitas may just refer to the proprietary blend.
It's the same study - it's just the Australians were sent a summary drafted by Pfizer instead of the BioNTech paper. But since the Australians didn't maul said summary with redactions, it ends up revealing the missing information for the other two formulations, and the graphs. LNP8 and 5 also have different encapsulation and size values.
LNP12 is the non-Acuitas formulation, which is the one that the other two have 20X the luciferase expression vs. So it would seem that the lower T Cell response is simply an outcome of lower payload delivery/expression.
The lack of transparency in data submitted to federal agencies happens at the EPA also. For pesticide approvals, only the active ingredient in the pesticide has to be declared. The active ingredient can be as little as 1% of the whole formula.
There is an urban myth that the government tests everything and nothing unsafe would ever be released on to the market. We all need to dispel that myth. Talk to family and friends and explain why they can't trust any product. Buyer beware!
It is rather weird that the FDA is arguing that they are so busy that they couldn't release all of these documents, since that would at least mean that the FDA is probably always too busy to deal with all of the requests they get and therefore a lot of things may be missed or slipped.
I think it's definitely true that the FDA has outsourced a lot of these things to the pharmaceutical companies and they just hope that they are being trustful. It really is such a strange spot to be in right now, and I think everyone should try viewing everything with a good degree of skepticism.
Thanks so much for digging into the data! I just read naked emperor too, and I'm excited for the scientist substackers to work together on this data. I have to say it's really fun and so educating to watch you all collaborate. 👍🏼💕
I love your white pill conclusion, that while it's unethical that so much is redacted and cannot really be peer reviewed, hopefully it will get out that this is the way the FDA review process works. You concluded that your brief experience interacting with the FDA means that is the normal way they operate. I imagine that is true, even with your brief anecdotal experience, because it showed what type of person they want on board; someone who is okay skirting the scientific and strict review process.
I should have elaborated, but the job would have essentially meant that I look at these types of papers for "weird things". What weird things? I don't know, considering many times a large portion of the paper is gone. But yes this seems to be the standard practice that you just block a ton of stuff and pass it onto the FDA for review as if it doesn't look suspicious at all.
I hope a lot of people see the end and really understand that this is the norm not the exception and to really question a lot of the bureaucratic processes that have been going on.
And yes, I don't want to spend my entire time on these especially if it means really trying to filter through a lot of the information. I did a very preliminary glance of this paper and considering there are tons more I hope it just means that there will be plenty of people to find some things, even if it doesn't turn out fruitful.
Thanks for elaborating. That is very strange.
I read the article on AOC in the New Yorker and she said Congress is a shitshow. "Honestly, it is a shit show. It’s scandalizing, every single day. What is surprising to me is how it never stops being scandalizing. Some folks perhaps get used to it, or desensitized to the many different things that may be broken, but there is so much reliance on this idea that there are adults in the room, and, in some respect, there are. But sometimes to be in a room with some of the most powerful people in the country and see the ways that they make decisions—sometimes they’re just susceptible to groupthink, susceptible to self-delusion."
I bet this is true throughout the government, a few adults, and a lot of childish adults running things.