The main concern
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wste...@williamstewart.com
Feb 23, 2021, 7:54:26 AM2/23/21
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(The first serious discussion I have found on this issue was Dr. Jacob Wes Ulm’s comments on Derek Lowe’s 2021-01-11 article “RNA Vaccines And Their Lipids”. Search the link below for “Ulm” for a very interesting discussion. I have excerpted his first comment below for convenience, other comments in the discussion can be found at the link.)
https://blogs.sciencemag.org/pipeline/archives/2021/01/11/rna-vaccines-and-their-lipids
The key open question is what exactly is the tissue tropism and cellular localization of the lipid nanoparticles used to carry the mRNA vaccines, and could this pose a side effect threat through errant MHC-I-mediated autoimmunity? Are they crossing the blood-brain barrier? Entering the parenchyma of vital organs (that even SARS-CoV-2 can’t access) and expressing the coronavirus spike protein on MHC-1 molecules, making these critical tissues targets of cytotoxic attack?
Briefly, a major safety checkbox for the mRNA vaccine modality in general is the tissue localization of the lipid nanoparticle vehicles. Most vaccines (called Type 1, e.g. subunit and inactivated virus) are essentially “MHC-2 only,” get taken up by dendritic cell phagocytosis and presented to CD4 T-cells in lymph nodes, so little to no CD8-mediated cytotoxicity against presenting cells. Attenuated virus vaccines like MMR (“Type 2”) do have some cytotoxicity mediated by CD8 lymphocytes attacking target cells presenting viral epitopes on MHC-1 cell-surface molecules, *but still limited to the tropism of the wild-type virus*. That’s where the lipid nanoparticles make mRNA vaccines elementally different from both, with a much broader potential tropism. Even if they’re not omnitropic, it seems that they can enter a much broader tissue range compared to even attenuated virus vaccines. And since the mRNA vaccines would induce SARS-CoV-2 viral spike protein expression, that seems to mean that people who get the mRNA vaccines are going to have a much greater range of cells and tissues vulnerable to cytotoxic attack, since they’d be expressing the spike protein on MHC-I molecules. While this may prove to be more immunostimulatory, it also seems to indicate that the mRNA vaccines pose a much greater risk of systemic and critical tissue and organ damage than other vaccines, especially if multiple booster shots are needed, with side effects that may not manifest for years (with cumulative damage and chronic inflammation).
This is where the picture gets aggravatingly murky, since it seems that neither Pfizer nor Moderna has posted up much of anything in the peer-reviewed literature about cellular and tissue localization from what many of us can tell, and this doesn’t seem to show up in the regulatory documents either, even though it would seem to be THE critical safety question for any proposed COVID-19 mass vaccination campaign. For the animal studies, it’d be as simple as using the companies’ nanoparticles to package GFP or equivalent indicator proteins, and seeing which tissues they go to and express the gene product. But there seems to be precious little published on this, and again from your descriptions here, it seems those tissue localizations would be quite broad. There have been published studies on LNP formulations in the past with varying tropisms but again, from what I can tell, the specific formulations in the actual vaccines are hard to get a handle on — perhaps because they’re considered trade secrets, and Pfizer and Moderna are worried about the other stealing the formula? — and even more crucially, we don’t know where in the body they’re going (through endocytosis, which leads to an MHC-1 expression pathway for viral antigens). And therefore, which tissues the vaccines’ mRNA payload is thus expressing the SARS-CoV-2 spike protein in, inviting cytotoxic attack.
The nightmare scenario would be if e.g. the mRNA vaccines’ lipid nanoparticles are, indeed, crossing the BBB and getting endocytosed into critical glial cells, like oligodendrocytes, or even worse, into neurons themselves in the brain and spinal cord, putting a bullseye on these critical cells for cytotoxic CD8 lymphocytes. If so, we’d be setting the stage for a rash of multiple sclerosis and ALS-type clinical scenarios down the road with multiple boosters. My old medical colleagues have been getting especially concerned about this possibility, and I think this may be behind the recent sharp plunge in willingness among more and more healthcare workers to take the mRNA vaccines. in the absence of long-term safety or efficacy data, which is an unfortunate shortcoming given the pandemic’s urgency, we can only go with fragmented hints here and there about potential downstream issues, so we need a wealth of information with full transparency to make up for that shortcoming. And I think the recent reports of some severe adverse effects in the VAERS (esp. neurological issues, or the vaccinated Ob-Gyn physician in Miami dying suddenly of ITP that from early reports, seems to have been triggered by the vaccine) are causing cold feet among doctors and healthcare workers, esp. in the absence of tissue localization information. I used to work in gene therapy and recall how we’d obsess on tissue tropism for our vectors before considering clinical trials, so I’m bewildered that this information seems almost absent for an almost entirely new vaccine modality (for mass vaccination of healthy populations) here — it would go a long way toward reassuring fears and increasing uptake of the mRNA vaccines, both among the general public and medical professionals.
https://blogs.sciencemag.org/pipeline/archives/2021/01/11/rna-vaccines-and-their-lipids
The key open question is what exactly is the tissue tropism and cellular localization of the lipid nanoparticles used to carry the mRNA vaccines, and could this pose a side effect threat through errant MHC-I-mediated autoimmunity? Are they crossing the blood-brain barrier? Entering the parenchyma of vital organs (that even SARS-CoV-2 can’t access) and expressing the coronavirus spike protein on MHC-1 molecules, making these critical tissues targets of cytotoxic attack?
Briefly, a major safety checkbox for the mRNA vaccine modality in general is the tissue localization of the lipid nanoparticle vehicles. Most vaccines (called Type 1, e.g. subunit and inactivated virus) are essentially “MHC-2 only,” get taken up by dendritic cell phagocytosis and presented to CD4 T-cells in lymph nodes, so little to no CD8-mediated cytotoxicity against presenting cells. Attenuated virus vaccines like MMR (“Type 2”) do have some cytotoxicity mediated by CD8 lymphocytes attacking target cells presenting viral epitopes on MHC-1 cell-surface molecules, *but still limited to the tropism of the wild-type virus*. That’s where the lipid nanoparticles make mRNA vaccines elementally different from both, with a much broader potential tropism. Even if they’re not omnitropic, it seems that they can enter a much broader tissue range compared to even attenuated virus vaccines. And since the mRNA vaccines would induce SARS-CoV-2 viral spike protein expression, that seems to mean that people who get the mRNA vaccines are going to have a much greater range of cells and tissues vulnerable to cytotoxic attack, since they’d be expressing the spike protein on MHC-I molecules. While this may prove to be more immunostimulatory, it also seems to indicate that the mRNA vaccines pose a much greater risk of systemic and critical tissue and organ damage than other vaccines, especially if multiple booster shots are needed, with side effects that may not manifest for years (with cumulative damage and chronic inflammation).
This is where the picture gets aggravatingly murky, since it seems that neither Pfizer nor Moderna has posted up much of anything in the peer-reviewed literature about cellular and tissue localization from what many of us can tell, and this doesn’t seem to show up in the regulatory documents either, even though it would seem to be THE critical safety question for any proposed COVID-19 mass vaccination campaign. For the animal studies, it’d be as simple as using the companies’ nanoparticles to package GFP or equivalent indicator proteins, and seeing which tissues they go to and express the gene product. But there seems to be precious little published on this, and again from your descriptions here, it seems those tissue localizations would be quite broad. There have been published studies on LNP formulations in the past with varying tropisms but again, from what I can tell, the specific formulations in the actual vaccines are hard to get a handle on — perhaps because they’re considered trade secrets, and Pfizer and Moderna are worried about the other stealing the formula? — and even more crucially, we don’t know where in the body they’re going (through endocytosis, which leads to an MHC-1 expression pathway for viral antigens). And therefore, which tissues the vaccines’ mRNA payload is thus expressing the SARS-CoV-2 spike protein in, inviting cytotoxic attack.
The nightmare scenario would be if e.g. the mRNA vaccines’ lipid nanoparticles are, indeed, crossing the BBB and getting endocytosed into critical glial cells, like oligodendrocytes, or even worse, into neurons themselves in the brain and spinal cord, putting a bullseye on these critical cells for cytotoxic CD8 lymphocytes. If so, we’d be setting the stage for a rash of multiple sclerosis and ALS-type clinical scenarios down the road with multiple boosters. My old medical colleagues have been getting especially concerned about this possibility, and I think this may be behind the recent sharp plunge in willingness among more and more healthcare workers to take the mRNA vaccines. in the absence of long-term safety or efficacy data, which is an unfortunate shortcoming given the pandemic’s urgency, we can only go with fragmented hints here and there about potential downstream issues, so we need a wealth of information with full transparency to make up for that shortcoming. And I think the recent reports of some severe adverse effects in the VAERS (esp. neurological issues, or the vaccinated Ob-Gyn physician in Miami dying suddenly of ITP that from early reports, seems to have been triggered by the vaccine) are causing cold feet among doctors and healthcare workers, esp. in the absence of tissue localization information. I used to work in gene therapy and recall how we’d obsess on tissue tropism for our vectors before considering clinical trials, so I’m bewildered that this information seems almost absent for an almost entirely new vaccine modality (for mass vaccination of healthy populations) here — it would go a long way toward reassuring fears and increasing uptake of the mRNA vaccines, both among the general public and medical professionals.
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