Some thoughts

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Kiang-Hua Goh

Mar 7, 2021, 7:32:39 AM3/7/21
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Shin, enjoyed reading your draft. I think it is probably the precursors of the platelets, megakaryocytes, not the platelets themselves that could be the target of the immune response.

I have been researching around this topic and these are some of my thoughts (all speculative though):

1. The vector vaccines should be subjected to the same concerns (although the tissues of localisation may be different from the lipid nanoparticles). These vector vaccines have a much longer history than mRNA vaccines. In fact, there are approved vector vaccines e.g from J & J against Ebola and there do not seem to be any indication of autoimmunity induction so far.

2. Let us see what happens when a mRNA vaccine is given intramuscularly into the deltoid muscle. The lipid nanoparticles (LNPs) will have 3 fates:
a. Phagocytosis and destruction by cells of the innate inmmune systems like the macrophages
b. Endocytosis by the muscle cells
c. Escape into the lymphatic system

3. Fate (a) is probably of no concern

4. Fate (b) is the desired outcome as it will result in the production of the spike proteins. I will discuss more on this later

5. Fate (c) is what we are worried about - the escape of the lipid nanoparticles into the lymphatic system and subsequently into the vascular system and hence to the rest of the body. I will discuss this first.

6. For the LNPs to escape and get distributed to the rest of the body, there is a long, long tortuous journey ahead, fraught with obstacles.
(i) If you look at the microscopic anatomy of the muscles, it is a mass of closely packed myocytes. The LNPs have to escape endocytosis by these masses of cells to reach the lymphatic system
(ii) The lymphatic system is lined by cells whiich potentially can endocytose the LNPs
(iii) From the muscles, the lymphatic system will drain into the lymph nodes. Again, if you look at the microscopic anatomy of the lymph nodes, the lymph carrying the LNPs has to percolate through masses of cells which potentially can gobble up the LNPs.
(iv) If the LNPs manage to escape intact, they will then be carried to the venous system - the superior vena cava, then through the right side of the heart into the pulmonary artery, then through the capillary networks in the lungs, subsequently into the pulmonary vein into the left side of the heart. Along the way, especially in the capillary beds of the lungs where the blood flow is slow, the LNPs face multiple hurdles as the whole route is lined by living cells.
(v) If the LNPs survive the journey so far, the next stage is equally if not more treacherous. The left ventricle will expel the blood (with the LNPs) with great speed and force out into the aorta. I am not certain how well the LNPs can withstand the turbulence generated.
(vi) If the LNPs disintegrate from the turbulence, the mRNAs will be rapidly destroyed by ribonucleases. Those that remain intact will be sent to the WHOLE body.
(vii) The central nervous system is of particularly concern. However, there is the blood-brain barrier (BBB) which prevents pathogens and macro-molecules from crossing into the CNS. The BBB is made up living endothelial cells, astrocytes and glial cells. To cross the BBB, the LNPs will need to be endocystosed by these cells in which case the production of the spike proteins should be limited only to the BBB.
(viii) In areas of the brain where the BBB is more leaky and the LNPs may be able to cross, they will be taken up by the neurons and spike proteins will be produced in the neurons. The result of this will probably depend on the duration the spike protens remain displayed on the neurons. If they are rapidly degraded, they may not be a concern. However, even if they remain for a long time, they may not be an issue. The danger of neurons displaying spike proteins is from activated cytotoxic CD8 T cells honing on and destroying the neurons. But these T cells will not be able to cross the BBB unless it is inflammed. (However, this postulate of mine ignores the role that immune cells resident in the CNS may play as I am not very familar with this aspect of immunology)
(viii) For the LNPs that are carried by the blood stream to other areas of the body, they will be taken up by cells there where spike proteins will be expressed. The cells there can then be the target of activated CD8 T cells which can result in autoimmune damage to organs. An example of this could be cases of ITP that had been reported after mRNA vaccines. Check the article below:
The case of Dr. Michael, an OBGY in Florida has generated a lot of interest. However, he developed ITP 3 days after the FIRST DOSE and there is no plausible mechanism how this could be due to the mRNA vaccine.

5. Let us discuss fate (b) - the desired outcome of mRNA vaccines which is the production of spike proteins by the muscle cells. These spike proteins will be (i) secreted into the extracellular space (ii) displayed on the surface of muscle cells

6. Spike proteins secreted into the extracellular space will be either (i) phagocytosed and destroyed by macrophages or (ii) taken up by antigen presenting cells, the APCs (dendritic cells, macrophages and lymphocytes (iii) escape into the lymph system.
(i) Phagocytosis and destruction by macrophages - probably of no concern
(ii) Taken up by APCs - the spike proteins will be broken down into bits of antigen and displayed on the surface of the APCs. These APCs will migrate to the lymph nodes where they will initiate the adaptive immune response resulting in the productiion of specific antibodies and helper CD4 and cytotoxic CD8 T lymphocytes. This is the desired outcome of vaccination.
(iii) Escape into the lymph. The spike proteins will be carried to the lymph nodes where there will be scavenging by resident macrophages in the lymph nodes. Those that remain intact will reach the venous system. They will then be circulated first via the right side of the heart to the lungs where further scavenging will occur in the pulmonary capillary beds. The remaining spike proteins will reach the left side of the heart and subsequently distributed to the whole body. At the capillary beds of each organ that are perfused, the spike proteins will likely be destroyed by resident macrophages as they are foreign antigens.
(iv) What if the spike proteins reach the CNS? Being a macromolecule, it will have difficulty crossing the BBB. Even if they do cross, they will probably be gobbled up resident macrophages in the CNS.

7. Spike proteins displayed on the surface of muscle cells. The issue is how long they remain on the muscle cells, how quickly they get degraded. If they remain till the activation of the adaptive immune response, the cytotoxic CD8 T cells will target and destroy these cells. It could be the reason why the second dose of vaccine results in more pain at the injection site. But muscle cells can regenerate and this probably will have no long term consequences.

8. So, overall, I feel that there is very little risk from the mRNA vaccines. I know that there are studies in mice where after intramuscular injections, the LNPs can be detected in the liver and elsewhere in the body. But, the structural integrity of these LNPs after being expelled from the left ventricle is doubtful.

9. The LNPs face numerous hurdles to get to the CNS (muscle cells, lymph nodes, pulmonary capillary beds, ejection from the left ventricle, the BBB). They are not distributed specifically to the CNS but are circulated to the whole body. The LNPs that reach the CNS are probably of questionable integrity and are in minuscule concentration. They have somehow to cross the BBB. Even then activated cytotoxic CD8 T cells will have to somehow cross the BBB into order to cause neuronal damage (provided again the spike proteins remain displayed long enough on the neurons)

9. There are now more than 250 million doses of vaccines given world wide. The first patients given the vaccines in phase 1 trials have been followed up for a year now. This is probably the most closely watched vaccine roll-up ever in the history of vaccinology. To date, thankfully, there has been no signal of any long term issues of concern.

10. These are all speculations and conjecture and hopefully further data will be forthcoming.

Dr. Goh

Shaw, Christopher

Mar 7, 2021, 2:35:08 PM3/7/21
to Kiang-Hua Goh, mrnadiscuss

Interesting analysis. Not sure, based on the Gherardi group work in Paris on aluminum adjuvants, that the encapsulated mRNA doesn't go from the injection site into immune cells and then into other systems, including CNS. The Bahl et al studies need to be followed up with more comprehensive localization studies. Maybe, as you suggest, the mRNA found in mouse brain is degraded and thus unable to impact neurons or glia. It would be nice to be sure.

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Shin jie Yong

Mar 8, 2021, 7:59:53 AM3/8/21
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Thank you Dr. Goh for your well-reasoned thoughts.

I am indeed amazed by what you have written with many insightful points that I have not thought of. 

I have further edited the draft, mostly in the 'more context' section, where I mentioned your name and quoted quite a fair bit of what you have written about fate (c). I hope that's alright with you, but let me know if not. 
I have also corrected the part of platelets and megakaryocytes. 

If everything seems fine, I'll go ahead and publish it sometime this week. 

Kind regards,

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