Can the Lipid Nanoparticles Carrying mRNA Vaccine Really Cross the Blood-brain Barrier?


mRNA Vaccine and the Brain: A Recap and Update

A few researchers have previously raised the hypothetical concern of mRNA vaccine, encapsulated in lipid nanoparticles (LNPs), entering the brain, given that LNPs are usually used to deliver medical drugs across the blood-brain barrier (BBB) to enter the brain.

I detailed this issue in detail in “Concerns of Lipid Nanoparticle Carrying mRNA Vaccine into the Brain: What to Make of It?” back in March 2021, discussing arguments favoring and disfavoring this issue, with the conclusion that such issue isn’t an alarming problem. Let’s see why again iand what are the more recent developments.

What was the initial concern?

Jacob Wes Ulm, MD, Ph.D., a geneticist specializing in gene therapy, first emphasized that the biodistribution data of the LNP-encapsulated mRNA vaccine is lacking. (All mRNA vaccine mentioned herein refers to the Covid-19’s one that is encapsulated in LNPs.)

Assuming that the LNPs carried the mRNA vaccine into the brain, brain cells (e.g., neurons) might translate the mRNA into spike protein, which might then be marked as foreign by the immune system. With repeated vaccine boosters, more and more neurons might possibly be marked for destruction by the immune system over time.

This issue doesn’t have to involve brain cells but could be anywhere in the body where the mRNA vaccine might end up in. Dr. Ulm suspected the brain because LNPs of certain formulations are used to bypass the blood-brain barrier that blocks foreign matter, such as medical drugs or pathogens, from entering the brain. The BBB is lipid-soluble, after all, and LNPs are lipids.

Here is a summary of Dr. Ulm’s hypothetical concern that was published as a rapid response in the British Medical Journal (BMJ) in March 2021:

More recently, Botond Z. Igyártó, Ph.D., an associate professor in immunology and microbiology, and colleagues have raised similar concerns about the off-targets of mRNA vaccine. In a paper published in Current Opinion in Virology in June 2021, titled “Future considerations for the mRNA-lipid nanoparticle vaccine platform,” they wrote:

Based on the current mRNA-LNP vaccine design, LNPs can be taken up by almost any cell type, near or far from the site of injection, transfecting them with the antigen-encoding mRNA. Moreover, the mRNA used in these vaccines are nucleoside-modified to decrease inflammatory responses and increase its stability in vivo, allowing extended periods of mRNA translation. Also, a significant portion of the mRNA can be re-packaged and expelled from transfected cells in extracellular vesicles (EVs). These vesicles could reach cells far from the injection site, further increasing the number of cells translating the antigen and extending the duration of its expression.

*hyperlinks added based on the references cited in the paper.

Addressing the brain biodistribution concern

But animal studies, using luciferase visualization as a proxy for the cellular localization of mRNA vaccine, have shown that off-targets don’t really happen. In fact, the mRNA vaccine is mostly localized in the muscles (at the injection site), liver, spleen, and lymph nodes, with only very tiny traces ended up elsewhere such as the heart and brain.

These studies are detailed in my previous article:
Screenshot from “Concerns of Lipid Nanoparticle Carrying mRNA Vaccine into the Brain: What to Make of It?” published on 19 March 2021.SJ Yong (2021)

Such biodistribution patterns in animals are also consistent with the European Medicines (EMA) assessment reports and, more recently, the Japanese biodistribution study.

For example, the EMA report of Moderna’s mRNA vaccine stated that:

Low levels of mRNA could be detected in all examined tissues except the kidney. This included heart, lung, testis and also brain tissues, indicating that the mRNA/LNP platform crossed the blood/brain barrier, although to very low levels (2–4% of the plasma level). Liver distribution of mRNA-1647 is also evident in this study, consistent with the literature reports that liver is a common target organ of LNPs…. The mRNA constructs were not measurable after maximum 3 days in tissues other than the muscle, lymph nodes, and spleen (~25 hours in brain).

For Pfizer’s mRNA vaccine biodistribution, the EMA report stated that:

Over 48 hours, distribution from the injection site to most tissues occurred [presumably including the brain], with the majority of tissues exhibiting low levels of radioactivity…. Total recovery (% of injected dose) of radiolabeled LNP+modRNA outside the injection site was greatest in the liver (up to 21.5%) and was much less in spleen (≤1.1%), adrenal glands (≤0.1%) and ovaries (≤0.1%).

*bolded for emphasis

The Japanese biodistribution study of Pfizer’s mRNA vaccine has also found that 0.009% of the vaccine administered dose ended up in the brain at 48-hour. (This Japanese study has also been widely misused to push the notion that the mRNA vaccine could concentrate in the ovaries.)

(These biodistribution data are discussed more in-depth here: “Biodistribution and Spike Protein Safety of mRNA Vaccines: An Update.”)

So, yes, the EMA and Japanese Government did admit that tiny traces of the mRNA vaccine could enter other unintended tissues, including the brain. But no clinical signs of brain toxicity were noted.

For how long? I doubt there’s sufficient data but at least the EMA reported that Moderna’s mRNA vaccine is no longer detectable in the brain after about 25 hours. Plus, the abovementioned luciferase-based animal studies find that the mRNA vaccine’s activities last for a few days only, indicating that spike protein production from cells that received the mRNA vaccine would also last for a few days only.

So, overall, we see that the Covid-19 mRNA vaccines can get into the brain but in very tiny amounts that should be likely harmless and cleared within days.

Addressing the brain tropism concern

But why can’t the mRNA vaccine get into the brain easily? (Tropism refers to the tendency of a biological entity to move to a target, such as SARS-CoV-2’s tendency to infect the lower respiratory tract.)

For one, Dr. Goh Kiang Hua, MD, a consultant general surgeon and Fellow of the Royal College of Surgeons (FRCS), theorized that it isn’t easy for the mRNA vaccine to reach the brain all the way from the injection site.

The mRNA vaccine is injected into the muscles (intramuscular) at the arm. Muscles at the injection site are highly vascularized (numerous blood vessels) and densely packed with cells that can take up the mRNA vaccine. Assuming that some mRNA vaccine managed to bypass such cell denseness and enter the blood circulation, the mRNA vaccine still has to resist tremendous force as the heart pumps blood throughout the body.

“The left ventricle [of the heart] will expel the blood (with the LNPs) with great speed and force out into the aorta…If the LNPs disintegrate from the turbulence, the mRNAs will be rapidly destroyed by ribonucleases,” Dr. Goh said. “[But] those that remain intact will be sent to the WHOLE body.” Still, he further cautioned that “the structural integrity of these LNPs after being expelled from the left ventricle is doubtful.”

Second, the LNP of the mRNA vaccine is not the same as the ones used for drug delivery into the brain. The former is neutrally charged while the latter is positively charged (cationic) suitable for drug delivery into the brain.

In a paper in press in Drug Discovery Today, titled “Brain safety concerns of nanomedicines: The need for a specific regulatory framework,” Bartlomiej Szabat-Iriaka, presumably a postgraduate student, and Marc Le Borgne, Ph.D., a professor of medicinal chemistry, wrote:

Cationic [+ve charge] lipid NPs (LNPs) are frequently used as drug delivery systems because they can enter cells more easily compared with anionic [-ve charge] NCs. However, cationic LNPs are in general more toxic than anionic LNPs. [Cationic] LNPs are likely to increase brain vascular volume, to cause BBB damage, and potentially lead to the formation of cerebral edema. Some NMs, such as mRNA vaccines, contain optimized LNPs with an ionizable surface charge that is supposed to remain neutral at physiological pH. However, it cannot be ruled out that this surface charge might change in individuals with conditions that can cause pH variations….Thus, toxicity risks resulting from NM interactions with the BBB are not negligible.

Yes, it’s not negligible, as what scientists would say for most things for the sake of accuracy. Sure, people with pH disorders might alter the charge of the mRNA vaccine’s LNP, which might or might not be a problem. It’s might, as the authors stated, because this concern is purely speculative.

(For reference, conditions that can affect the body’s pH include (i) respiratory acidosis from chronic obstructive pulmonary disease, opiate abuse, severe obesity, or brain injury; (ii) metabolic alkalosis from vomiting, hypovolemia, or diuretic use; and (iii) respiratory alkalosis from panic attacks with hyperventilation, pulmonary embolism, pneumonia, and salicylate intoxication.)

Therefore, to conclude, the LNPs of mRNA vaccine are not designed to cross the blood-brain barrier. While minute traces of mRNA vaccine have been discovered in the brain of animals, they are of negligible consequences with no harmful consequences.

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