Decoding the Long-term Effects of mRNA Vaccine

Shin

While the mRNA, spike protein, and lipid nanoparticle shouldn't pose any long-term health problems, it's a different matter for the immune response.

One of the primary drivers of hesitancy about the Covid-19 mRNA vaccine from Pfizer-BioNTech and Moderna is that it’s a new technology with no long-term safety data. Whereas traditional vaccine technology — such as inactivated, protein-based, and live-attenuated vaccines — has been used to combat infectious diseases for decades. 

So, we are relatively more comfortable and less worried about the safety of traditional than modern vaccine technology. We shouldn’t be surprised, though. After all, risk-aversion is a universal trait in humans and animals, built from eons of evolution. 

But should we really be that uncertain about mRNA vaccines? 

How mRNA vaccines work in brief

The central dogma of molecular biology states that DNA makes messenger RNA (mRNA) via transcription, and mRNA makes proteins via translation. 

The mRNA vaccine delivers the protein-coding mRNA inside the cell, capitalizing on the cell’s machinery to translate the mRNA into the desired protein. But mRNA is incredibly fragile and easily degradable. So, mRNA vaccines are encased within lipid nanoparticles (LNPs) to promote enough stability until the mRNA gets inside the cells. 

For the Covid-19 mRNA vaccine, the mRNA stores genetic codes for the modified spike protein of SARS-CoV-2 (the coronavirus that causes Covid-19). The cells (typically muscle cells at the injection site) that receive the mRNA vaccine are instructed to make the modified spike proteins, which helps the immune system build immunity. 

The immune system will then mount a more robust and efficient immune response the next time it encounters those spike proteins, such as during the actual virus infection. 

What could go wrong in the long term?

1. The mRNA

The mRNA supply is limited, and the cells will stop making spike proteins once the mRNA supply runs out. Multiple animal studies have already confirmed that the mRNA vaccine’s activities last for several days only. So, the limited amount of mRNA in mRNA vaccines gets used by the body quickly.

Ribonucleases are abundant in the body. They degrade RNA, including mRNA, outside of cells almost instantaneously, serving as a safety mechanism to prevent foreign mRNA from influencing what proteins a cell produces. So, we also don’t have to worry about mRNA escaping cells and triggering some unknown biomolecular effects. mRNA by itself can’t survive outside cells.

The mRNA doesn’t alter the human genome that’s DNA in nature. DNA and mRNA are different. For example, DNA is double-stranded and consists of deoxyribonucleotides, whereas mRNA is single-stranded and consists of ribonucleotides. Plus, there are no known transporters that can carry mRNA from the cytoplasm into the nucleus, where the DNA genome resides.

2. The spike protein

But will the manufactured spike proteins (from cells that receive the mRNA vaccine) harm us in the long run then? This concern is also unlikely as spike proteins denature naturally in the body. If this concern is actually a problem, then nearly all the Covid-19 vaccines will have the same problem. 

In fact, it’s actually the SARS-CoV-2’s spike protein that’s dangerous. One person infected with SARS-CoV-2 could produce 1–100 billion virus particles during peak infection, with each particle having numerous spike proteins on its surface. So, the spike proteins a SARS-CoV-2-infected person carries are just unimaginable. 

Plus, the Covid-19 mRNA vaccines contain the double proline mutations that keep the spike protein in a ‘closed’ state. The SARS-CoV-2’s spike protein, by contrast, can enter an ‘open’ state to bind to the ACE2 receptor to infect cells. Excessive binding and activation of ACE2 can cause blood clots, explaining why Covid-19 is also a vascular disease

So, in terms of spike protein, the real coronavirus poses a real threat but not the Covid-19 mRNA vaccine. (See here for more info on this topic: “Biodistribution and Spike Protein Safety of mRNA Vaccines: An Update.”)

3. The lipid nanoparticles (LNPs)

As mRNA can’t survive outside of cells due to its fragility and ribonucleases floating around (see section #1 above), mRNA vaccines use lipid nanoparticles (LNPs) to encase and deliver the mRNA into cells. 

LNPs have also been a controversial topic. LNPs have been used to bypass the lipid-soluble blood-brain barrier that blocks foreign substances from entering the brain, including life-saving medications. For this reason, the LNPs in mRNA vaccines have had biodistribution concerns: that is, where will the LNPs carry the mRNA vaccine into? 

Thankfully, multiple biodistribution studies in animals have confirmed that the LNP-encased mRNA vaccine doesn’t simply go whenever they want to. They are mostly localized in the injection site, lymph nodes, and liver (suggesting that mRNA vaccine is cleared via liver metabolism), with very minute amounts ended in other intended tissues, including the brain. 

But they are too minute to pose a threat as no toxicity effects were noted. For example, the European Medicines Agency (EMA) reported that about 2–4% of plasma levels of mRNA vaccine entered the brain of rats, but they were gone at 25-hour. Another animal study from the Japanese Government found 0.009% of the administered dose of mRNA vaccine in the brain at 48-hours; this number is similarly minute for other tissues. 

Looking at the LNP’s structure more closely tells us that the LNP (of mRNA vaccine) is neutrally charged on the surface. It’s not positively charged, and it doesn’t have the necessary coating to bind to interact with the blood-brain barrier. Being lipid-soluble alone isn’t a magic trait that can bypass the blood-brain barrier. (I detailed this matter more in-depth here: “mRNA Vaccine and the Brain: A Recap and Update.”)

4. The immune response

Here is the tricky part. Unlike the mRNA, spike protein, and LNP that have no mechanism in which they might possibly cause long-term harm, it’s a different matter for the immune response that can be long-lasting. 

The workings of the immune system can differ substantially between individuals. So, not everyone responds to vaccines the same way. Vaccines can generate a strong immunity in some and a weaker immunity in others. Known factors that influence vaccination responses include age, sex, comorbidities, genetics, pre-existing immunity, and personal stress levels.

Speaking of comorbidities and genetics, people with or at risk for autoimmune diseases might also be at risk for post-vaccine autoimmunity, also called Shoenfeld’s syndrome. But this appears very rare, estimated to occur in less than 0.01% of all vaccinations performed worldwide. 

Shoenfeld’s syndrome includes both symptoms (e.g., fatigue, muscle weakness, joint pain, sleep problems, cognitive impairments, and dry mouth) and disorders (e.g., arthritis, lupus, type I diabetes, thrombocytopenia, vasculitis, dermatomyositis, and Guillain-Barré syndrome). 

At least 300 cases of symptomatic Shoenfeld’s syndrome have been diagnosed and recorded in the international ASIA registry, mainly managed by physicians specializing in autoimmune disorders, as of December 2016. But it’s difficult to infer any cause-and-effect relationship from this registry that does not have a comparison or control group.

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In fact, authorities and large cohort studies have already cautioned that the Covid-19 DNA-based vaccines from AstraZeneca and Johnson & Johnson come with the risks of vaccine-induced thrombotic thrombocytopenia (VITT) and Guillian-Barre syndrome (GBS). VITT is an acute (short-term) disease of blood clots with low platelets, caused by autoantibodies targeting platelet factor 4 (PF4). GBS happens when the immune system attacks the peripheral nerves outside of the brain and spinal cord, causing symptoms like pain, prickling sensation in hands and feet, muscle weakness, poor coordination, and abnormal heart rhythm. GBS can last for several weeks or even years

Large cohort studies with proper control groups have estimated 38 excess cases of GBS per 10 million people vaccinated with the AstraZeneca’s DNA vaccine against Covid-19. (This number is 145 excess cases per 10 million people tested positive for SARS-CoV-2.) For VITT, it’s more difficult to estimate as it’s more complex; current estimates are 7–20 excess cases of VITT per 10 million people vaccinated with the Covid-19 DNA vaccine from AstraZeneca. So, both conditions are very rare and autoimmune in nature.

Other types of vaccines linked to GBS include the influenza inactivated vaccine and human papillomavirus recombinant vaccine. But the overall evidence on the causal relationship between vaccines and GBS is still highly debated. Whereas VITT is a novel condition coined just this year, so it’s not linked to other vaccines at present.

Therefore, long-term autoimmune disorders can happen after vaccination in a very rare subset of people, likely because of aberrant immune reactions against certain components of the vaccine. In other words, the immune system of a person may not be compatible with a given vaccine. 

But at least the Covid-19 mRNA vaccine has not been found to be associated with GBS, VITT, or any other long-term autoimmune disorders.

It’s also crucial to note that pathogens like viruses and bacteria can cause more serious and frequent long-term medical problems, such as chronic fatigue syndrome, pulmonary fibrosis (long-term lung scarring), post-sepsis syndrome, long-Covid syndrome, and Guillian-Barre syndrome.

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MSc Biology student | 5x first-author academic papers | 100+ articles on coronavirus | Freelance medical writer

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