Are We Confident in the Long-term Safety of mRNA Vaccines?

This article aims to summarize the essential knowledge we currently have about mRNA vaccine safety.

A significant factor contributing to hesitancy regarding the Covid-19 mRNA vaccines developed by Pfizer-BioNTech and Moderna is their status as new technology, lacking long-term safety data. In contrast, traditional vaccines—such as inactivated, protein-based, and live-attenuated vaccines—have been utilized for decades to combat infectious diseases.

Consequently, we tend to feel more secure about the safety of conventional vaccines compared to modern methods. This reaction is understandable, as risk aversion is an inherent trait in both humans and animals, shaped by countless years of evolution.

However, should we really harbor such doubts about the safety of mRNA vaccines?

How mRNA Vaccines Function

The foundational principle of molecular biology states that DNA is transcribed into messenger RNA (mRNA), which is then translated into proteins.

The mRNA vaccine introduces protein-coding mRNA into the cells, leveraging cellular machinery to create the desired proteins. However, mRNA is highly delicate and susceptible to degradation, necessitating its encapsulation within lipid nanoparticles (LNPs) for stability until it can enter the cells.

In the case of the Covid-19 mRNA vaccine, the mRNA encodes the genetic instructions for producing a modified spike protein of SARS-CoV-2, the virus responsible for Covid-19. The cells—typically muscle cells at the site of injection—are directed to produce these spike proteins, aiding the immune system in developing immunity.

This preparation enables the immune system to mount a stronger and more effective response upon subsequent exposure to those spike proteins, such as during a real viral infection.

Potential Long-term Concerns

1. The mRNA

   The supply of mRNA is finite; once it is depleted, the cells will cease to produce spike proteins. Animal studies have demonstrated that the mRNA vaccine's effects last only a few days. The body quickly utilizes the limited mRNA present in these vaccines.

   Ribonucleases, which are plentiful in the body, degrade RNA—including mRNA—almost instantaneously outside of cells. This mechanism serves as a safeguard against foreign mRNA influencing protein production within cells. Thus, we need not worry about mRNA escaping cells and causing unknown biological effects, as mRNA cannot survive outside of cells.

   Additionally, the mRNA does not alter the human genome, which is composed of DNA. DNA and mRNA are fundamentally different; for instance, DNA is double-stranded and made up of deoxyribonucleotides, while mRNA is single-stranded and consists of ribonucleotides. Moreover, there are no known transporters that can carry mRNA from the cytoplasm into the nucleus, where the DNA genome resides.

2. The Spike Protein

   Will the spike proteins manufactured by the cells that receive the mRNA vaccine be harmful in the long term? This concern is unlikely, as spike proteins naturally denature within the body. If this were a legitimate issue, all Covid-19 vaccines would face the same scrutiny.

   In reality, it is the spike protein of SARS-CoV-2 that poses a significant danger. An individual infected with SARS-CoV-2 can produce between 1 to 100 billion viral particles during peak infection, each particle adorned with numerous spike proteins. The quantity of spike proteins present in an infected person is astounding.

   Furthermore, the Covid-19 mRNA vaccines incorporate double proline mutations that keep the spike protein in a 'closed' configuration. In contrast, the spike protein of SARS-CoV-2 can shift to an 'open' state, allowing it to bind to the ACE2 receptor and facilitate infection. Excessive interaction with ACE2 can lead to blood clots, explaining why Covid-19 is also classified as a vascular disease.

   Hence, when considering spike proteins, the actual coronavirus poses a genuine risk, while the Covid-19 mRNA vaccine does not.

3. The Lipid Nanoparticles (LNPs)

   Given that mRNA is fragile and cannot survive outside of cells, lipid nanoparticles (LNPs) are employed to encapsulate and deliver the mRNA into cells.

   LNPs have raised some controversy. They have been used to navigate the lipid-soluble blood-brain barrier that restricts foreign substances from entering the brain, including essential medications. As a result, concerns have emerged regarding the biodistribution of LNPs in mRNA vaccines—specifically, where the LNPs will transport the mRNA.

   Fortunately, multiple animal biodistribution studies have confirmed that LNP-encased mRNA vaccines do not disperse indiscriminately. They predominantly remain localized at the injection site, lymph nodes, and liver (indicating that mRNA vaccine clearance occurs via liver metabolism), with only trace amounts detected in other unintended tissues, including the brain.

   These trace amounts are negligible and pose no danger, as no toxic effects have been reported. The European Medicines Agency (EMA) indicated that around 2–4% of the mRNA vaccine plasma levels reached the brains of rats, but these levels dissipated within 25 hours. Another study from the Japanese Government found only 0.009% of the administered mRNA vaccine dose in the brain after 48 hours, a similarly minuscule amount for other tissues.

   Examining the structure of LNPs reveals that they are neutrally charged on the surface. They lack a positive charge and do not possess the necessary coating to interact with the blood-brain barrier. Being lipid-soluble alone does not guarantee passage through this barrier.

4. The Immune Response

   This aspect is more complex. Unlike the mRNA, spike proteins, and LNPs, which lack mechanisms for potential long-term harm, the immune response can be enduring.

   Individual immune responses can vary significantly, meaning not everyone will react to vaccines in the same way. Factors influencing these responses include age, sex, existing health conditions, genetics, pre-existing immunity, and stress levels.

   Individuals with autoimmune diseases or those at risk may face a slight risk of post-vaccination autoimmunity, known as Shoenfeld’s syndrome. However, this appears to be exceedingly rare, with estimates suggesting it occurs in less than 0.01% of all vaccinations globally.

   Shoenfeld’s syndrome can manifest through symptoms like fatigue, muscle weakness, joint pain, sleep disturbances, cognitive impairments, and dry mouth, along with disorders such as arthritis, lupus, type I diabetes, and Guillain-Barré syndrome.

   As of December 2016, at least 300 symptomatic cases of Shoenfeld’s syndrome have been documented in the international ASIA registry, primarily managed by specialists in autoimmune disorders. However, establishing a cause-and-effect relationship from this registry is challenging due to the absence of a control group.

   Authorities and extensive cohort studies have warned that the Covid-19 DNA-based vaccines from AstraZeneca and Johnson & Johnson carry risks of vaccine-induced thrombotic thrombocytopenia (VITT) and Guillain-Barré syndrome (GBS) shortly after vaccination.

   VITT is an acute condition characterized by blood clots combined with low platelets, driven by autoantibodies targeting platelet factor 4 (PF4). GBS occurs when the immune system attacks peripheral nerves, leading to symptoms like pain, tingling sensations, muscle weakness, and abnormal heart rhythms that can persist for weeks or even years.

   Researchers estimate that there are 38 excess cases of GBS per 10 million people vaccinated with the DNA vaccine from AstraZeneca. In comparison, this number rises to 145 excess cases per 10 million individuals who test positive for SARS-CoV-2. Current estimates for VITT suggest 7–20 excess cases per 10 million people vaccinated with AstraZeneca's DNA vaccine.

   Consequently, long-term autoimmune disorders could potentially arise after vaccination in a very small fraction of individuals, likely due to atypical immune reactions to specific vaccine components. This means that an individual's immune system may not be compatible with a particular vaccine.

   If such post-vaccination autoimmune issues were to arise, they would likely manifest within a month of vaccination. The innate and adaptive immune systems begin responding to vaccines within hours and weeks, respectively, so any reactions would not occur months or years later, as the vaccines would no longer be present in the body. Unlike medical drugs, which can accumulate and lead to prolonged side effects, vaccines are administered one dose at a time.

   Importantly, the Covid-19 mRNA vaccine has not been associated with GBS, VITT, or other long-term autoimmune disorders.

   Additionally, it’s essential to recognize that pathogens like viruses and bacteria can lead to more severe and frequent long-term health issues, including chronic fatigue syndrome, pulmonary fibrosis, post-sepsis syndrome, long-Covid syndrome, and Guillain-Barré syndrome.