Spike Proteins Used in Covid-19 Vaccines: Are They Safe?
Although studies have found harmful effects of SARS-CoV-2 spike proteins, the proper interpretation is key.
Within a year of the pandemic, science has developed many vaccines for Covid-19, with a few already gaining FDA authorization for public emergency use. But many are still worried about the potential undiscovered side effects of such vaccines, which this article aims to address.
All candidate vaccines —the mRNA, DNA, viral vectored, recombinant protein, viral-like particles, and peptide-based vaccines—use the coronavirus’s spike protein to induce immunity in some way or another. Even live attenuated and inactivated vaccines using the whole virion (in a weakened form) still rely on the spike protein, at least partly, to induce immunity.
The CDC has stated that the spike protein of SARS-CoV-2 is harmless, which assures that current Covid-19 vaccines would be safe. But recent studies — in animals and cultured cells — have found that this may not be entirely true, although we must interpret these studies more cautiously.
Before going further, the conclusion in this article is that Covid-19 vaccines are still most likely safe. It’s not 100% safe as some at-risk people may show allergic or other unpleasant reactions to it. So, this article will make sense of what studies showing the harmful effects of SARS-CoV-2 spike protein mean for the safety of Covid-19 vaccines.
(Note: The spike protein of SARS-CoV-2 is made up of two portions, which are S1 and S2. The S1 binds to the ACE2 receptor on the human cell surface, and S2 initiates membrane fusion to complete cell infection.)
Spike protein and the brain
A study titled “The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice” was published in Nature Neuroscience this month. Herein, researchers at the University of Washington inoculated a dose of S1 portion of SARS-CoV-2 spike protein — without the whole virion or genome — into the blood or nose of adult age mice.
When injected into the bloodstream, the study found that the spike proteins were gradually cleared from the blood but got uptaken by the brain. After performing a series of experiments, the study discovered that SARS-CoV-2 spike proteins cross the blood-brain barrier via adsorptive transcytosis. In this process, the protein — in this case, the spike proteins — enters the cell through its surface glycoproteins.
Whether the ACE2 receptor — which SARS-CoV-2 normally uses to infect cells in the lungs — is involved in the brain uptake of spike proteins is uncertain. Administering ACE2 into the mice to occupy the ACE2 receptors did not block spike protein entry but rather enhanced it. And the mechanisms responsible for this remain unclear.
Notably, inducing inflammation in the mice with lipopolysaccharide (LPS; a bacterial toxin) treatment further enhanced the brain uptake of spike proteins. This is because the inflammation had disrupted the blood-brain barrier integrity, making it more permeable to foreign invaders.
When nasally inoculated, the spike proteins also invaded the brain, but to a lesser extent than when injected into the blood. Interestingly, only <1% of the spike proteins from the nose entered the blood. This suggests that spike proteins can enter the brain through the olfactory (smell sensing system) route, without the need to bypass the blood-brain barrier defense.
Overall, in mice, the spike protein of SARS-CoV-2 has the ability to cross the blood-brain barrier. But that’s the extent this study shows. What happens after that was not studied. For example, will the mice became sick and show neurological symptoms or behavioral abnormalities like cognitive impairments or appetite changes? Or will the mice's brain respond to the spike proteins with unhealthy levels of inflammation?
Lastly, this study also did cell culture experiments. Since mice are not humans, as the researchers admitted, they cultured human endothelial cells that mimic the human blood-brain barrier. Contrary to expectations, they found that the spike proteins did not penetrate the human endothelial cells. This negative result, the authors suggested, could mean two things:
- The cell model is not suitable for studying SARS-CoV-2 spike proteins.
- The SARS-CoV-2 spike proteins alone cannot cross the blood-brain barrier in humans, which contradicts the animal experiments' findings.
Spike protein and blood vessels
Last month, the study “SARS-CoV-2 spike protein-mediated cell signaling in lung vascular cells” was published in Vascular Pharmacology. Researchers at Georgetown University Medical Center found that the S1 portion of SARS-CoV-2 spike protein — without the whole virion or genome — triggered growth signals in cultured human blood vessels from the lungs.
In human blood vessel cells, the MEK/ERK pathway that initiates cell growth was activated in response to the spike proteins. This is consistent with the autopsy analyses that the same study also performed, where the blood vessel walls in deceased patients from Covid-19 were twice as thick than influenza cases — i.e., 15.4 vs. 6.7 μm. This study suggests that SARS-CoV-2 spike proteins may activate blood vessel growth, leading to vascular thickening.
“The present study shows that cell growth signaling may be triggered by this virus in both cultured cells and in Covid-19 patient samples,” the authors stated. “We propose that SARS-CoV-2 spike protein-mediated cell signaling promotes the hyperplasia and/or hypertrophy of vascular smooth muscle and endothelial cells, contributing to the complex cardiovascular outcomes in Covid-19.” (Vascular means blood vessels.)
Implications for vaccine safety
But, at this point, there’s no concrete evidence that SARS-CoV-2 spike proteins are dangerous to humans. It’s only in animal and cell culture experiments, as well as autopsy observations, that SARS-CoV-2 spike proteins may be harmful. These studies, however, do not prove the same in humans or that the same applies to vaccine-introduced spike proteins.
It’s also crucial to understand that optimizations —trial and error to set up the right experimental conditions to get desirable results — are normal for cell culture and animal studies. . Therefore, even if such results apply to humans, the effect size may not be as potent. Not to mention that dosage used in experimental settings may not reflect real-life settings.
Let’s take the FDA-authorized Moderna’s and Pfizer’s mRNA vaccines for Covid-19 as examples. Upon injection into muscle cells, the mRNA genetic code enters the cell and gets translated into spike proteins. These spike proteins then train the immune system to mount proper immune responses and form immunological memory to SARS-CoV-2. “COVID-19 mRNA vaccines give instructions for our cells to make a harmless piece of what is called the “spike protein,” the CDC stated. It’s harmless because the coronavirus can’t hijack the cell’s replication machinery without its genome.
As mRNA is extremely fragile and does not enter the cell nucleus or genome, it gets degraded easily and has strict storage conditions and a short lifespan. In animal and cell culture research, the mRNA vaccines induced the highest protein production within 48 hours and declined soon after. Thus, mRNA-indued protein production is short-term. As follows, any harmful effects of the spike proteins will be observable within a few days.
Indeed, flu-like symptoms — such as fever, chills, fatigue, and headache — may happen within 1–2 days following Covid-19 mRNA vaccination. Rare allergic reactions may also happen within a few minutes of vaccination. But no prevalent life-threatening side effects have been documented in clinical trials of Covid-19 mRNA vaccines, at least in the span of two months. This is assuring as mRNA-induced spike protein production should be gone by then, at least in animal findings and according to rules of mRNA genetics.
Besides, human clinical trials have found potent B-cell and T-cell immune reactions specific for the SARS-CoV-2 spike proteins within a few days of receiving a given mRNA vaccine. This indicates that any spike proteins the Covid-19 vaccines introduce are quickly taken care of by the immune system. Perhaps the mRNA vaccines make our cells produce spike proteins in safe amounts that are favorable for training the immune system.
Short abstract
With the advent of many Covid-19 vaccines in a short time, it’s expected that their long-term safety is questioned. All Covid-19 vaccines use the coronavirus spike protein to induce immunity in some way or another. But recent studies have found that coronavirus spike proteins alone — without the whole virion or genome — are sufficient to induce biological abnormalities in brain and blood vessel cells. However, these studies have to be put in proper contexts and interpreted carefully before any generalization to humans. Besides, mRNA is short-lived, which makes our cells produce the coded proteins for about 48-hour only. So, any side effects of mRNA vaccines will be observable within a few days. This is reassuring as we currently have good safety data of Covid-19 mRNA vaccines for up to two months.
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