Lipid-based Vaccines Have a Catch!
Don’t Judge a Book by its Cover
Vaccines are a powerful tool used to treat diseases such as cancer and COVID-19. A vaccine does this by expressing a part of or a weakened form of a microorganism to humans.
However, all that glitters is not gold. Vaccines that are made out of fatty acids (lipids) can create a massive storm of protective molecules that do more harm than good to our immune system.
At first, this sounds a bit contradictory. Why would an excess of protection be harmful to our body? Picture this: there is an uncontrollable natural disaster that you cannot contain. On the same token, an excess of protective molecules in our body called cytokines can create a cytokine storm. If not monitored, a cytokine storm can lead to an unstoppable series of symptoms unleashing inside of us.
To investigate this problem further, a recent study led by Tahtinen and several authors saw how an RNA-lipid vaccine, which contains genetic information surrounded by fatty acids, worked in humans and mice.
To their surprise, they found that only mice are equipped with resistive molecules that rescue them from a cytokine disaster.
Before we dive into this discovery, let’s first describe how an RNA-lipid vaccine normally behaves in humans.
INTERLEUKIN-1 RESPONDS TO THE LIPID
Like any other superhero, lipid vaccines need a partner in crime to carry out its tasks. This is interleukin-1. Interleukin-1 is expressed because the body is triggered by the lipid formulation of the vaccine.
To humans, the lipid is seen as a stranger since it resembles a part of a foreign microorganism. Therefore, in response to the lipid, interleukin-1 gets expressed in the body. Later, interleukin-1 can bind to a receptor, or a particular region of the cell, called an interleukin-1 receptor.
HOW DOES A LIPID VACCINE WORK?
On top of interleukin-1 being expressed, the interaction between interleukin-1 and its receptor also causes interleukin-1β to be released. You can think of interleukin-1β as a type of interleukin-1.
Interleukin-1β is a special activator. Why? Because it is the first molecule to activate its teammates tumor necrosis factor and interleukin-6. Both of these molecules are responsible for triggering the cytokine storm!
In addition to the storm, the lipid part of the vaccine triggers an inflammasome, or a factory to form. This factory contains toxic oxygen molecules which spike calcium levels inside cells. This event is extremely important as it contributes to the cytokine storm.
Now that we know how the lipid vaccine functions, how do mice tolerate the RNA-lipid vaccine better than humans? Well, let’s find out.
INTERLEUKIN-1RA: THE SHIELD AGAINST A STORM
Mice defend themselves against the vaccine by expressing high levels of interleukin-1 receptor antagonist, which reverses the effects of a cytokine storm.
As if in a race, interleukin-1 receptor antagonist and interleukin-1 compete to see who attracts the interleukin-1 receptor the best. Thus, by preventing interleukin-1 from binding to its key receptor, interleukin-1 receptor antagonist can protect mice from out-of-control inflammation.
THE MODERNA VACCINE CONTAINS LIPIDS TOO?
Along with interleukin-1β and the presence of lipid, did you know that the type of lipid used in RNA vaccines can determine a cytokine storm’s fate?
• The lipid used in the Moderna COVID-19 vaccine can cause the release of interleukin-1β and initiate the formation of the inflammasome/factory. This type of charged lipid can lead to a strong immune reaction!
• When the lipid is structured as a sac to carry modified RNA, there is barely any immune response.
• Conversely, the lipid itself (without RNA) could still trigger receptors in the cell to recognize foreign particles.
Hence, these examples emphasize the power of the lipid component in an RNA vaccine to trigger a cytokine storm.
LIPIDS AND THEIR IMPORTANCE FOR VACCINE DESIGN
So what else explains how mice are more tolerant towards RNA-lipid vaccines compared to humans?
One reason is because of evolutionary history. Since mice may have experienced different living conditions, this would allow mice to acquire the necessary skills for tolerating a lipid vaccine.
Another reason is that humans naturally have more monocytes, or disease-killing cells, than mice. These cells also happen to generate interleukin-1β.
For future work, researchers should explore alternatives to the composition of lipid structures in vaccine design. By creating a safer and productive vaccine, the destructive effects of cytokine storms may be prevented!
To learn more about this topic, I suggest reading the Nature article, from which I took information while researching for this blog post. Thank you to Austin Mardon for providing his insight into a draft of this blog post.
Figure 1. An RNA Vaccine. Image: Medigene Press SL
Figure 2. Interleukin-1 Receptor Antagonist leads to reduced IL-1 signaling. Image: LookForDiagnosis.com
Interleukin 1 Receptor Antagonist Protein. (n.d.). lookfordiagnosis. Retrieved from lookfordiagnosis.com/mesh_info.php? term=interleukin+1+receptor+antagonist+protein&lang=5.
Medigene Press SL. (2019). Rna vaccine. genotipia. Retrieved from https://genotipia.com/genetica_medica_news/atrofia-muscular-espinal/rna- vaccine-4/.
Tahtinen, S., Tong, A.-J., Himmels, P., Oh, J., Paler-Martinez, A., Kim, L., Wichner, S., Oei, Y., McCarron, M. J., Freund, E. C., Amir, Z. A., de la Cruz, C. C., Haley, B., Blanchette, C., Schartner, J. M., Ye, W., Yadav, M., Sahin, U., Delamarre, L., & Mellman, I. (2022). IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines. Nature Immunology. doi.org/10.1038/s41590-022-01160-y