A noninflammatory mRNA vaccine for treatment of
experimental autoimmune encephalomyelitis
Christina Krienke, Laura Kolb, Elif Diken et al
Science 371, 145–153 (2021) 8 January 2021
Bottom Line:
The adaptive immune system can react to stimuli in multiple ways. These are described in more detail in the “Discussion” section below. Using a vaccination technique shown to be safe and effective in preventing severe COVID-19 in humans the authors of the above paper were able to alter immune responses in mice to myelin proteins in a way that protected the mice from developing experimental autoimmune encephalomyelitis (EAE), an animal model for MS.
The authors vaccinated mice with messenger RNA (mRNA) that coded for fragments (peptides) of two myelin proteins. They chose peptides that caused EAE when mice were immunized with the peptides. Two forms of mRNA were used for each peptide. One was a “normal” form, the other an altered form (m1Y mRNA) with a changed genetic sequence. As a result, the peptide produced was different from the normal peptide. Vaccination with the altered peptide resulted in an immune response that prevented and mitigated EAE, even after the illness had already developed. Vaccination with the normal mRNA had no effect on the course of EAE.
Most important were two additional observations. The first was that vaccination with myelin protein peptides did not affect immune responses to non-myelin peptides. In other words, vaccination did not cause a general immune suppression. Second, when mice were vaccinated with an altered mRNA for one disease-causing peptide, mice were still protected from EAE induced by the other myelin protein peptide. This phenomenon is called “bystander suppression.”
We don’t know what triggers MS. We do know that persons with MS have heightened immune responses to certain myelin protein peptides. Such responses may contribute to tissue destruction in the central nervous system. Vaccinating persons with MS with m1Y mRNA coding for myelin protein peptides implicated in MS, using a technique already shown to be safe and effective in humans, may prove to be a new and potent treatment.
Key Points:
1. A positive outcome of the SARS-CoV-2 pandemic was the amazingly rapid development of effective vaccines. One of the most effective vaccination techniques involves administration of messenger RNA that codes for the spike protein of the coronavirus. The mRNA is packaged in tiny fat particles called “lipid nanoparticles.” The authors of the above paper used this vaccination technique to induce an immune response in mice that protected them from developing an animal model of MS, experimental autoimmune encephalomyelitis (EAE).
2. T cells are major cells in the adaptive immune system. There are many different types of T cells. Some, called “effector T cells,” (Teff) have the ability to attack and kill injured or infected tissue. They also release toxic substances (cytokines) that increase inflammation and tissue damage. Other T cells have the ability to regulate Teff cells and release cytokines that reduce inflammation. These T cells are called “regulatory T cells” (Treg).
3. In a “normal” immune response both patterns of response are present, but in varying proportions. The proportions also change over time. Many factors are involved in determining which pattern of response predominates. One factor is the nature of the stimulant. Substances that stimulate specific immune responses are called “antigens.”
4. The authors of the above paper chose two myelin protein peptides as antigens. These peptides were chosen because they induce EAE when are immunized with them. For the sake of clarity let’s call the two EAE-inducing peptides (PLP139-151 and MOG35-55) Peptide #1 and Peptide #2.
5. The researchers prepared two “normal” mRNAs, each coding for one of the two peptides; they then prepared two slightly changed mRNAs by altering the genetic coding of the mRNAs. These altered mRNAs produced slightly altered peptides. They called the altered or modified mRNAs “m1Y mRNAs”.
6. Mice were vaccinated with either normal or altered mRNAs. Effects on the immune systems were very different. Vaccination with “normal” mRNA resulted in the stimulation and expansion of Teff cells and the release of inflammatory cytokines. Vaccination with the genetically modified m1Y mRNAs stimulated immune systems in an opposite fashion, inducing Treg cells which in turn released cytokines that reduced inflammation.
7. EAE was then induced in groups of mice with either Peptide #1 or Peptide #2. Some groups of mice were first vaccinated with “normal” mRNA to Peptide #1 or to Peptide #2. Other groups of mice were vaccinated with modified m1Y mRNA to Peptide #1 or Peptide #2.
8. Mice vaccinated with normal mRNAs had normal courses of EAE compared to unvaccinated mice. Mice first vaccinated with one of the two m1Y mRNAs either did not develop EAE or had a very mild form of illness. When vaccination was delayed until early EAE had already developed, vaccination with either of the two m1YmRNAs changed the course of disease, making it milder, and in some instances resulting in recovery.
9. The researchers also showed that vaccination with m1Y mRNAs had no effect on immune responses to antigens unrelated to the central nervous system. Thus, there was no general immune suppression, the suppression of EAE being “organ specific.”
10. Most importantly, the protective effects of vaccination with m1Y mRNAs were not limited to EAE caused by a specific peptide. Thus, mice that developed EAE after immunization with Peptide #1 were still protected from developing disease or having disease progression when vaccinated with m1Y mRNA specific for Peptide #2. The reverse was also true. This phenomenon is called “bystander suppression.”
11. The phenomenon of “bystander suppression” is especially important as it relates to a possible vaccine for persons with MS. We don’t know which myelin peptides, if any, are responsible for starting MS. We do know that persons with MS, after developing the illness, have higher than normal immune responses to certain myelin peptides. Such responses could be involved in the disease process.
12. If one were to vaccinate persons with MS with a m1Y mRNA specific for one of the myelin peptides implicated in MS, and this resulted “bystander suppression” of responses to other myelin or brain protein peptides, a dramatic and safe new therapy may emerge.
Discussion:
We have two immune systems, the innate immune system and the adaptive immune system. The innate immune system is “pre-programmed” to immediately respond to tissue injury and/or infection. The adaptive immune system, using different populations of immune cells and triggering mechanisms, responds to specific stimuli in several different ways. If stimulation is incomplete or insufficient, the immune system becomes “tolerant” to the stimulus and does not react. Another pattern of response results in high levels of inflammation and tissue destruction. Such a response can be beneficial at sites of infection or malignancy, but is destructive if directed against a host organ, such as the brain. The adaptive immune system can also respond in a way that is non-destructive, with the generation of immune cells and cytokines that are able to control or regulate its inflammatory and destructive components. Most adaptive immune system reactions involve a balance of both types of responses. As a result, most immune response can be controlled and limited.
What determines the balance between a highly inflammatory and destructive immune response and a non-destructive pattern? The answer is complex, but essentially it relates to how the immune cells are stimulated. It’s not enough for an immune cell to recognize a stimulating substance (called an “antigen”) via its surface receptor. The cell also needs additional “co-stimuli” to fully respond. The nature of the antigen, the type of co-stimuli and the degree of co-stimulation determine the pattern of the immune response.
The authors of the discussed paper changed the structures of two antigenic peptides (Peptide #1 and Peptide #2) derived from myelin proteins that induced experimental autoimmune encephalomyelitis (EAE). They did so by altering the genetic sequences of the “normal” coding mRNAs. When peptides coded for by the “normal” mRNAs were enclosed in lipid nanoparticles and used as vaccines, it stimulated a population of T cells (Teff) that secreted inflammatory cytokines. In contrast, peptides that resulted from vaccination with altered peptide mRNAs (m1Y mRNAs) stimulated a population of regulatory cells (Treg). These secreted anti-inflammatory cytokines.
Dramatic differences on the courses of EAE were observed with vaccination. Vaccination with m1Y mRNAs specific for either Peptide #1 or Peptide #2, before or after induction of EAE resulted in a dramatic reduction in the severity of disease and in some instances recovery. No such effect was noted when mice were vaccinated with unaltered or “normal” mRNAs.
Importantly, vaccination with m1Y mRNAs did not affect immune response to peptides unrelated to the brain. Also, most importantly, the researchers showed that the ability of Treg cells induced by vaccination with Peptide #1 were able to reduce disease induced Peptide #2, and vice versa. This phenomenon is called “bystander suppression.”
We don’t know what starts the tissue-destructive inflammation in MS. We do know that persons with MS have increased numbers of cells in their brains that respond to particular myelin peptides. Such immune responses could be contributing to the disease process. If this population of cells, and cells responding to other myelin antigens, could be suppressed via the phenomenon of bystander suppression, the course of the disease could be modified.
There have been other attempts using multiple techniques, to reduce Teff activity to myelin peptides in persons with MS . The clinical trials were small, with modest to no beneficial effects noted. We now know that mRNA vaccines are safe, potent and effective treatments against COVID-19 in humans. This increases the possibility of using such vaccination techniques to suppress anti-myelin responses in persons with MS, allowing the development of a potentially important and effective therapy.