Potential mRNA vaccine for MS
Posted on Feb 17, 2021
Potential Multiple Sclerosis mRNA Vaccine
BioNTech in Germany is one of two companies (the other being Moderna in the US) that have successfully developed mRNA vaccines against SARS-CoV-2, the virus responsible for COVID-19. BioNTech has now published research1 done in collaboration with researchers from Johannes Gutenberg University (Mainz, Germany) demonstrating in mice that another mRNA vaccine it has developed may eventually become a successful treatment for multiple sclerosis (MS) in humans.
MS is an often disabling, although rarely fatal, autoimmune disorder of the central nervous system in which autoreactive T lymphocyte cells of the immune system erroneously attack and damage the myelin sheath that surrounds and protects nerve cells. There is no current cure for the disorder, which is experienced by an estimated 1 million persons in the US, with women three times more likely to contract MS than men. Existing treatments systemically suppress the immune system. While these do work somewhat on MS symptoms, they have the side-effect of creating vulnerability to infections.
The BioNTech research was conducted using an MS model known as experimental autoimmune encephalomyelitis (EAE), a pathology induced by immunizing mice with a myelin glycoprotein. As with the vaccine against SARSCoV2, a lipid nanoparticle was used to optimize delivery of the mRNA to lymphoid tissue-resident CD11c+ antigen-presenting cells (APCs). Also, in common with the COVID19 vaccine, a key aspect of making an autoimmune encephalomyelitis-protective vaccine was the use of a modified uridine ribonucleoside, 1methylpseudouridine (m1Ψ), in the encoding of the antigen used to vaccinate the mice.
Administration of native mRNA vaccines can result in activation of Toll-like receptors (TLRs) leading to strong T helper cell responses driving inflammation. However, mRNA with the modified ribonucleoside will not bind to TLR7, which greatly reduces the induction of inflammatory cytokines and activation of immune cells seen in negative controls using mRNA without the modified ribonucleoside. The muted response allows for higher and prolonged expression of the vaccine antigen, myelin glycoprotein, thereby allowing the immune system to tolerate specific MS-related proteins without depressing normal immune function.
The experimental protocol for induction of experimental autoimmune encephalomyelitis in mice was the injection of a peptide derived from myelin oligodendrocyte glycoprotein (MOG35–55), and this was the antigen encoded by the mRNA vaccine. Mice that had been vaccinated prior to receiving the induction peptide were completely protected from developing experimental autoimmune encephalomyelitis. Even more encouraging was that vaccination of mice with experimental autoimmune encephalomyelitis already established experienced no further progression of their disease, and in some cases even saw some reversion of symptoms.
The vaccine was also effective against experimental autoimmune encephalomyelitis induced with a peptide from a different myelin molecule, proteolipid protein (PLP139151), an indication that the treatment promotes “bystander tolerance.” Bystander tolerance is provided by regulatory T (Treg) cells by suppressing the activity of T helper cells against antigens in the inflamed tissue. Such inhibition is key to treatment of a complex autoimmune disease like MS in which specific self-antigens may vary from patient to patient. However, administration of the vaccine did not impact immune responses to completely unrelated antigens. Single-cell sequencing revealed that the vaccine induced specific suppression of disease-promoting T helper cells via the de novo induction of Treg cells, rather than by deletion of autoreactive cells. Interestingly, “checkpoint inhibitors” proteins PD1 and CTLA4, well known for their activity to allow the immune system to recognize and destroy cancer cells, appeared to be involved in this suppression of T helpers in experimental autoimmune encephalomyelitis. When these co-inhibitory molecules were blockaded, the protective effect of the vaccine was nearly abolished, and elements of the immune system began to attack cells presenting the myelin oligodendrocyte glycoprotein (MOG peptide).
CEO Ugur Sahin, also listed as senior author on the paper, founded BioNTech as a cancer vaccine company with the stated goal of individualizing cancer medicine using mRNA vaccines that are quick to design and can readily code for virtually any antigen. Therefore, it is not surprising that the authors propose in the discussion, “Thus, tailoring the treatment for the disease-causing antigens of individual patients is conceivable, similar to that which has been successfully executed in the setting of personalized cancer vaccines.” Without referencing what disorders, they might have in mind (as the current study involves a single antigen vaccine), the manuscript concludes with the suggestion that combinations of mRNAs “encoding either multiple personalized autoantigens or autoantigens that confer bystander tolerance may enable control of even complex autoimmune diseases.”
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1Krienke C, Kolb L, Diken E, et al. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science. 2021 Jan 8; 371(6525):145-153.