Dechert LLP

[author: Charles Swingland]*

Albert Einstein said, “To raise new questions, new possibilities, to regard old problems from a new angle, requires creative imagination and marks real advance in science”. Despite tremendous progress in some fields, many new pharmaceutical products deliver modest incremental improvements for patients and real advances in medical science are sadly infrequent.

It is therefore very exciting that the success of the mRNA COVID vaccines has opened the door to long-awaited solutions for other widespread, life-threatening and debilitating diseases; an advance that could transform the standard of care of patients. There are many companies that are working with mRNA for the treatment of cancer and infectious diseases. The potential of nucleic acids to address these diseases has been recognized for more than 20 years. However, there are only two companies, Vaxerna and BioNTech, that are known to be working on mRNA vaccines to suppress an immune response rather than to deliver the protective immune response sought by most companies.

In line with Einstein’s suggestion, Vaxerna and BioNTech have indeed considered the old problem of autoimmune and allergic diseases from a new angle. These diseases profoundly damage the quality of life of sufferers and are potentially fatal. Everyone knows someone with multiple sclerosis, type 1 diabetes, rheumatoid arthritis or peanut allergy. Current treatments are expensive and usually address the symptoms but not the causes. At best, they slow the progress rather than alter the course of the disease.

Despite the apparent diversity of these diseases, they have in common an unwanted and inappropriate immune response. It will surprise some people that vaccines have the potential to stimulate or, alternatively, suppress an immune response and the creative advance which Vaxerna and BioNTech have made is to see the potential of mRNA in the suppression of immune responses or, more accurately, the induction of tolerance.

This is how it works. Thanks to COVID, most people will have heard of T-cells. These cells lie at the heart of the immune system and are a vital part of many immune responses. There are many different types of T-cells but they fall into two broad categories respectively called T-helper cells and T-regulatory cells. T-helper cells recognize proteins seen by the immune system as associated with pathogens. They then attack the pathogen. T-regulatory cells are part of the self-recognition process whereby the immune system does not respond to proteins from the host’s own tissues or harmless non-self-proteins, for example, proteins in food.

Healthy people have a quiescent immunological state. When a danger signal is detected, which is usually associated with inflammation, the body’s immune system will produce T-helper cells which are specific to a protein which it associates with the threat. This alters the equilibrium between the two classes of T-cells in favour of T-helper cells which, hopefully, destroy the pathogen. However, when the immune system encounters a protein in the absence of danger signals, it will see no threat and produce T-regulatory cells.

Vaxerna and BioNTech’s creative idea is to design vaccines for autoimmune and allergic diseases which induce production of T-regulatory cells to the proteins that the immune system is inappropriately attacking and thus restore tolerance to these proteins. To get the required response to the vaccines, they must be delivered at a time at which there is no inflammatory immune activity which the T-cells will see as a sign of danger. For example, in the case of autoimmune diseases treatment should take place during remissions and in the case of allergy, in the absence of the allergen which causes allergic disease. Unlike other mRNA vaccine approaches, these vaccines do not themselves create inflammation and accordingly generate the required T-regulatory tolerising response.

These new tolerising vaccines combine two technologies which are now well proven and appear made for each other. First, there is the evidence from COVID that shows that mRNA vaccines, which have been talked about for twenty years, actually work. Secondly, there is the long experience of allergy immunotherapy and, most notably, peptide immunotherapy. Powerful data has been produced showing that delivery of carefully selected peptides derived from allergens can suppress allergic symptoms for an extended duration when presented in the absence of inflammation. Patients were followed for two years after conclusion of treatment and the patients showed no signs of their allergy returning. Since the patients were not followed for longer the treatment cannot be called a cure, but other forms of allergen immunotherapy have shown amelioration of symptoms for seven years with no further treatment. Vaxerna will encode peptides derived from allergens into mRNA to deliver them with the same economy, convenience and efficiency that has been shown in the COVID vaccines.

In a paper, which was published in January this year, called “A non-inflammatory mRNA vaccine for the treatment of experimental autoimmune encephalomyelitis”, BioNTech showed that an mRNA vaccine encoding antigen peptide sequences associated with the mouse form of multiple sclerosis could prevent further disease progression and restore motor functions. This included the reversal of paralysis in some cases, although they attributed this mostly to the anti-inflammatory effect of the treatment rather than any tissue repair. Of course, scientists will say that you can cure a mouse of anything and that this will not necessarily translate to humans – and that is true. However, the reverse is just as true. If you can’t do it in a mouse it is unlikely that you will be able to do it in a human. BioNTech’s work is very important.

The combination of Vaxerna’s and BioNTech’s mRNA technologies offer long-lasting potentially disease-altering treatments for important conditions which are currently addressed by symptom suppression. The changes to the immune system brought about by these new mRNA tolerising vaccines may last for the patient’s life. What is more, their specificity means that other important immune responses are unaffected by the vaccines leaving the patient’s immune system intact – unlike many general immune-suppressant treatments offered for autoimmune and allergic diseases today.

By any standard, these new tolerising mRNA vaccines have the potential to mark a real advance in science and change the treatment paradigm for patients who currently have to manage their diseases for the rest of their lives.

*Chairman of Vaxerna Limited