Inverse vaccines: a new hope for millions of patients with autoimmune diseases

What are inverse vaccines?

Clinical disorders like autoimmune and autoinflammatory diseases, as well as allergies, arise from inappropriate immune reactions and misdirected inflammation. Existing therapies for these conditions, which include non-specific immunosuppressive drugs and supportive treatments, necessitate ongoing treatment and can lead to substantial side effects.

Inverse vaccines are one antigen-specific approach to induce the tolerance to a specific antigen. Unlike a traditional vaccine that instructs the immune system to identify a virus or bacteria as a threat that needs to be combated, an inverse vaccine is a therapeutic vaccine and works differently, by recognizing an antigen as a friend and thereby teaching the immune system to stop attacking the body’s own tissues.

They suppress the adverse response through deletion, inhibition or deviation of antigen-specific effector T cells and aiding in the initiation and/or growth of antigen-specific T regulatory cells.

What vaccine strategies have been studied to develop inverse vaccines?

The concept of inverse vaccine isn’t new. Fifteen years ago, Dr. Lawrence Steinman of Stanford University School of Medicine in California firstly introduced the term “inverse vaccination”. He managed to test his two DNA inverse vaccines in clinical trials but was unable to demonstrate that it was more effective than the existing standard-of-care drugs.

In 2021, Dr. Krienke and her fellows explored a mRNA vaccine in experimental mouse models of multiple sclerosis and were able to show that vaccination delayed or decreased the severity of immune mediated injury.

The latest well-known strategy is communicated in Sep. 2023 and developed by Prof. Jeffrey Hubbell and fellow researchers at the University of Chicago’s Pritzker School of Molecular Engineering (PME). Their novel inverse vaccine leverages the liver’s inherent mechanism of tagging molecules from degraded cells, with a sugar known as N-acetylgalactosamine (pGal) and “do not attack” signals to avert autoimmune responses to cells that perish through normal processes.

The concept of inverse vaccines is moving forward by the increasing engagement of industry players. Start-ups like Anokion, COUR Pharma and Imcyse as well as large players like Pfizer, Bristol Myers Squibb, Novartis, Roche and Boehringer Ingelheim have already established a presence in this field.

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What benefits can inverse vaccines bring to patients?

Inverse vaccines offer several potential benefits for patients with autoimmune diseases.

Targeted approach

A study reported that the rate of infection was especially high in patients receiving several courses of certain biological agents and in patients with severe infections, survival was significantly reduced.¹https://arthritis-research.biomedcentral.com/articles/10.1186/ar3397 Inverse vaccines specifically target disease-associated antigens without leaving the patient vulnerable to infections.

Reduced side effects

Traditional treatments for autoimmune diseases often involve drugs that suppress the entire immune system, leading to a range of side effects. For example, damage to the heart muscle, headaches, seizures, kidney failure, etc. Inverse vaccines aim to avoid these by targeting only the problematic immune responses.

Applicability to various diseases

The same basic approach could potentially be adapted to treat a variety of autoimmune diseases. As of today, the pipeline covers not only multiple sclerosis and type 1 diabetes but also other autoimmune diseases such as celiac disease, Primary Biliary Cholangitis, Graves’ disease, Vitiligo and Myasthenia Gravis.

What are challenges ahead?

Determining the critical antigen for a given disease

Autoimmune disorders are caused by physiologic immune responses to autoantigens. In conditions where we understand the disease mechanisms and identify the problematic autoantigens, it’s theoretically possible to alter these pathways to promote immune system tolerance to these self-antigens, for instance, in multiple sclerosis and type 1 diabetes.

However, for most autoimmune diseases, we still do not have enough understanding of the mechanism. For instance, in inflammatory bowel disease and psoriasis, there is no consensus on what the autoantigen is.

Dealing with difficult clinical trial designs

While there have been encouraging advances, the promising animal studies of inverse vaccines have not yet been translated into clinical efficacy. To design clinical trials for further testing, in addition to choose an appropriate disease and determine the critical antigen for designing a clinical trial, there are still questions not yet answered regarding the mechanism of the existing inverse vaccine strategy. According to the immunologist Jane Buckner of the Benaroya Research Institute, the latest inverse vaccine is “a good first step,” but the mechanisms that produce tolerance remain poorly understood.

To conclude, the emergence of inverse vaccines marks a promising step in the battle against autoimmune diseases, offering a beacon of hope for millions of individuals worldwide burdened by these debilitating conditions. However, despite these remarkable advancements, challenges persist. We at Alcimed will keep you updated with further development of inverse vaccines. Should you have any question or project on this topic, do not hesitate to contact our team.

About the author, 

Chaoyue, Senior Consultant in Alcimed’s Life Sciences team in France