Can Inverse Vaccines Cure Autoimmunity?

FOR MORE than two centuries, vaccines have worked to teach the immune system to recognize and attack outside intruders, thus protecting the body from severe infection. They are the first-line, preventive defense against disease, and have saved millions of lives. According to a study published in The Lancet, global immunization efforts have saved more than 154 million lives over the past 50 years alone. “Vaccines are among the most powerful inventions in history, making once-feared diseases preventable,” said Tedros Adhanom Ghebreyesus, PhD, director general of the World Health Organization.¹ First used to defend the body against smallpox, vaccines became a reliable method for defending against and ultimately eradicating the devastating infectious disease.¹

But like other medical breakthroughs, vaccine science isn’t static. Researchers are constantly trying to learn more about them and their promise, pushing the envelope to move from what is possible now to what could be possible next. Of particular interest: autoimmune disease. Millions of people suffer from these devastating diseases; more people are being diagnosed with them all the time; and there is no known cure for them. With both incidence and prevalence rising, it’s a significant problem.

Making matters worse, diagnosing and treating autoimmune diseases is notoriously complex and difficult. Overlapping and intermittent symptoms are common: Vague, general complaints such as fatigue, joint pain and skin rashes point to many diseases, not just one. And, symptoms often come and go, making confusion and misdiagnosis rampant. The lack of specificity in diagnostic tests makes pinpointing an exact disease state difficult, and finding a treatment to which patients respond takes trial, error and time. For the millions who live with autoimmune diseases, it is a frustrating and expensive cycle.

Researchers are turning their attention to vaccine technology, investigating whether it can be leveraged to help address the growing public health crisis. “Just as we can prevent infectious diseases with a traditional vaccine by turning on the immune response, could we turn off an unwanted immune response?” asks Lawrence Steinman, MD, an expert on autoimmune diseases and professor at Stanford Medicine whose research focuses on the promise and potential of inverse vaccines.² The driving questions behind the research: Can the immune system be trained to leave its own cells alone, and do inverse vaccines have the potential to transform the treatment of autoimmune disease, shifting the therapeutic goal from achieving remission to complete reversal?

A Complex, Costly Crisis

Researchers the world over are still trying to understand the root cause(s) for autoimmune diseases and develop targeted treatments to both relieve symptoms and prevent them from returning, but the answers are not always easy to pin down. When a diagnosis is made, treatments available focus on general immune system suppression to reduce overall inflammation and slow disease progression. Although these immunosuppressive treatments are the “gold standard” for managing autoimmune disease and provide relief for millions of patients, they put them at increased risk of infection and malignancy; patient response to them varies; and the treatments carry a hefty price tag.³

In fact, the estimated annual cost to collectively diagnose, treat and manage these diseases ranges between $100 billion to more than $168 billion every year.^4,5 This figure will certainly increase as more patients are diagnosed. But despite the enormous amount of money being spent, there are still unmet needs in autoimmune disease treatment and management, according to the National Institute of Allergy and Infectious Diseases (NIAID), including:⁶

• Immune therapies that are less toxic and create less risk of infection
• Precision approaches for selecting the right therapy for each person with autoimmune disease
• Treatment options for people who do not respond to current therapies
• Treatments that delay or prevent the onset of disease

Current treatments suppress the immune system and tamp down inflammation, which helps alleviate the symptoms of autoimmune disease, but they also come with side effects such as preventing necessary immune system responses to fight off infections and putting patients at increased risk of infection and cancers. Inverse vaccines do not suppress the immune system as a whole: They target the specific immune response that attacks a particular autoantigen. “If we could treat patients with an inverse vaccine instead, it could be much more specific and lead to fewer side effects,” Jeffrey Hubbell, PhD, the Eugene Bell Professor in tissue engineering at the University of Chicago’s Pritzker School of Molecular Engineering and lead author of the new study investigating inverse vaccines explained.⁷

According to a peer-reviewed paper published in 2012 in Science Translational Medicine that discusses our evolving understanding of autoimmune disease and the future of its treatment, understanding the way the body naturally trains itself to ignore its own cells is central to understanding how autoimmune disease develops, and using these processes for therapeutic benefit may provide exciting and novel targeted approaches to treat autoimmune disease.⁸ According to the paper, optimal therapy for autoimmune diseases would 1) target specific pathogenic cells without suppressing the immune system as a whole; 2) reestablish immune tolerance that remains stable over time; 3) have low toxicity and few side effects; and 4) be cost-effective and affordable compared to other treatment approaches.⁸ Inverse vaccines seem to offer the promise of meeting all of these requirements, and indeed may be the key to finding a cure.

Inverse Vaccines Explained

Traditional vaccines work by introducing pathogens such as an inactive version of a virus or bacterium into the body to imitate an infection. Molecules from the pathogen (antigens) used to incite the immune response are typically external, usually a weakened or dead bacteria particle or inactivated virus. These antigens stimulate the immune system and teach it to recognize and attack the foreign invaders, and thus defend the body against serious disease. Vaccines mimic the immune system’s natural process (recognize, attack, remember, defend).

Also called tolerogenic vaccines, inverse vaccines teach the immune system to tolerate its own antigens. Though similar to traditional vaccines, which introduce foreign antigens to the body with the purpose of teaching the immune system to recognize and attack them, inverse vaccines work the other way around: They work by introducing autoantigens — familiar, self-antigens — responsible for a given autoimmune disease and teaching the body to ignore them.³ Instead of introducing foreign antigens to stimulate an immune response  inverse vaccines introduce autoantigens to tell the immune system to remain calm.⁹

Encouraging Research

In a recent study at the University of Chicago’s Pritzker School of Molecular Engineering, researchers tested inverse vaccines to see if they could be used to reverse autoimmune diseases such as multiple sclerosis (MS). Specifically, they combined vaccine technology and the power of the body’s natural process of peripheral immune tolerance to teach the immune system to tolerate small bits of myelin from a disease similar to MS in mice in which the immune system attacked the myelin.⁷

Peripheral immune tolerance is a process that happens in the liver that prevents the immune system from reacting to every damaged cell in the body. Tagging molecules with a sugar known as N-acetylgalactosamine (pGal) mimics the body’s natural peripheral immune tolerance process by sending molecules to the liver where tolerance to them has already been acquired.³ Tagging target antigens with pGal mimics this natural process, sending the tagged molecules to the liver and tricking the immune system’s T cells to tolerate and protect target antigens rather than attack them.

In the mouse model, researchers tagged a myelin protein with pGal to mimic this process in mice with MS-like disease and found the immune system stopped attacking the myelin, reversed the autoimmune attack and restored nerve function.³ “The idea is that we can attach any molecule we want to pGal and it will teach the immune system to tolerate it,” explained Dr. Hubbell. “Rather than rev up immunity as with a vaccine, we can tamp it down in a very specific way with an inverse vaccine.”⁷ Their research showed the same approach worked to minimize other ongoing immune reactions as well.

The method has already been tested on human patients with celiac disease, and Phase I safety trials for use in multiple sclerosis are currently under way.⁷

A Curative Solution?

According to Dr. Hubbell, inverse vaccines represent an exciting opportunity to significantly shift treatment of autoimmune disease. “In the past, we showed that we could use this approach to prevent autoimmunity,” he said, “but what is so exciting about this work is that we have shown that we can treat diseases like [MS] after there is already ongoing inflammation, which is more useful in a real-world context.”⁷ Inverse vaccines could be given to patients who are known to have autoimmune disease, versus given to those who may or may not develop it later. “The best-case scenario is that inverse vaccines reprogram the immune system to permanently ignore the autoantigen, leading to long-term remission or even a cure for some diseases,” explained Rumiana Tenchov, PhD, DSc, an information scientist at the Chemical Abstracts Service (CAS), a division of the American Chemical Society (ACS).³ According to Dr. Tenchov, this approach would lead to fewer side effects (such as increased susceptibility to infections), more effective treatment, reduced treatment burden and, ultimately, better quality of life.³

Limitations

Inverse vaccines show an immense amount of promise, but they are not without challenges. Some 105 autoimmune diseases have been identified so far, but inverse vaccines are highly specific and do not offer a “one-size-fits-all” solution. Since they are targeted treatments that use autoantigens for specific disease states, it is yet unknown whether inverse vaccines can confer immunity for a wide swath of autoimmune diseases. So far, research has focused on reversing autoimmune disease once it has been diagnosed.

According to Dr. Tenchov, there are five major challenges to inverse vaccines, including:

• Autoantigen identification. Accurately pinpointing specific autoantigen(s) for each autoimmune disease is complex. Some diseases may involve multiple autoantigens, which makes it tricky to design a targeted vaccine.
• Vaccine delivery. Delivering vaccine tothe relevant antigen-presenting cells and making sure it reaches the targeted T cells involved remains difficult.
• High specificity. Even slight variations in the autoantigen’s presentation could lead to unpredictable immune responses.
• Clinical trials. Clinical trials are needed to determine safety, but they are lengthy and expensive.
• Long-term effects. We don’t yet know how inverse vaccines may affect people over time.

Looking Ahead

Despite the challenges, research presses on. Clinical trials for inverse vaccines in MS, celiac disease and type 1 diabetes have been conducted, and there is reason to be optimistic that inverse vaccines for these and many other autoimmune diseases could lead to long-term remission or even a cure. The global burden of autoimmune diseases is weighty; working toward a cure is a worthwhile endeavor.