Inverse Vaccines: Teaching the Immune System to Tolerate

Inverse Vaccines: Teaching the Immune System to Tolerate

Prepared by the Hesperion Research Team For decades, vaccines have trained the immune system to recognize and attack pathogens. But what if we could create the opposite — a therapy that teaches the immune system to ignore a harmless antigen and stop autoimmune attack? This is the promise of inverse vaccines, also called tolerogenic vaccines. In the past two years, several breakthroughs have brought this idea closer to reality.

1) What Are Inverse Vaccines?

Inverse vaccines are designed to induce immune tolerance to specific antigens rather than activating an immune response. They typically work by presenting autoantigens in a way that mimics normal cell death or directs them to tolerogenic organs like the liver. Instead of generating inflammation, the immune system “learns” that these proteins are harmless, turning down autoreactivity while leaving normal immunity intact.

2) Landmark Study: KAN-101 in Celiac Disease

In 2024, Anokion presented results of their phase 1 trial of KAN-101, a tolerogenic therapy for celiac disease. KAN-101 delivers gluten peptides directly to the liver, teaching the immune system not to attack them. The findings were important:

• Demonstrated safety and tolerability in humans.
• Evidence of immune tolerance induction to gluten antigens.
• Currently advancing into phase 2 to evaluate clinical benefit in real-world dietary gluten exposure.

This represents the first time an inverse vaccine showed safety and biological activity in a human autoimmune disease.

3) Expanding to Type 1 Diabetes and Multiple Sclerosis

Beyond celiac disease, inverse vaccine strategies are being tested in other autoimmune conditions:

• Type 1 Diabetes (T1D): Preclinical work with mRNA–lipid nanoparticles (LNPs) encoding insulin peptides has shown restoration of tolerance in NOD mice. Human trials are anticipated within the next few years.
• Multiple Sclerosis (MS): Tolerogenic nanoparticles carrying myelin antigens have demonstrated reduction of disease severity in mouse models. Early-stage human studies are being designed.

4) Mechanisms of Action

• Liver targeting: Antigens directed to the liver are processed by tolerogenic antigen-presenting cells, inducing regulatory T cells instead of effector T cells.
• Apoptotic mimicry: Nanoparticles coated to resemble dying cells send a “do not attack” signal to the immune system.
• Antigen specificity: Unlike broad immunosuppression, tolerance is induced only for the targeted antigen, preserving immune defense against infections.

5) Opportunities and Challenges

• Precision medicine: Works best in diseases with well-defined autoantigens (celiac disease, T1D, MS).
• Safety profile: Early studies suggest lower risk of infections compared to global immunosuppression.
• Durability: Key open question — how long does tolerance last after treatment stops?
• Translation to complex diseases: In conditions with many antigens (e.g., lupus, RA), inverse vaccines may need multi-antigen approaches.

6) Clinical Implications Today

• Celiac disease: Phase 2 trials are ongoing; KAN-101 could become the first disease-modifying therapy for patients.
• Other autoimmune diseases: Still in preclinical or early clinical development, but highly promising.
• Research directions: Development of biomarkers of tolerance (e.g., regulatory T-cell expansion, antigen-specific assays).

7) Hesperion’s Perspective

• Inverse vaccines represent the clearest route to curative, antigen-specific therapies in autoimmunity.
• We see near-term application in celiac disease, with potential expansion to T1D and MS.
• Our work integrates these discoveries into endotype mapping — identifying patients with clear antigen targets for future clinical trials.

Conclusion

The concept of “inverse vaccines” is no longer theoretical. Early human data show safety and signs of antigen-specific tolerance. If successful in phase 2 and 3 trials, these therapies could transform how we treat autoimmunity: not with suppression, but with education of the immune system itself.